CN101808516A

CN101808516A - The N-that comprises polymorph (virtue is amino) sulfamide derivative and composition, its using method and preparation method as mek inhibitor

Info

Publication number: CN101808516A
Application number: CN200880108829A
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: 2010-08-18
Anticipated expiration: 2028-07-28
Also published as: KR20150091434A; EA020624B1; CO6470808A2; CR11244A; JP6309880B2; AP2817A; HK1147396A1; JP2010535232A; TN2010000049A1; JP2015078199A; AU2008282338A1; CA2693390A1; WO2009018233A1; NZ582929A; EA032294B1; KR20140098185A; BRPI0815659A2; MA31881B1; AU2008282338B2; EA201400552A1

Abstract

The present invention relates to mek inhibitor N-(the 2-virtue is amino) arylsulfonamide compounds, it comprises the crystalline polymorph that demonstrates particular powder X-ray diffractogram and/or specific differential scanning amount thermal map.The invention still further relates to the pharmaceutical composition that comprises compound described herein and the using method of compound as herein described and composition, it is included in the purposes that treats and/or prevents in cancer, excess proliferative disease and the inflammatory patient's condition.The invention still further relates to preparation compound as herein described and method for compositions.

Description

The N-that comprises polymorph (virtue is amino) sulfamide derivative and composition, its using method and preparation method as mek inhibitor

The cross reference of related application

The application requires in the U.S. Provisional Application 61/044 of submission on April 14th, 2008, No. 886, the U.S. Provisional Application 61/034 submitted on March 6th, 2008, No. 466 and the U.S. Provisional Application 61/034 submitted on March 6th, 2008, No. 464 priority, it intactly quotes adding herein separately.The application also requires in the U. S. application 11/830 of submission on July 30th, 2007, No. 733 priority, this application requires in the U.S. Provisional Application 60/833 of submission on July 28th, 2006, No. 886 rights and interests and International Application PCT/US2006/028326 number the rights and interests of submitting on July 21st, 2006 as the part continuation application, it intactly quotes adding herein separately.Also require the priority of No. 60/701,814, the U.S. Provisional Application submitted on July 21st, 2005 for International Application PCT/US2006/028326 number; 60/706,719 the priority of submitting on August 8th, 2005, and 60/731,633 the priority of submitting on October 28th, 2005, it intactly quotes adding herein separately.

Technical field

Background technology

The mutant form of some normal cell gene (" proto-oncogene ") of the gene that oncogene-cause cancer produces-normally.The anomaly pattern of the common code signal path of oncogene component (for example receptor tyrosine kinase, serine-threonine kinase or downstream signaling molecule).Main downstream signaling molecule is a Ras albumen, and it is fixed on the inner surface of cytoplasma membrane, and the GTP (GTP) of combination is hydrolyzed into guanosine diphosphate (GDP).When the grown factor activator of growth factor receptors, its initiation causes the reaction chain of guanylic acid to the activation of the exchange activity of Ras.Ras have in conjunction with " opening " state of the activation of GTP (after this being called as " Ras.GTP ") and between having in conjunction with inactive " pass " state of GDP alternately." opening " state of activation, Ras.GTP is in conjunction with the albumen that also activates growth of control cell and differentiation.

For example, in " mitogen activity protein kinase (map kinase) cascade ", Ras.GTP causes the activation of serine/threonine kinase cascade.It is known that to need Ras.GTP to activate one of they self some groups of kinases be Raf family.Raf albumen activates " MEK1 " and " MEK2 ", and promptly mitogen activity ERK activates kinase whose abbreviation (wherein ERK represents extracellular signal adjusting protein kinase, and it is the another kind name of MAPK).MEK1 and MEK2 are the serine/threonine and the tyrosine protein kinase of dual-use function, are also referred to as the map kinase kinases.Therefore, Ras.GTP activates Raf, activates MEK1 and MEK2 thus, activates map kinase (MAPK) then.Activate map kinase by mitogen and it seems propagation is absolutely necessary, and this kinase whose constitutively activate is enough to the inducing cell conversion.No matter from cell surface receptor still from carcinogenic Ras mutation induction, blocking-up downstream Ras signal transduction as by using dominant Raf-1 albumen, can fully suppress mitosis and take place.

In the control of cell proliferation, the interaction of Raf and Ras is crucial regulating step.So far, except MAPK, other substrates of identification of M EK not as yet; But report shows that MEK also can be by for example MEK kinases or MEKK1 and the PKC activation of other stream signal albumen recently.The MAPK that activates shifts also and accumulates in the cell nucleus, and it can make transcription factor for example EIk-1 and Sapla phosphorylation and with its activation in cell nucleus, cause gene for example the c-fos expression of gene strengthen.

In case be activated, (for MEK1 is S at two adjacent serine residues for Raf and other kinases ²¹⁸And S ²²²) on make the MEK phosphorylation.These phosphorylations are necessary for the activation as kinase whose MEK.Then, two residues being separated by single amino acid of MEK: tyrosine Y ¹⁸⁵With threonine T ¹⁸³On make the map kinase phosphorylation.Before making the map kinase phosphorylation, MEK it seems and the map kinase strong bonded, and this shows by MEK makes the map kinase phosphorylation may need between these two kinds of albumen in advance strong interaction.The selectivity of two factor-MEK uniquenesses and before phosphorylation, need with map kinase between strong interaction-show that the mechanism of action of MEK may be enough different with the mechanism of other protein kinases, to such an extent as to allow the selective depressant of MEK.The such inhibitor of possibility can be by allosterism by not relating to the more common machining function of blocking ATP-binding site.

Therefore, even when Cancer-causing mutation does not influence the structure of MEK or expresses, MEK1 and MEK2 also are the verified and received target spots that is used for the anti proliferative treatment.Referring to people's such as people's such as for example Barrett U.S. Patent Publication 2003/0149015 and Boyle 2004/0029898.

Reported that the 1-of MEK replaces some examples of-2 (contraposition substituted 4-phenyl amino)-aryl inhibitor.United States Patent (USP) 6,440, No. 966 and 6,750, No. 217 and corresponding sulfonamide-replacement-2 (4-iodophenyl the amino)-benzoic ether that WO 00/42003 has described to work as mek inhibitor and carboxylate and the Hydroxamates and the N substituted amide derivative of N-substituted benzamide announced.Described sulfonamide also can be that N-replaces.

United States Patent (USP) 6,545,030 and corresponding announce that WO 00/42029 has described mek inhibitor 1-heterocyclic radical-2 (4-iodophenyl amino)-benzene, wherein said heterocycle is 5 yuan and contains azo-cycle, for example pyrazoles, triazole, oxazole, isoxazole and isoxazolinone (isoxazolinone).More recently U.S. Patent Publication 2005/004186 has been described relevant compound, and wherein ' 030 the 4-iodine substituting group of patent is comprised that a class group very widely of alkyl, alkoxyl, acyloxy, thiazolinyl, carbamyl, carbamyl alkyl, carboxyl, carboxyalkyl, N-acyl group sulfonamido and other group substitutes.

United States Patent (USP) 6,469,004 and corresponding announce that WO 00/42022 has described one group of heterocycle and the carboxylate and the Hydroxamates of the phenylene compound (being benzimidazole, benzoxazole, benzothiazole, diazosulfide, quinazoline etc.) that condenses.Described heterocycle is 7-F-6-(4-iodo-phenyl amino)-5-carboxylate, carboxylic acid amide or Hydroxamates.More recently similar compound has been described by the announcement U.S. 2005/0026970, and wherein 4-iodine substituting group is by a class formation is alternative very widely.Relevant compound is described in patent and announces among WO 03/077855, WO 03/77914 and the US 2005/0554701.In WO 2005/028426, other examples that can find to be in the news as 2-(4-iodophenyl the amino)-benzohydroxamic acid ester of mek inhibitor.

Patent announcement WO 02/06213 and corresponding U. S. application series 10/333, No. 399 (U.S.2004/0054172) have been described 1-oxamic acid-2 (4-halogenophenyl amino)-3, and the hydroxyl of 4-two fluorobenzene replaces the ester of acid.United States Patent (USP) 6,891, No. 066 and corresponding announce that WO 03/62191 has described similar compound, wherein the 4-halogenic substituent is substituted by a class formation very widely.Substituting group on the 4-position has methyl, ethyl, acetenyl and 2-hydroxyethyl.At United States Patent (USP) 6,770, concrete related compound has been described in No. 778.

The patent that is published on September 30th, 2004 announce WO 04/083167 (Japanese) disclose surpass 2000 kinds-but provide only NMR data-1-of 400 kinds (N-substituted sulphonyl urea)-2 (2; 4-dihalogenated phenyl amino)-3; 4-two fluorobenzene, and assert that they are used as mek inhibitor.For a subgroup only 12 kinds of compounds provided and shown the data that suppress MEK.Except secondary amine or tertiary amine, these 12 kinds of compounds all comprise one of following group: N, N-two substituted sulphonyl ureas, N-piperazine sulfonamide, N-piperidine sulfonamide or N-pyrrolidines sulfonamide.

Also related to the MEK cascade in inflammatory disease and the illness.People's such as people's such as Koch No. 2006/0030610, U. S. application announcement, Furue U. S. application is announced No. 2006/0140872.This had both comprised the acute inflammation illness, also comprised the chronic inflammatory illness.The example of such illness is allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disease disease, psoriasis, multiple sclerosis, asthma, diabetic complication relevant disease and illness, and such as the inflammatory complication of the cardiovascular system of acute coronary syndrome.Inflammatory bowel disease has Crohn's disease and ulcerative colitis.

Even when Cancer-causing mutation does not influence the structure of MEK or expresses, MEK1 and MEK2 also are the verified and received target spots that is used for the anti proliferative treatment.Referring to people's such as people's such as for example Barrett U.S. Patent Publication 2003/0149015 and Boyle 2004/0029898.

Summary of the invention

Compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or the prodrug of formula I are provided herein:

Formula I

Wherein

Z is H or F;

X is F, Cl, CH ₃, CH ₂OH, CH ₂F, CHF ₂Or CF ₃

Y is I, Br, Cl, CF ₃, C ₁-C ₃Alkyl, C ₂-C ₃Thiazolinyl, C ₂-C ₃Alkynyl, cyclopropyl, OMe, OEt, SMe, phenyl or Het, wherein Het is 5 to 10 yuan of monocyclic heterocycles groups or bicyclic heterocyclic groups that comprise 1-5 the ring hetero atom that is independently selected from N, O and S, described heterocyclic group be saturated, olefinic or aromatics; Wherein

Whole described phenyl or Het group are randomly by F, Cl, Br, I, acetyl group, methyl, CN, NO ₂, CO ₂H, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl, C ₁-C ₃Alkyl-C (=O)-, C ₁-C ₃Alkyl-C (=S)-, C ₁-C ₃Alkoxy-C (=S)-, C ₁-C ₃Alkyl-C (=O) O-, C ₁-C ₃Alkyl-O-(C=O)-, C ₁-C ₃Alkyl-C (=O) NH-, C ₁-C ₃Alkyl-C (=NH) NH-, C ₁-C ₃Alkyl-NH-(C=O)-, two-C ₁-C ₃Alkyl N-(C=O)-, C ₁-C ₃Alkyl-C (=O) N (C ₁-C ₃Alkyl)-, C ₁-C ₃Alkyl-S (=O) ₂NH-or trifluoromethyl replace;

Whole described methyl, ethyl, C ₁-C ₃Alkyl and cyclopropyl group are randomly replaced by OH;

Whole described methyl groups are randomly by 1,2 or 3 F atoms replacements;

R ⁰Be H, F, Cl, Br, I, CH ₃NH-, (CH ₃) ₂N-, C ₁-C ₆Alkyl, C ₁-C ₄Alkoxyl, C ₃-C ₆Cycloalkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, phenyl, monosubstituted phenyl, O (C ₁-C ₄Alkyl), O-C (=O) (C ₁-C ₄Alkyl) or C (=O) O (C ₁-C ₄Alkyl); Wherein

1-3 the substituting group that described alkyl, alkoxyl, cycloalkyl, thiazolinyl, alkynyl and phenyl group randomly are independently selected from F, Cl, Br, I, OH, CN, cyanogen methyl, nitro, phenyl and trifluoromethyl replaces;

Described C ₁-C ₆Alkyl and C ₁-C ₄Alkoxy base is also randomly by OCH ₃Or OCH ₂CH ₃Replace;

G is G ₁, G ₂, R _1a, R _1b, R _1c, R _1d, R _1e, Ar ₁, Ar ₂Or Ar ₃Wherein

G ₁Be randomly by an amino, C ₁-C ₃The C that alkyl amino or dialkyl amino group replace ₁-C ₆Alkyl, described dialkyl amino group comprise 2 can be identical or different C ₁-C ₄Alkyl group; Perhaps

G ₁Be C ₃-C ₈The Diaminoalkyl group;

G ₂Be 5 yuan of rings or the 6 yuan of rings that comprise saturated, the undersaturated or aromatics of 1-3 the ring hetero atom that is independently selected from N, O and S, it randomly is independently selected from F, Cl, OH, O (C ₁-C ₃Alkyl), OCH ₃, OCH ₂CH ₃, CH ₃C (=O) NH, CH ₃C (=O) O, CN, CF ₃Replace with 1-3 substituting group of 5 yuan of aromatic heterocyclic groups that comprise 1-4 the ring hetero atom that is independently selected from N, O and S;

R _1aBe methyl, it is randomly by 1-3 fluorine atom or 1-3 chlorine atom, perhaps OH, ring propoxyl group or C ₁-C ₃Alkoxyl replaces, wherein said ring propoxyl group group or described C ₁-C ₃The C of alkoxy base ₁-C ₃Moieties is randomly replaced by a hydroxyl or methoxy group, and described C ₁-C ₄All C in the alkoxyl ₃-alkyl group is all randomly further replaced by another OH group;

R _1bBe CH (CH ₃)-C _1-3Alkyl or C ₃-C ₆Cycloalkyl, described alkyl and group of naphthene base randomly are independently selected from F, Cl, Br, I, OH, OCH ₃Replace with 1-3 the substituting group of CN;

R _1cBe (CH ₂) _nO _mR '; Wherein

M is 0 or 1; And wherein

When m was 0, n was 1 or 2;

When m was 1, n was 2 or 3;

R ' is C ₁-C ₆Alkyl, it randomly is independently selected from F, Cl, OH, OCH ₃, OCH ₂CH ₃And C ₃-C ₆The 1-3 of cycloalkyl substituting group replaces;

R _1dBe C (A) (A ') (B)-; Wherein

B is H or C _1-4Alkyl, it is randomly replaced by one or two OH group;

A and A ' are H or C independently _1-4Alkyl, it is randomly replaced by one or two OH group; Perhaps

The carbon atom that A and A ' are attached thereto with them forms 3-6 unit saturated rings;

R _1eBe

Wherein

Q is 1 or 2;

R ₂And R ₃Be H, F, Cl, Br, CH independently of one another ₃, CH ₂F, CHF ₂, CF ₃OCH ₃, OCH ₂F, OCHF ₂, OCF ₃, ethyl, n-pro-pyl, isopropyl, cyclopropyl, isobutyl group, sec-butyl, the tert-butyl group or mesyl;

R ₄Be H, F, Cl, Br, CH ₃, CH ₂F, CHF ₂, CF ₃OCH ₃, OCH ₂F, OCHF ₂, OCF ₃, ethyl, n-pro-pyl, isopropyl, cyclopropyl, isobutyl group, sec-butyl, the tert-butyl group, mesyl, nitro, acetylamino, amidino groups, cyano group, carbamyl, methyl carbamyl, dimethylamino formoxyl, 1,3,4-oxadiazole-2-base, 5-methyl isophthalic acid, 3,4-oxadiazole, 1,3,4-thiadiazoles, 5-methyl isophthalic acid, 3,4-thiadiazoles, 1H-tetrazole radical, N-morpholinyl carbonyl amino, N-morpholinyl sulfonyl and N-pyrrolidinyl carbonylamino;

R ₅Be H, F, Cl or methyl;

R ₆Be H, F, Cl or methyl;

Ar ₁Be

Wherein

U and V are N, CR independently ₂Or CR ₃

R ₂, R ₃And R ₄Be H, F, Cl, Br, CH independently ₃, CH ₂F, CHF ₂, CF ₃OCH ₃, OCH ₂F, OCHF ₂, OCF ₃, ethyl, n-pro-pyl, isopropyl, cyclopropyl, isobutyl group, sec-butyl, the tert-butyl group, acetylamino, amidino groups, cyano group, carbamyl, methyl carbamyl, dimethylamino formoxyl, 1,3,4-oxadiazole-2-base, 5-methyl isophthalic acid, 3,4-oxadiazole base, 1,3,4-thiadiazolyl group, 5-methyl isophthalic acid, 3,4-thiadiazolyl group, 1H-tetrazole radical, N-morpholinyl carbonyl amino, N-morpholinyl sulfonyl, N-pyrrolidinyl carbonylamino and mesyl;

R ₅And R ₆Be H, F, Cl or methyl independently;

Ar ₂Be

Wherein

Dotted line is represented the optional pro forma position of second two key of ring;

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

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

When U be-during N=, V is-CH=,-CCl=, or-N=;

R ₇Be H or methyl;

R ₈Be H, acetylamino, methyl, F or Cl;

Ar ₃Be

Wherein

U is-NH-,-NCH ₃-or-O-;

R ₇And R ₈Be H, F, Cl or methyl independently.

In some embodiments, the invention provides the compound of the formula I that is selected from following compound:

In some embodiments, the invention provides the compound of formula I, described compound is selected from:

Wherein 2-OH carbon is in the R configuration.

Wherein 2-OH carbon is in the S configuration.

In some embodiments, the invention provides and comprise the formula I compound compositions that is selected from compound shown below, wherein 2-OH carbon is in the R configuration, the essentially no S-isomer of described composition.

In some embodiments, the invention provides and comprise the formula I compound compositions that is selected from compound shown below, wherein 2-OH carbon is in the S configuration, the essentially no R-isomer of described composition.

In some embodiments, the invention provides the compound of formula I, wherein Y is phenyl, pyridine radicals or pyrazolyl.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein Y is phenyl, pyridine radicals or the pyrazolyl that replaces.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein Y is Br or I.In the embodiment of a subgenus, the invention provides the compound of formula I, wherein G is 1-piperidyl, 2-piperidyl, 3-piperidyl or 4-piperidyl.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is 1-piperazinyl or 2-piperazinyl.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is a morpholinyl.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is N-methyl-2-amino-ethyl.In the embodiment of a subgenus, the invention provides the compound of formula I, wherein G is N-methyl-3-amino-n-pro-pyl.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is (CH ₃) ₂N-CH ₂CH ₂-NH-(CH ₂) _n-, wherein n is 1,2 or 3.In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is (CH ₃CH ₂) ₂N-CH ₂CH ₂-NH-(CH ₂) _n-, wherein n is 1 or 2.In the embodiment of subgenus more specifically, the invention provides the compound of formula I, wherein G is 1-piperidyl, 2-piperidyl, 3-piperidyl or 4-piperidyl; R ^oBe H, halogen or methoxyl group; X is F; And Y is I.More specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is 1-piperazinyl or 2-piperazinyl; R ^oBe H, halogen or methoxyl group; X is F; And Y is I.More specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is a morpholinyl; R ^oBe H, halogen or methoxyl group; X is F; And Y is I.More specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is N-methyl-2-amino-ethyl; R ^oBe H, halogen or methoxyl group; X is F; And Y is I.More specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is N-methyl-3-amino-n-pro-pyl; R ^oBe H, halogen or methoxyl group; X is F; And Y is I.More specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is (CH ₃) ₂N-CH ₂CH ₂-NH-(CH ₂) _n-, wherein n is 1,2 or 3; R ^oBe H, halogen or methoxyl group; X is F; And Y is I.More specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is (CH ₃CH ₂) ₂N-CH ₂CH ₂-NH-(CH ₂) _n-, wherein n is 1 or 2; R ^oBe H, halogen or methoxyl group; X is F; And Y is I.

In some embodiments, the invention provides the pharmaceutical composition that comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug.In some embodiments, described pharmaceutical composition also comprises at least a pharmaceutically acceptable carrier.

In some embodiments, the invention provides to comprise and be selected from:

With

Compound or the pharmaceutical composition of the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug.In some embodiments, described pharmaceutical composition also comprises at least a pharmaceutically acceptable carrier.In some embodiments, described compound is in the R configuration.In some embodiments, described compound is in the R configuration, essentially no S-isomer.In some embodiments, described compound is in the S configuration.

In some embodiments, described compound is in the S configuration, essentially no R-isomer.In some embodiments, described compound is:

In some embodiments, described compound is:

The invention still further relates to N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide (being also referred to as " compd A " and " N-(-)-(3; 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide " herein):

Crystalline polymorph A, it demonstrates specific x-ray diffractogram of powder.In some embodiments, described x-ray diffractogram of powder comprises the peak shown in Fig. 5 of at least 50%.In some embodiments, described x-ray diffractogram of powder comprises the peak shown in Fig. 5 of at least 70%.In some embodiments, described x-ray diffractogram of powder comprises the peak shown in Fig. 5 of at least 90%.In some embodiments, the x-ray diffractogram of powder shown in described x-ray diffractogram of powder and Fig. 5 is basic identical.By R and S-MTPA ester and the contrast chemical shift of proton difference of preparation on secondary alcohol, compd A has been characterized as being " S " isomer.Referring to for example Dale, J.A.; Mosher, H.S., J.Am.Chem.Soc., 1973,95,512 and Ohtani etc., J.Am.Chem.Soc., 1991,113,4092.

The invention still further relates to N-(R)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide (being also referred to as " compd B " and " N-(+)-(3; 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide " herein):

By R and S-MTPA ester and the contrast chemical shift of proton difference of preparation on secondary alcohol, compd B has been characterized as being " R " isomer.Referring to for example Dale, J.A.; Mosher, H.S., J.Am.Chem.Soc., 1973,95,512 and Ohtani etc., J.Am.Chem.Soc., 1991,113,4092.

The invention still further relates to the crystalline polymorph A of N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide:

It demonstrates specific differential scanning calorimetric figure.In some embodiments, the differential scanning calorimetric figure shown in described differential scanning calorimetric figure and Fig. 6 is basic identical.

The invention still further relates to pharmaceutical composition, it comprises the N-(S)-(3 of effective dose, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-crystalline polymorph A and the pharmaceutically acceptable carrier or the carrier of 1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide.

In some embodiments, the crystalline polymorph A of N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide is used to treatment or prophylaxis of cancer or inflammatory disease.The invention further relates to the method for treatment or prophylaxis of cancer or inflammatory disease, it comprises to the N-of experimenter's effective dosage that these needs are arranged (S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the crystalline polymorph A of 1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide.

In other respects, the present invention relates to comprise the formula I compound of effective dose or the pharmaceutical composition of the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug.In some embodiments, described pharmaceutical composition also comprises pharmaceutically acceptable carrier.Such composition can comprise assistant agent, excipient and preservative, be used to reagent, filler, adhesive, adsorbent, buffer, disintegrant, solubilizer, other carriers of postponing to absorb, and other inert fractions.The compound method of such composition is well known in the art.

In other respects, the present invention relates to comprise the pharmaceutical composition of formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug.In some embodiments, described pharmaceutical composition is for being fit to the form of oral administration.Further or in other the embodiment, described pharmaceutical composition is the form of tablet, capsule, pill, powder, sustained release preparation, solution, supensoid agent, for parenteral injection is sterile solution agent, supensoid agent or emulsion, for topical is ointment or emulsifiable paste, is suppository for rectally perhaps.Further or in other the embodiment, described pharmaceutical composition is the unit dosage forms that is suitable for accurate dosage single-dose.Further or the amount of other embodiment Chinese style I compound about 0.001 to the scope of about 1000mg/kg body weight/day.Further or the amount of other embodiment Chinese style I compound in the scope of about 0.5 to about 50mg/kg/ day.Further or the amount of other embodiment Chinese style I compound be about 0.001 to about 7g/ day.Further or the amount of other embodiment Chinese style I compound be about 0.002 to about 6g/ day.Further or the amount of other embodiment Chinese style I compound be about 0.005 to about 5g/ day.Further or the amount of other embodiment Chinese style I compound be about 0.01 to about 5g/ day.Further or the amount of other embodiment Chinese style I compound be about 0.02 to about 5g/ day.Further or the amount of other embodiment Chinese style I compound be about 0.05 to about 2.5g/ day.Further or the amount of other embodiment Chinese style I compound be about 0.1 to about 1g/ day.

Further or in other the embodiment, the dosage level that is lower than above-mentioned scope lower limit may enough be had a surplus.Further or in other the embodiment, the dosage level that is higher than above-mentioned range limit may be essential.Further or in other the embodiment with the single dose compound of Medicine-feeding type I once a day.Further or in other the embodiment with compound multiple dose every day more than single administration formula I.Further or in other the embodiment every day twice Medicine-feeding type I compound.Further or in other the embodiment every day three Medicine-feeding type I compound.Compound at four times a day Medicine-feeding type I further or in other the embodiment.Every day further or in other the embodiment more than the compound of four Medicine-feeding type I.

In some embodiments, described pharmaceutical composition is used for to the mammal administration.Further or in other the embodiment, described mammal is human.

Further or in other the embodiment, described pharmaceutical composition also comprises pharmaceutical carrier, excipient and/or assistant agent.Further or in other the embodiment, described pharmaceutical composition also comprises at least a therapeutic agent.Further or in other the embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic.Further or in other the embodiment, described antineoplastic is selected from alkylating agent, antimetabolite, epidophylltoxin (epidophyllotoxins); Antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibitor, hormone/antihormones therapeutic agent and hemopoieticgrowth factor.Further or in other the embodiment, described therapeutic agent is taxol, bortezomib or the two.Further or in other the embodiment, the described pharmaceutical composition of administration is with other therapy couplings.Further or in other the embodiment, described other therapies are radiotherapy, chemotherapy, operation or their any combination.Further or in other the embodiment, described pharmaceutical composition comprises the acceptable salt of pharmacy of formula I compound.

Provide herein to comprise and be selected from Compound compositions and use comprise and be selected from The method of compound compositions.In some embodiments, the 2-OH carbon on the described compound is in the R configuration.In some embodiments, the 2-OH carbon on the described compound is in the S configuration.In some embodiments, the S-isomer of the essentially no described compound of described composition.In some embodiments, the R-isomer of the essentially no described compound of described composition.In some embodiments, described compound comprises the S-isomer that is less than 10% described compound.In some embodiments, described compound comprises the R-isomer that is less than 10% described compound.In some embodiments, described compound comprises the S-isomer that is less than 5% described compound.In some embodiments, described compound comprises the R-isomer that is less than 5% described compound.In some embodiments, described compound comprises the S-isomer that is less than 1% described compound.In some embodiments, described compound comprises the R-isomer that is less than 1% described compound.

Also provide herein and comprise the compound that about 1-100mg has following structure:

Composition and with comprising the compound that about 1-100mg has following structure: The combination treatment cancer or the method for inflammation.In some embodiments, described composition allows to improve the described compound of release.In some embodiments, described composition allows to continue to discharge described compound.In some embodiments, described composition 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 exists with the amount of about 1-10mg.In some embodiments, described compound exists with the amount of about 10-20mg.In some embodiments, described compound exists with the amount of about 20-40mg.In some embodiments, described compound exists with the amount of about 40-50mg.

Also provide herein and comprise the compound that about 1-50mg has following structure:

Composition and with comprising the compound that about 1-50mg has following structure:

The combination treatment cancer or the method for inflammation, wherein said composition allows to improve and discharges described medicine.In some embodiments, described composition also comprises microcrystalline cellulose.In some embodiments, described composition also comprises cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises lauryl sodium sulfate.In some embodiments, described composition also comprises dolomol.

Also provide herein and comprise the compound that about 1mg has following structure: Composition.In some embodiments, described composition also comprises about 222.2mg microcrystalline cellulose.In some embodiments, described composition also comprises about 12.0mg cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises about 2.4mg lauryl sodium sulfate.In some embodiments, described composition also comprises about 2.4mg dolomol.

Also provide herein and comprise the compound that about 10mg has following structure:

Composition and with comprising the compound that about 10mg has following structure:

The combination treatment cancer or the method for inflammation.In some embodiments, described composition also comprises about 213.2mg microcrystalline cellulose.In some embodiments, described composition also comprises about 12.0mg cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises about 2.4mg lauryl sodium sulfate.In some embodiments, described composition also comprises about 2.4mg dolomol.

Also provide herein and comprise the compound that about 20mg has following structure:

Composition and with comprising the compound that about 20mg has following structure:

The combination treatment cancer or the method for inflammation.In some embodiments, described composition also comprises about 203.2mg microcrystalline cellulose.In some embodiments, described composition also comprises about 12.0mg cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises about 2.4mg lauryl sodium sulfate.In some embodiments, described composition also comprises about 2.4mg dolomol.

Also provide herein and comprise the compound that about 40mg has following structure: Composition and with comprising the compound that about 40mg has following structure:

The combination treatment cancer or the method for inflammation.In some embodiments, described composition also comprises about 183.2mg microcrystalline cellulose.In some embodiments, described composition also comprises about 12.0mg cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises about 2.4mg lauryl sodium sulfate.In some embodiments, described composition also comprises about 2.4mg dolomol.

The compound with following structure that comprises about 0.4 weight % also is provided herein:

With the composition of about 99.6 weight % pharmaceutically acceptable carriers or carrier and with the compound that comprises about 0.4 weight % with following structure:

With about 99.6 weight % pharmaceutically acceptable carriers or the combination treatment cancer of carrier or the method for inflammation.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.In some embodiments, described microcrystalline cellulose accounts for the about 92.6 weight % of described composition.In some embodiments, described composition also comprises about 5 weight % cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises about 1 weight % lauryl sodium sulfate.In some embodiments, described composition also comprises about 1 weight % dolomol.

The compound with following structure that comprises about 4.2 weight % also is provided herein:

With the composition of about 95.8 weight % pharmaceutically acceptable carriers or carrier and with the compound that comprises about 4.2 weight % with following structure:

With about 95.8 weight % pharmaceutically acceptable carriers or the combination treatment cancer of carrier or the method for inflammation.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.In some embodiments, described microcrystalline cellulose accounts for the about 88.8 weight % of described composition.In some embodiments, described composition also comprises about 5 weight % cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises about 1 weight % lauryl sodium sulfate.In some embodiments, described composition also comprises about 1 weight % dolomol.

Also provide herein and comprise the compound with following structure of about 2 weight % to about 10 weight %:

With about 98 weight % to the composition of about 90 weight % pharmaceutically acceptable carriers or carrier and with comprising extremely the compound of about 10 weight % of about 2 weight % with following structure:

With about 98 weight % to about 90 weight % pharmaceutically acceptable carriers or the combination treatment cancer of carrier or the method for inflammation.In some embodiments, described pharmaceutically acceptable carrier or carrier also comprise microcrystalline cellulose.In some embodiments, described microcrystalline cellulose accounts for about 85 weight % of described composition to about 95 weight %.In some embodiments, described composition also comprises about 1 weight % to about 6 weight % cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises about 0.1 weight % to about 2 weight % lauryl sodium sulfate.In some embodiments, described composition also comprises about 0.25 weight % to about 1.5 weight % dolomols.

Also provide herein and comprise the compound that about 1mg has following structure:

Composition and with comprising the compound that about 1mg has following structure: The combination treatment cancer or the method for inflammation.In some embodiments, described composition also comprises about 222.2mg microcrystalline cellulose.In some embodiments, described composition also comprises about 12.0mg cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises about 2.4mg lauryl sodium sulfate.In some embodiments, described composition also comprises about 2.4mg dolomol.

Also provide herein and comprise the compound that about 40mg has following structure:

Composition and with comprising the compound that about 40mg has following structure:

With the composition of about 99.6 weight % pharmaceutical acceptable carriers or carrier and with the compound that comprises about 0.4 weight % with following structure With about 99.6 weight % pharmaceutical acceptable carriers or the combination treatment cancer of carrier or the method for inflammation.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.In some embodiments, described microcrystalline cellulose accounts for the about 92.6 weight % of described composition.In some embodiments, described composition also comprises about 5 weight % cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises about 1 weight % lauryl sodium sulfate.In some embodiments, described composition also comprises about 1 weight % dolomol.

With the composition of about 95.8 weight % pharmaceutical acceptable carriers or carrier and with the compound that comprises about 4.2 weight % with following structure:

With about 95.8 weight % pharmaceutical acceptable carriers or the combination treatment cancer of carrier or the method for inflammation.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.In some embodiments, described microcrystalline cellulose accounts for the about 88.8 weight % of described composition.In some embodiments, described composition also comprises about 5 weight % cross-linked carboxymethyl cellulose sodium.In some embodiments, described composition also comprises about 1 weight % lauryl sodium sulfate.In some embodiments, described composition also comprises about 1 weight % dolomol.

With about 98 weight % to the composition of about 90 weight % pharmaceutical acceptable carriers or carrier and with comprising extremely the compound of about 10 weight % of about 2 weight % with following structure:

With about 98 weight % to about 90 weight % pharmaceutical acceptable carriers or the combination treatment cancer of carrier or the method for inflammation.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.In some embodiments, described microcrystalline cellulose accounts for the about 85 weight % of described composition to about 95 weight %.In some embodiments, described composition also comprises about 1 weight % cross-linked carboxymethyl cellulose sodium to about 6 weight %.In some embodiments, described composition also comprises about 0.1 weight % to about 2 weight % lauryl sodium sulfate.In some embodiments, described composition also comprises about 0.25 weight % to about 1.5 weight % dolomols.

N-(-)-(3 also is provided herein, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) the crystalline polymorph A of cyclopropane-1-sulfonamide and comprise this compound compositions, described crystalline polymorph A demonstrate the x-ray diffractogram of powder that comprises the peak of being identified in the x-ray diffractogram of powder shown in Fig. 5 of at least 50%.In some embodiments, described crystalline polymorph A, wherein said x-ray diffractogram of powder comprise the peak of being identified in the x-ray diffractogram of powder shown in Fig. 5 of at least 70%.In some embodiments, described x-ray diffractogram of powder comprises the peak of being identified in the x-ray diffractogram of powder shown in Fig. 5 of at least 90%.In some embodiments, the x-ray diffractogram of powder shown in described x-ray diffractogram of powder and Fig. 5 is basic identical.In some embodiments, described crystalline polymorph has 143 ℃ the fusing point starting point (melting point onset) of being about through determine with dsc method.In some embodiments, described crystalline polymorph is anhydrous basically.In some embodiments, the essentially no solvent of described crystalline polymorph.

N-(-)-(3 also is provided herein, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) the crystalline polymorph A of cyclopropane-1-sulfonamide and comprise this compound compositions, described crystalline polymorph A demonstrates and the essentially identical differential scanning calorimetric of the calorimetric of differential scanning shown in Fig. 6 figure figure.In some embodiments, described crystalline polymorph has 143 ℃ the fusing point starting point of being about through determine with dsc method.In some embodiments, claim 67 or 68 crystalline polymorph, wherein said crystalline polymorph is anhydrous basically.In some embodiments, each crystalline polymorph among the claim 67-69, the essentially no solvent of wherein said crystalline polymorph.

N-(3 also is provided herein, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) polymorph of cyclopropane-1-sulfonamide and comprise this compound compositions, described polymorph makes unbodied N-(3 by comprising, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the method preparation of the step of 1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide crystallization.In some embodiments, described crystallisation step comprises crystallization from the mixture of ethyl acetate and heptane.In some embodiments, the ratio of the mixture of described ethyl acetate and heptane is that 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 is that about 2 parts of ethyl acetate are than about 5 parts of heptane.

The method that suppresses the MEK enzyme also is provided herein, and it comprises makes described MEK enzyme contact with compound as herein described or composition, and there is the amount of described enzyme inhibition 25% in wherein said compound being enough at least.In some embodiments, described MEK enzyme is the MEK kinases.In some embodiments, described contact occurs in the cell.

The method of illness described in the individuality for the treatment of the illness of suffering from the MEK mediation also is provided herein, and it comprises compound as herein described or composition to described individual effective dosage.In some embodiments, the described mek inhibitor of administration is with other therapy couplings.In some embodiments, described other therapies are radiotherapy, non-MEK kinase inhibition agent therapy, chemotherapy, operation, glucocorticoid, methotrexate (MTX), biological response modifier or their any combination.In some embodiments, the illness of described MEK mediation is selected from inflammatory disease, infection, autoimmune disease, apoplexy, ischemic, cardiac conditions, neurological disorders, fibrillatable illness, proliferative disorders, excess proliferative illness, tumour, leukemia, knurl (neoplasms), cancer, cancer, metabolic disease and malignant diseases.In some embodiments, the illness of described MEK mediation is an excess proliferative disease.In some embodiments, the illness of described MEK mediation is cancer, tumour, leukemia, knurl or cancer.In some embodiments, the illness of described MEK mediation is an inflammatory disease.In some embodiments, described inflammatory disease is rheumatoid arthritis or multiple sclerosis.

The method of proliferative diseases in treatment or the prevention individuality also is provided herein, and it comprises compound as herein described or composition to described individual effective dosage.In some embodiments, described proliferative diseases is cancer, psoriasis, ISR, disease or atherosclerotic.In some embodiments, described proliferative diseases is a cancer.In some embodiments, described cancer is the cancer of the brain, breast cancer, lung cancer, oophoroma, cancer of pancreas, prostate cancer, kidney, colorectal cancer, leukemia, myeloid leukemia, glioblastoma, folliculus type lymphoma (follicular lymphoma), preceding B acute leukemia, chronic lymphocytic B leukemia, cancer of the stomach, celiothelioma or small-cell carcinoma of the lung.In some embodiments, described method also comprises at least a therapeutic agent of administration.In some embodiments, this step comprises and uses at least a other cancer therapies.In some embodiments, described other therapies are radiotherapy, non-MEK kinase inhibition agent therapy, chemotherapy, operation, glucocorticoid, methotrexate (MTX), biological response modifier or their any combination.

The method of inflammatory disease in treatment or the prevention individuality also is provided herein, and it comprises to comprising of described individual effective dosage of compound compositions described herein.In some embodiments, described inflammatory disease is rheumatoid arthritis or multiple sclerosis.

The method that makes cancer cell degeneration, anticancer growth or kill cancer cell also is provided herein, and it comprises makes described cell contact with the compound as herein described or the composition of the amount that makes cancer cell degeneration, anticancer growth or kill cancer cell effectively.In some embodiments, described cancer cell comprises 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.

Also be provided at herein in the individuality and suppress the method that the tumour size increases, reduces the tumour size, reduces tumor proliferation or prevention tumor proliferation, it comprises to the compound as herein described of described individual effective dosage or composition and increases, reduces the tumour size to suppress the tumour size, reduces tumor proliferation or prevention tumor proliferation.In some embodiments, described tumour comes across in brain, mammary gland, lung, ovary, pancreas, prostate, kidney, stomach, colon or the rectum.

The method of treatment or prevention ankylosing spondylitis, gout, myotenositis, bursal synovitis or sciatica also is provided herein, and it comprises formula (I) compound or pharmaceutically acceptable salt thereof to experimenter's effective dosage that these needs are arranged:

Wherein:

Z is H or F;

X is F, Cl, CH ₃, CH ₂OH, CH ₂F, CHF ₂Or CF ₃

Whole described phenyl or Het group are randomly by F, Cl, Br, I, acetyl group, methyl, CN, NO ₂, CO ₂H, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl, C ₁-C ₃Alkyl-C (=O)-, C ₁-C ₃Alkyl-C (=S)-, C ₁-C ₃Alkoxy-C (=S)-, C ₁-C ₃Alkyl-C (=O) O-, C ₁-C ₃Alkyl-O-(C=O)-, C ₁-C ₃Alkyl-C (=O) NH-, C ₁-C ₃Alkyl-C (=NH) NH-, C ₁-C ₃Alkyl-NH-(C=O)-, two-C ₁-C ₃Alkyl-N-(C=O)-, C ₁-C ₃Alkyl-C (=O) N (C ₁-C ₃Alkyl)-, C ₁-C ₃Alkyl-S (=O) ₂NH-or trifluoromethyl replace;

Whole described methyl groups are randomly by 1,2 or 3 F atoms replacements;

G ₁Be C ₃-C ₈The Diaminoalkyl group;

R _1cBe (CH ₂) _nO _mR '; Wherein

M is 0 or 1; And wherein

When m was 0, n was 1 or 2;

When m was 1, n was 2 or 3;

R _1dBe C (A) (A ') (B)-; Wherein

B is H or C _1-4Alkyl, it is randomly replaced by one or two OH group;

R _1eBe

Wherein

Q is 1 or 2;

R ₅Be H, F, Cl or methyl;

R ₆Be H, F, Cl or methyl;

Ar ₁Be

Wherein

U and V are N, CR independently ₂Or CR ₃

R ₅And R ₆Be H, F, Cl or methyl independently;

Ar ₂Be

Wherein

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

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

When U be-during N=, V is-CH=,-CCl=, or-N=;

R ₇Be H or methyl;

R ₈Be H, acetylamino, methyl, F or Cl;

Ar ₃Be

Wherein

U is-NH-,-NCH ₃-or-O-;

R ₇And R ₈Be H, F, Cl or methyl independently.

In some embodiments, described compound is selected from:

In some embodiments, described compound is selected from

Wherein 2-OH carbon is in the R configuration.In some embodiments, the compound or pharmaceutically acceptable salt thereof of described formula (I) is selected from

With

Wherein 2-OH carbon is in the S configuration.In some embodiments, described compound is

In some embodiments, described compound is

Also provide herein by the compound as herein described of drug treatment effective dose or the method for combination treatment cancer of the stomach.Also provide herein by the compound as herein described of drug treatment effective dose or the method for combination treatment leukemia melanoma (leukemiam melanoma) or hepatoma.

Method by the compound as herein described or the combination treatment non-small cell lung cancer of drug treatment effective dose also is provided herein.Also provide herein by the compound as herein described of drug treatment effective dose or the method for combination treatment colon cancer.Compound as herein described or combination treatment CNS method for cancer by the drug treatment effective dose also are provided herein.Also provide herein by the compound as herein described of drug treatment effective dose or the method for combination treatment oophoroma.Also provide herein by the compound as herein described of drug treatment effective dose or the method for combination treatment kidney.Also provide herein by the compound as herein described of drug treatment effective dose or the method for combination treatment prostate cancer.Also provide herein by the compound as herein described of drug treatment effective dose or the method for combination treatment breast cancer.In various embodiments, these methods also comprise at least a other treatment agent of administration.In some embodiments, use at least a other cancer therapies.In some embodiments, described other cancer therapies are radiotherapy, chemotherapy, operation or their any combination.

Also provide herein by with the compound as herein described or the combination treatment of topical formulations drug treatment effective dose or prevent psoriatic method.

In various embodiments, the described composition of oral administration.In some embodiments, once a day or the described composition of twice administration every day.In some embodiments, the described composition of administration once a day continues at least one week.

In some embodiments, when the described composition of oral administration, to the T that reaches described compound behind the described composition of fasted subjects administration between 1 hour to 3 hours _MaxIn some embodiments, when to experimenter's administration, reach C at the 1st day described compound _MaxAbout 0.01 μ g/ml is to about 1.0 μ g/ml.In some embodiments, when to experimenter's administration, reach C at the 1st day described compound _MaxAbout 0.01 μ g/ml is to about 0.8 μ g/ml.In some embodiments, when to experimenter's administration, reach C at the 1st day described compound _MaxAbout 0.03 μ g/ml is to about 0.5 μ g/ml.In some embodiments, the AUC of described compound is that about 0.1 μ g hr/mL is to about 5.0 μ g hr/mL between 0-12 hour.In some embodiments, the AUC of described compound is that about 0.1 μ g hr/mL is to about 4.0 μ g hr/mL.In some embodiments, the AUC of described compound is that about 0.5 μ g hr/mL is to about 3.0 μ g hr/mL.In some embodiments, the T of described compound _MaxBetween 0.5 to 5.0 hour.In some embodiments, the T of described compound _MaxBetween 1.0 to 3.0 hours.In some embodiments, the T of described compound _MaxBetween 1.0 to 2.5 hours.In some embodiments, the plasma concentration at single-dose described compound after 5 hours is higher than about 0.01mg/mL.In some embodiments, the plasma concentration at single-dose described compound after 10 hours is higher than about 0.01mg/mL.In some embodiments, the plasma concentration at single-dose described compound after 15 hours is higher than about 0.01mg/mL.

In some embodiments, when to one group of 10 experimenter's administration, reach average C at the 1st day described compound _MaxAbout 0.01 μ g/ml is to about 1.0 μ g/ml.In some embodiments, when to one group of 10 experimenter's administration, reach average C at the 1st day described compound _MaxAbout 0.01 μ g/ml is to about 0.8 μ g/ml.In some embodiments, when to one group of 10 experimenter's administration, reach average C at the 1st day described compound _MaxAbout 0.03 μ g/ml is to about 0.5 μ g/ml.In some embodiments, the average A UC of described compound is that about 0.1 μ g hr/mL is to about 5.0 μ g hr/mL.In some embodiments, the average A UC of described compound is that about 0.1 μ g hr/mL is to about 4.0 μ g hr/mL.In some embodiments, the average A UC of described compound is that about 0.5 μ g hr/mL is to about 3.0 μ g hr/mL.In some embodiments, the average T of described compound _MaxBetween 0.5 to 5.0 hour.In some embodiments, the average T of described compound _MaxBetween 1.0 to 3.0 hours.In some embodiments, the average T of described compound _MaxBetween 1.0 to 2.5 hours.

The method that reduces gross tumor volume by administration compound as herein described and composition also is provided herein.In some embodiments, after 5 days, described gross tumor volume reduces at least about 25% at the described medicine of administration every day.In some embodiments, after 5 days, described gross tumor volume reduces at least about 50% at the described medicine of administration every day.In some embodiments, after 5 days, described gross tumor volume reduces at least about 20-70% at the described medicine of administration every day.In some embodiments, after 15 days, described gross tumor volume reduces at least about 25% at the described medicine of administration every day.In some embodiments, after 15 days, described gross tumor volume reduces at least about 50% at the described medicine of administration every day.In some embodiments, after 15 days, described gross tumor volume reduces at least about 20-70% at the described medicine of administration every day.In some embodiments, after 30 days, described gross tumor volume reduces at least about 25% at the described medicine of administration every day.In some embodiments, after 30 days, described gross tumor volume reduces at least about 50% at the described medicine of administration every day.In some embodiments, after 30 days, described gross tumor volume reduces at least about 20-70% at the described medicine of administration every day.

The method that suppresses tumor growth by administration compound as herein described and composition also is provided herein.In some embodiments, behind the described medicine of administration, described tumor growth is suppressed at least about 20%.In some embodiments, behind the described medicine of administration, described tumor growth is suppressed at least about 40%.In some embodiments, behind the described medicine of administration, described tumor growth is suppressed at least about 60%.In some embodiments, behind the described medicine of administration, described tumor growth is suppressed at least about 80%.In some embodiments, behind the described medicine of administration, described tumor growth is suppressed about 20% to about 100%.In some embodiments, behind the described medicine of administration, described tumor growth is suppressed substantially.

In some embodiments, the described composition of twice administration every day.In some embodiments, the described composition of administration once a day.

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

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

In some embodiments, described composition also comprises at least a filler that is selected from microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sompressible sugar, xylitol, sorbierite, mannitol, pregelatinized starch, maltodextrin, calcium phosphate, calcium carbonate, starch and calcium silicates.

In some embodiments, described composition also comprises at least a disintegrant that is selected from cross-linked carboxymethyl cellulose sodium, primojel, Crospovidone, methylcellulose, alginic acid, mosanom, starch derivatives, bentonite (betonite) and aluminium-magnesium silicate.

In some embodiments, described composition also comprises at least a dolomol, metallic stearate, talcum, sodium stearyl fumarate and the stearic lubricant of being selected from.

In some embodiments, described composition also comprises at least a wetting agent or the surfactant that is selected from lauryl sodium sulfate, glycerine, sorbitan monooleate, Span60, polyoxyethylene anhydrous sorbitol laurate, palmitate, stearate, oleate or six oleates (hexaolate), the pure and mild sorbitan mono-laurate of polyoxyethylene stearyl.

It is the composition of capsule or tablet that form is provided herein, and use American Pharmacopeia (USP) apparatus II under 50rpm, as dissolution medium, described capsule or tablet discharged at least 60% described medicine in 30 minutes with 1% lauryl sodium sulfate in the water.In some embodiments, described composition is the form of capsule or tablet, and use American Pharmacopeia (USP) apparatus II under 50rpm, as dissolution medium, described capsule or tablet discharged the described medicine of about 60-100% in 30 minutes with 1% lauryl sodium sulfate in the water.In some embodiments, described composition is the form of capsule or tablet, and use American Pharmacopeia (USP) apparatus II under 50rpm, as dissolution medium, described capsule or tablet discharged the described medicine of about 60-90% in 30 minutes with 1% lauryl sodium sulfate in the water.In some embodiments, described composition is the form of capsule or tablet, and use American Pharmacopeia (USP) apparatus II under 50rpm, as dissolution medium, described capsule or tablet discharged the described medicine of about 60-80% in 30 minutes with 1% lauryl sodium sulfate in the water.

In batch capsule or tablet also are provided herein, and it respectively comprises about 1 to about 50mg compound as herein described, and has and be lower than about 15 content uniformity USP admitted value (acceptance value).

Methods of treatment

The present invention relates to treat or the method for prophylaxis of cancer, it comprises the pharmaceutical composition that comprises formula as described herein (I) compound to experimenter's effective dosage that needs are arranged.In various embodiments, useful compound and composition are suc as formula the kind of (I) or as described in as an example any subgenus or kind in formula (I) scope that runs through the application in these methods.

The present invention relates to treat or prevent the method for inflammatory disease, it comprises the pharmaceutical composition that comprises formula as described herein (I) compound to experimenter's effective dosage that needs are arranged.In various embodiments, useful compound and composition are suc as formula the kind of (I) or as described in as an example any subgenus or kind in formula (I) scope that runs through the application in these methods.

In some embodiments, the present invention relates to treat or prevent the method for ankylosing spondylitis, gout, myotenositis, bursal synovitis or sciatica, it comprises the pharmaceutical composition to comprising of the individual effective dosage that these needs are arranged of formula as described herein (I) compound.In various embodiments, useful compound and composition are suc as formula the kind of (I) or as described in as an example any subgenus or kind in formula (I) scope that runs through the application in these methods.

In some respects, the invention still further relates to treatment and suffer from the method for disease in the individuality of described disease, it comprises the composition that comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug to described individual effective dosage.

In other respects, the present invention relates to treat the method for illness in the mammal, it comprises to the formula I compound of described mammal drug treatment effective dose or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug.

In other respects, the present invention relates to treat the method for illness among the mankind, it comprises to the formula I compound of described mammal drug treatment effective dose or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug.

In other respects, the present invention relates to treat the method that comprises excess proliferative illness in the human mammal, it comprises to the formula I compound of described mammal drug treatment effective dose or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug.

In other respects, the present invention relates to treat the method that comprises inflammatory disease, the patient's condition or illness in the human mammal, it comprises to the formula I compound of described mammal drug treatment effective dose or the acceptable salt of its pharmacy, ester, prodrug, solvate, hydrate or derivative.

In other respects, the present invention relates to treat and comprise the illness of being regulated by the MEK cascade in the human mammal or the method for the patient's condition, it comprises formula I compound or the acceptable salt of its pharmacy, ester, prodrug, solvate, hydrate or the derivative of regulating the amount of described cascade to described mammal administration effectively.In accordance with known methods, those skilled in the art can determine the suitable dosage of particular patient.

Suppress the MEK enzyme

In other respects, the present invention relates to suppress the method for MEK enzyme.In some embodiments, described method comprises makes described MEK enzyme contact with a certain amount of composition that comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug that is enough to suppress described enzyme, and wherein said enzyme is suppressed.Further or in other the embodiment, described enzyme is suppressed at least about 1%.Further or in other the embodiment, described enzyme is suppressed at least about 2%.Further or in other the embodiment, described enzyme is suppressed at least about 3%.Further or in other the embodiment, described enzyme is suppressed at least about 4%.Further or in other the embodiment, described enzyme is suppressed at least about 5%.Further or in other the embodiment, described enzyme is suppressed at least about 10%.Further or in other the embodiment, described enzyme is suppressed at least about 20%.Further or in other the embodiment, described enzyme is suppressed at least about 25%.Further or in other the embodiment, described enzyme is suppressed at least about 30%.Further or in other the embodiment, described enzyme is suppressed at least about 40%.Further or in other the embodiment, described enzyme is suppressed at least about 50%.Further or in other the embodiment, described enzyme is suppressed at least about 60%.Further or in other the embodiment, described enzyme is suppressed at least about 70%.Further or in other the embodiment, described enzyme is suppressed at least about 75%.Further or in other the embodiment, described enzyme is suppressed at least about 80%.Further or in other the embodiment, described enzyme is suppressed at least about 90%.Further or in other the embodiment, described enzyme is suppressed basically fully.Further or in other the embodiment, described MEK enzyme is the MEK kinases.Further or in other the embodiment, described MEK enzyme is MEK1.Further or in other the embodiment, described MEK enzyme is MEK2.Further or in other the embodiment, described contact occurs in the cell.Further or in other the embodiment, described cell is a mammalian cell.Further or in other the embodiment, described mammalian cell is the human cell.Further or in other the embodiment, suppress described MEK enzyme with the composition of the pharmaceutically acceptable salt that comprises formula I compound.

The illness of MEK mediation

In other respects, the present invention relates to treat the method for illness described in the individuality of the illness of suffering from MEK mediation, it comprises the composition that comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug to described individual effective dosage.In some embodiments, oral administration, intraduodenal administration, parenteral (comprising intravenous administration, subcutaneous administration, intramuscular administration, intravascular administration or infusion administration), topical or rectally comprise the described composition of formula I compound.In some embodiments, described pharmaceutical composition is the form that is suitable for oral administration.Further or in other the embodiment, described pharmaceutical composition is the form of tablet, capsule, pill, powder, sustained release preparation, solution, supensoid agent, for parenteral injection is sterile solution agent, supensoid agent or emulsion, for topical is ointment or emulsifiable paste, is suppository for rectally perhaps.Further or in other the embodiment, described pharmaceutical composition is the unit dosage forms that is suitable for accurate dosage single-dose.Further or in other the embodiment, described pharmaceutical composition also comprises pharmaceutical carriers, excipient and/or assistant agent.

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

Further or in other the embodiment, with the single dose compound of Medicine-feeding type I once a day.Further or in other the embodiment, with compound multiple dose every day more than single administration formula I.Further or in other the embodiment, every day twice Medicine-feeding type I compound.Further or in other the embodiment, every day three Medicine-feeding type I compound.Further or in other the embodiment, the compound of four times a day Medicine-feeding type I.Further or in other the embodiment, every day is more than the compound of four Medicine-feeding type I.In some embodiments, the individuality of suffering from the illness of MEK mediation is a mammal.Further or in other the embodiment, described individuality is human.

In some embodiments, administration comprises the described composition of formula I compound, with other therapy couplings.Further or in other the embodiment, described other therapies are radiotherapy, chemotherapy, operation or their any combination.Further or in other the embodiment, comprise the described composition and at least a therapeutic agent administering drug combinations of formula I compound.Further or in other the embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic.Further or in other the embodiment, described antineoplastic is selected from alkylating agent, antimetabolite, epidophylltoxin; Antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibitor, hormone/antihormones therapeutic agent and hemopoieticgrowth factor.Further or in other the embodiment, described therapeutic agent is selected from taxol, bortezomib or the two.

In some embodiments, the illness of described MEK mediation is selected from inflammatory disease, infection, autoimmune disease, apoplexy, ischemic, cardiac conditions, neurological disorders, fibrillatable illness, proliferative disorders, excess proliferative illness, non-cancer excess proliferative illness, tumour, leukemia, knurl, cancer, cancer, metabolic disease, malignant diseases, reangiostenosis, psoriasis, atherosclerotic, rheumatoid arthritis, osteoarthritis, heart failure, chronic ache, neuropathic pain, dry eyes, angle-closure glaucoma and open-angle glaucoma.Further or in other the embodiment, the illness of described MEK mediation is an inflammatory disease.Further or in other the embodiment, the illness of described MEK mediation is an excess proliferative disease.Further or in other the embodiment, the illness of described MEK mediation is selected from tumour, leukemia, knurl, cancer, cancer and malignant diseases.Further or in other the embodiment, described cancer is the cancer of the brain, breast cancer, lung cancer, oophoroma, cancer of pancreas, prostate cancer, cancer of the stomach, kidney, colorectal cancer or leukemia.Further or in other the embodiment, described fibrillatable illness is chorionitis, polymyositis, systemic lupus, rheumatoid arthritis, cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis.Further or in other the embodiment, the composition of the pharmaceutically acceptable salt that comprises formula I compound of effective dosage.

Obtain effect

In other respects, the present invention relates in the patient, obtain the method for effect, it comprises the composition that comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug to patient's effective dosage, and wherein said effect is selected from the inhibition to various cancers, immunological disease and inflammatory disease.In some embodiments, described effect is to suppress various cancers.Further or in other the embodiment, described effect is to suppress immunological disease.Further or in other the embodiment, described effect is to suppress inflammatory disease.

In some embodiments, administration comprises the described composition of formula I compound, with other therapy couplings.Further or in other the embodiment, described other therapies are radiotherapy, chemotherapy, operation or their any combination.Further or in other the embodiment, comprise the described composition and at least a therapeutic agent administering drug combinations of formula I compound.

In some embodiments, oral administration, intraduodenal administration, parenteral (comprising intravenous administration, subcutaneous administration, intramuscular administration, intravascular administration or infusion administration), topical or the described composition of rectally.Further or in other the embodiment, the amount of formula I compound about 0.001 to the scope of about 1000mg/kg body weight/day.Further or in other the embodiment, the amount of formula I compound is in the scope of about 0.5 to about 50mg/kg/ day.Further or in other the embodiment, the amount of formula I compound is about 0.001 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.01 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.02 to about 5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.05 to about 2.5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.1 to about 1g/ day.Further or in other the embodiment, the dosage level that is lower than above-mentioned scope lower limit may enough be had a surplus.Further or in other the embodiment, the dosage level that is higher than above-mentioned range limit may be necessary.

Further or in other the embodiment, with the single dose compound of Medicine-feeding type I once a day.Further or in other the embodiment, with compound multiple dose every day more than single administration formula I.Further or in other the embodiment, every day twice Medicine-feeding type I compound.Further or in other the embodiment, every day three Medicine-feeding type I compound.Further or in other the embodiment, the compound of four times a day Medicine-feeding type I.Further or in other the embodiment, every day is more than the compound of four Medicine-feeding type I.In some embodiments, the individuality of suffering from cancer is a mammal.Further or in other the embodiment, described individuality is human.Further or in other the embodiment, the composition of the pharmaceutically acceptable salt that comprises formula I compound of effective dosage.

In other respects, the present invention relates to make the method for cancer cell degeneration, anticancer growth or kill cancer cell, it comprises that the composition that makes described cell and make described cell degradation effectively, suppress described cell growth or kill the amount of described cell contacts, and described composition comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug.In some embodiments, described cancer cell comprises 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 the embodiment, described composition and at least a therapeutic agent administering drug combinations.Further or in other the embodiment, described therapeutic agent is taxol, bortezomib or the two.Further or in other the embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic.Further or in other the embodiment, described antineoplastic is selected from alkylating agent, antimetabolite, epidophylltoxin; Antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibitor, hormone/antihormones therapeutic agent and hemopoieticgrowth factor.In some embodiments, described cancer cell is degenerated.Further or in other the embodiment, 1% described cancer cell is degenerated.Further or in other the embodiment, 2% described cancer cell is degenerated.Further or in other the embodiment, 3% described cancer cell is degenerated.Further or in other the embodiment, 4% described cancer cell is degenerated.Further or in other the embodiment, 5% described cancer cell is degenerated.Further or in other the embodiment, 10% described cancer cell is degenerated.Further or in other the embodiment, 20% described cancer cell is degenerated.Further or in other the embodiment, 25% described cancer cell is degenerated.Further or in other the embodiment, 30% described cancer cell is degenerated.Further or in other the embodiment, 40% described cancer cell is degenerated.Further or in other the embodiment, 50% described cancer cell is degenerated.Further or in other the embodiment, 60% described cancer cell is degenerated.Further or in other the embodiment, 70% described cancer cell is degenerated.Further or in other the embodiment, 75% described cancer cell is degenerated.Further or in other the embodiment, 80% described cancer cell is degenerated.Further or in other the embodiment, 90% described cancer cell is degenerated.Further or in other the embodiment, 100% described cancer cell is degenerated.Further or in other the embodiment, whole basically described cancer cells are degenerated.In various embodiments, above-mentioned degeneration occurs in 1 day, 5 days, 10 days, 1 month, 2 months, 6 months or 1 year.

In some embodiments, described cancer cell is killed.Further or in other the embodiment, 1% described cancer cell is killed.Further or in other the embodiment, 2% described cancer cell is killed.Further or in other the embodiment, 3% described cancer cell is killed.Further or in other the embodiment, 4% described cancer cell is killed.Further or in other the embodiment, 5% described cancer cell is killed.Further or in other the embodiment, 10% described cancer cell is killed.Further or in other the embodiment, 20% described cancer cell is killed.Further or in other the embodiment, 25% described cancer cell is killed.Further or in other the embodiment, 30% described cancer cell is killed.Further or in other the embodiment, 40% described cancer cell is killed.Further or in other the embodiment, 50% described cancer cell is killed.Further or in other the embodiment, 60% described cancer cell is killed.Further or in other the embodiment, 70% described cancer cell is killed.Further or in other the embodiment, 75% described cancer cell is killed.Further or in other the embodiment, 80% described cancer cell is killed.Further or in other the embodiment, 90% described cancer cell is killed.Further or in other the embodiment, 100% described cancer cell is killed.Further or in other the embodiment, whole basically described cancer cells all are killed.In various embodiments, above-mentioned kill cancer cell occurs in 1 day, 5 days, 10 days, 1 month, 2 months, 6 months or 1 year.

Further or in other the embodiment, the growth of described cancer cell is suppressed.Further or in other the embodiment, the growth of described cancer cell is suppressed about 1%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 2%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 3%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 4%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 5%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 10%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 20%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 25%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 30%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 40%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 50%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 60%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 70%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 75%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 80%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 90%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 100%.In various embodiments, above-mentioned inhibition 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 the tumour size in individuality, suppress the method that the tumour size increases, reduces tumor proliferation or prevention tumor proliferation, it comprises the composition that comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug to described individual effective dosage.In some embodiments, the size of tumour is reduced.Further or in other the embodiment, the size of tumour is reduced at least 1%.Further or in other the embodiment, the size of tumour is reduced at least 2%.Further or in other the embodiment, the size of tumour is reduced at least 3%.Further or in other the embodiment, the size of tumour is reduced at least 4%.Further or in other the embodiment, the size of tumour is reduced at least 5%.Further or in other the embodiment, the size of tumour is reduced at least 10%.Further or in other the embodiment, the size of tumour is reduced at least 20%.Further or in other the embodiment, the size of tumour is reduced at least 25%.Further or in other the embodiment, the size of tumour is reduced at least 30%.Further or in other the embodiment, the size of tumour is reduced at least 40%.Further or in other the embodiment, the size of tumour is reduced at least 50%.Further or in other the embodiment, the size of tumour is reduced at least 60%.Further or in other the embodiment, the size of tumour is reduced at least 70%.Further or in other the embodiment, the size of tumour is reduced at least 75%.Further or in other the embodiment, the size of tumour is reduced at least 80%.Further or in other the embodiment, the size of tumour is reduced at least 85%.Further or in other the embodiment, the size of tumour is reduced at least 90%.Further or in other the embodiment, the size of tumour is reduced at least 95%.Further or in other the embodiment, described tumour is uprooted.In some embodiments, the size of tumour does not increase.In various embodiments, the above-mentioned effect of tumour size is occurred in 1 day, 5 days, 10 days, 1 month, 2 months, 6 months or 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 at least 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 reduced at least 70%.In some embodiments, tumor proliferation is reduced at least 75%.In some embodiments, tumor proliferation is reduced at least 75%.In some embodiments, tumor proliferation is reduced at least 80%.In some embodiments, tumor proliferation is reduced at least 90%.In some embodiments, tumor proliferation is reduced at least 95%.In some embodiments, tumor proliferation is prevented from.In various embodiments, the above-mentioned effect of on cell proliferation occurs in 1 day, 5 days, 10 days, 1 month, 2 months, 6 months or 1 year.

In some embodiments, administration comprises the described composition of formula I compound, with other therapy couplings.Further or in other the embodiment, described other therapies are radiotherapy, chemotherapy, operation or their any combination.Further or in other the embodiment, comprise the described composition and at least a therapeutic agent administering drug combinations of formula I compound.Further or in other the embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic.Further or in other the embodiment, described antineoplastic is selected from alkylating agent, antimetabolite, epidophylltoxin; Antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological respinse trim and growth inhibitor, hormone/antihormones therapeutic agent and hemopoieticgrowth factor.Further or in other the embodiment, described therapeutic agent is selected from taxol, bortezomib or the two.

Further or in other the embodiment, with the single dose compound of Medicine-feeding type I once a day.Further or in other the embodiment, with compound multiple dose every day more than single administration formula I.Further or in other the embodiment, every day twice Medicine-feeding type I compound.Further or in other the embodiment, every day three Medicine-feeding type I compound.Further or in other the embodiment, the compound of four times a day Medicine-feeding type I.Further or in other the embodiment, every day is more than the compound of four Medicine-feeding type I.In some embodiments, the described individuality of suffering from cancer is a mammal.Further or in other the embodiment, described individuality is human.Further or in other the embodiment, the composition of the pharmaceutically acceptable salt that comprises formula I compound of effective dosage.

Proliferative diseases

In other respects, the present invention relates to increase in treatment or the prevention individuality GrowThe method of property disease, it comprises the composition that comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug to described individual effective dosage.In some embodiments, described increasing GrowThe property disease is cancer, psoriasis, ISR, autoimmune disease or atherosclerotic.Further or in other the embodiment, described increasing GrowThe property disease is an excess proliferative disease.Further or in other the embodiment, described increasing GrowThe property disease is selected from tumour, leukemia, knurl, cancer, cancer and malignant diseases.Further or in other the embodiment, described cancer is the cancer of the brain, breast cancer, lung cancer, oophoroma, cancer of pancreas, prostate cancer, kidney, colorectal cancer, cancer of the stomach, head and neck cancer or leukemia.Further or in other the embodiment, described fibrillatable illness is chorionitis, polymyositis, systemic lupus, rheumatoid arthritis, cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis.Further or in other the embodiment, described cancer is cancer of the stomach, the cancer of the brain, breast cancer, lung cancer, non-small cell lung cancer, oophoroma, cancer of pancreas, liver cancer, prostate cancer, kidney, colorectal cancer or leukemia.Further or in other the embodiment, described cancer is the cancer of the brain or adrenocortical carcinoma.Further or in other the embodiment, described cancer is a breast cancer.Further or in other the embodiment, described cancer is an oophoroma.Further or in other the embodiment, described cancer is a cancer of pancreas.Further or in other the embodiment, described cancer is a prostate cancer.Further or in other the embodiment, described cancer is a kidney.Further or in other the embodiment, described cancer is a colorectal cancer.Further or in other the embodiment, described cancer is a myeloid leukemia.Further or in other the embodiment, described cancer is a glioblastoma.Further or in other the embodiment, described cancer is a folliculus type lymphoma.Further or in other the embodiment, described cancer is preceding B acute leukemia.Further or in other the embodiment, described cancer is a chronic lymphocytic B leukemia.Further or in other the embodiment, described cancer is a celiothelioma.Further or in other the embodiment, described cancer is a small-cell carcinoma of the lung.In other embodiments, described cancer is a cancer of the stomach.

In some embodiments, administration comprises the described combination of formula I compound, thing and other therapy couplings.Further or in other the embodiment, described other therapies are radiotherapy, chemotherapy, operation or their any combination.Further or in other the embodiment, comprise the described composition and at least a therapeutic agent administering drug combinations of formula I compound.Further or in other the embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic.Further or in other the embodiment, described antineoplastic is selected from alkylating agent, antimetabolite, epidophylltoxin; Antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological respinse trim and growth inhibitor, hormone/antihormones therapeutic agent and hemopoieticgrowth factor.

Further or in other the embodiment, described therapeutic agent is selected from taxol, bortezomib or the two.In some embodiments, oral administration, intraduodenal administration, parenteral (comprising intravenous administration, subcutaneous administration, intramuscular administration, intravascular administration or infusion administration), topical or the described composition of rectally.

Further or in other the embodiment, with the single dose compound of Medicine-feeding type I once a day.Further or in other the embodiment, with compound multiple dose every day more than single administration formula I.Further or in other the embodiment, every day twice Medicine-feeding type I compound.Further or in other the embodiment, every day three Medicine-feeding type I compound.Further or in other the embodiment, the compound of four times a day Medicine-feeding type I.Further or in other the embodiment, every day is more than the compound of four Medicine-feeding type I.In some embodiments, the described individuality of suffering from proliferative diseases is a mammal.Further or in other the embodiment, described individuality is human.Further or in other the embodiment, the composition of the pharmaceutically acceptable salt that comprises formula I compound of effective dosage.

Inflammatory disease

In other respects, the present invention relates to treat or prevent the method for inflammatory disease in the individuality, it comprises the composition that comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug to described individual effective dosage.Further or in other the embodiment, described inflammatory disease is selected from chronic inflammatory disease, rheumatoid arthritis, rheumatoid arthritis, spondyloarthropathy, urarthritis, osteoarthritis, juvenile arthritis,juvenile chronic arthritis,juvenile rheumatoid arthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, pyogenic arthritis, atherosclerotic, systemic loupus erythematosus, inflammatory bowel disease, IBS, ulcerative colitis, reflux esophagitis, Crohn's disease, gastritis, asthma, anaphylaxis, Respiratory Distress Syndrome(RDS), pancreatitis, COPD, pulmonary fibrosis, psoriasis, eczema or chorionitis.

In some embodiments, administration comprises formula I compound compositions, with other therapy couplings.Further or in other the embodiment, comprise the described composition and at least a therapeutic agent administering drug combinations of formula I compound.

Further or in other the embodiment, with the single dose compound of Medicine-feeding type I once a day.Further or in other the embodiment, with compound multiple dose every day more than single administration formula I.Further or in other the embodiment, every day twice Medicine-feeding type I compound.Further or in other the embodiment, every day three Medicine-feeding type I compound.Further or in other the embodiment, the compound of four times a day Medicine-feeding type I.Further or in other the embodiment, every day is more than the compound of four Medicine-feeding type I.In some embodiments, the described individuality of suffering from inflammatory disease is a mammal.Further or in other the embodiment, described individuality is human.Further or in other the embodiment, the composition of the pharmaceutically acceptable salt that comprises formula I compound of effective dosage.

Cancer

In other respects, the present invention relates to method for cancer in treatment or the prevention individuality, it comprises the composition that comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug to described individual effective dosage.Further or in other the embodiment, described cancer is the cancer of the brain, breast cancer, cancer of the stomach, lung cancer, oophoroma, cancer of pancreas, prostate cancer, kidney, colorectal cancer or leukemia.Further or in other the embodiment, described fibrillatable illness is chorionitis, polymyositis, systemic lupus, rheumatoid arthritis, cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis.Further or in other the embodiment, described cancer is the cancer of the brain, breast cancer, lung cancer, oophoroma, cancer of pancreas, prostate cancer, kidney, cancer of the stomach, colorectal cancer or leukemia.Further or in other the embodiment, described cancer is the cancer of the brain or adrenocortical carcinoma.Further or in other the embodiment, described cancer is a breast cancer.Further or in other the embodiment, described cancer is an oophoroma.Further or in other the embodiment, described cancer is a cancer of pancreas.Further or in other the embodiment, described cancer is a prostate cancer.Further or in other the embodiment, described cancer is a kidney.Further or in other the embodiment, described cancer is a colorectal cancer.Further or in other the embodiment, described cancer is a myeloid leukemia.Further or in other the embodiment, described cancer is a glioblastoma.Further or in other the embodiment, described cancer is a folliculus type lymphoma.Further or in other the embodiment, described cancer is preceding B acute leukemia.Further or in other the embodiment, described cancer is a chronic lymphocytic B leukemia.Further or in other the embodiment, described cancer is a celiothelioma.Further or in other the embodiment, described cancer is a small-cell carcinoma of the lung.In some embodiments, described cancer is a cancer of the stomach.

In some embodiments, oral administration, intraduodenal administration, parenteral (comprising intravenous administration, subcutaneous administration, intramuscular administration, intravascular administration or infusion administration), topical or the described composition of rectally.Further or in other the embodiment, the amount of formula I compound about 0.001 to the scope of about 1000mg/kg body weight/day.Further or in other the embodiment, the amount of formula I compound is in the scope of about 0.5 to about 50mg/kg/ day.Further or in other the embodiment, the amount of formula I compound is about 0.001 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.01 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.02 to about 5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.05 to about 2.5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.1 to about 1g/ day.Further or in other the embodiment, the dosage level that is lower than above-mentioned scope lower limit may enough be had a surplus.

Further or in other the embodiment, the dosage level that is higher than above-mentioned range limit may be necessary.Further or in other the embodiment, with the single dose compound of Medicine-feeding type I once a day.Further or in other the embodiment, with compound multiple dose every day more than single administration formula I.Further or in other the embodiment, every day twice Medicine-feeding type I compound.Further or in other the embodiment, every day three Medicine-feeding type I compound.Further or in other the embodiment, the compound of four times a day Medicine-feeding type I.Further or in other the embodiment, every day is more than the compound of four Medicine-feeding type I.In some embodiments, the described individuality of suffering from cancer is a mammal.Further or in other the embodiment, described individuality is human.Further or in other the embodiment, the composition of the pharmaceutically acceptable salt that comprises formula I compound of effective dosage.

Quote adding

Whole publications and the patent application mentioned are in this manual quoted adding herein, and its degree is equal to each publication or patent application and specifically and individually is indicated as being and quotes adding.

The accompanying drawing summary

In additional claim in detail, novel feature of the present invention has been described in detail.Following detailed description and accompanying drawing thereof with reference to illustrating the exemplary of using the principle of the invention will be better appreciated by feature of the present invention and advantage.

Fig. 1 represents: have in the mouse of A375 melanoma, Colo205 colon tumor, A431 epiderm-like tumour or HT-29 colon tumor cell in implantation, mean tumour volume is to the chart of time (fate).To mouse oral administration (25mg/kg, 50mg/kg or 100mg/kg) once a day, continue 14 days.

Fig. 2 represents: in the A375 heterograft mouse of administration 50mg/kg QD, 25mg/kg BID, 50mg/kg QD and 12.5mg/kg BID, the % tumor growth suppresses (%TGI) chart.

Fig. 3 represents: the chart that plasma concentration (log nM) suppresses pERK% is arranged in the female nu/nu mouse of Colo205 tumour cell in implantation.Single dose to mouse administration 2.5,5,10 or 25mg/kg.

Fig. 4 represents: among the mankind behind single dose administration 2mg (2x1mg capsule), 4mg (4x1mg capsule) or 6mg (6x1mg capsule), plasma concentration (ng/mL) to the time (hour) chart.

Fig. 5 is to use powder x-ray diffraction (PXRD) figure of N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulphonyl A type of Inel XRG-3000 diffractometer generation.Use by the peak intensity of per second counting definition the angle of diffraction 2 θ (degree) are mapped.

The N-(S)-(3 that Fig. 6 is to use TA instrument differential scanning calorimetry (DSC) Q1000 to produce, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-modulation differential scanning calorimetry (DSC) thermal analysis curue of 1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide A type.Be the sample temperature ℃ mapping of normalized heat flow to recording of unit in order to watt/gram (W/g).

Fig. 7 is: the N-(S)-(3 that uses Inel XRG-3000 diffractometer to produce, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) PXRD of cyclopropane-1-sulfonamide A type figure (top) and N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-PXRD of 1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide amorphous substance figure (bottom).Use by the peak intensity of per second counting definition the angle of diffraction 2 θ (degree) are mapped.

Fig. 8 represents: the N-(S)-(3 that uses VTI SGA-100 steam adsorption analysis instrument to produce, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-dynamic steam absorption/desorption (DVS) isotherm of 1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide A type.

Fig. 9 represents: DTG (TG) thermal analysis curue that uses N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide (A) type of TA instrument 2950 thermogravimeters generation.

Figure 10 (a) and Figure 10 (b) expression: with the N-(S)-(3 of concentration increase, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-growth retardation of the A375 cell that the logarithmic phase of 1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide contact is dividing.Analysis of cells is measured ATP content.Use 1 μ M N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide to determine 100% growth retardation.

Figure 11 represents: the 48hr AK in the A375 cell measures.A375 cell and N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide that logarithmic phase is being divided contact 48hr with PD-325901, and analyze AK release.

Figure 12 A-12C represents: N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide (A) suppresses human colorectal cancer Colo205 cell growth (GI ₅₀=11nM); (B) suppress A375 cell growth (GI ₅₀=22nM), and (C) suppress the MDA-MB231 cell, it does not demonstrate N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) growth retardation that cyclopropane-the 1-sulfonamide causes in two-dimentional anchorage dependence test.

Figure 13 A represents to suppress human colorectal cancer Colo205 cell growth, GI ₅₀Value is respectively 6nM and 11nM.

Figure 13 B represents to suppress the growth of A375 cell, GI ₅₀Value is 5nM and 22nM.

Figure 14 A and Figure 14 B represent: N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) effect of cyclopropane-1-sulfonamide cell cycle process, this explanation makes A375 cell and N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) contact of cyclopropane-1-sulfonamide causes the G1 that is stagnated in the cell cycle in the phase, and it is all reduced by the cell that is in G2 phase and S phase and shows.

Figure 15 A and Figure 15 B represent: N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide to cancer of the stomach (sdenocarcinoma of stomach) cell-line AGS in (Figure 15 A) after 3 days and the effect of (Figure 15 B) after 6 days.The y axle is the cell number with respect to carrier, and the x axle is N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration uM.

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

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

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

Figure 19 represents: in the figure of cell number (with respect to carrier) to N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration, and the inhibition of Hs746t cell proliferation.

Figure 20 A represents: handling the 5th day of non-small cell lung cancer (NSCLC) MV522 cell, along with N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration increases, and contrasts the chart of each level of apoptosis.

Figure 20 B represents: handling the 5th day of non-small cell lung cancer (NSCLC) H358 cell, along with N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration increases the chart of each level of apoptosis.

Figure 20 C represents: handling the 6th day of non-small cell lung cancer (NSCLC) A549 cell, along with N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration increases the chart of each level of apoptosis.

Figure 20 D represents: handling the 5th day of non-small cell lung cancer (NSCLC) H727 cell, along with N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration increases the chart of each level of apoptosis.

Figure 20 E represents: handling the 5th day of colon HT29 cell, along with N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration increases the chart of each level of apoptosis.

Figure 20 F represents: handling the 6th day of colon HCT116 cell, along with N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration increases the chart of each level of apoptosis.

Figure 20 G represents: handling the 5th day of colon HUH7 hepatoma cells, along with N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration increases the chart of each level of apoptosis.

Figure 20 H represents: handling the 5th day of sarcoma U2-OS cell, along with N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration increases the chart of each level of apoptosis.

Figure 20 I represents: handling the 5th day of glioma D37 cell, along with N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration increases the chart of each level of apoptosis.

Figure 21 represents: under 10 μ M, compd 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, to the N-of

rat administration

6,20,60 and 200mg/kg (S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) behind cyclopropane-1-sulfonamide, the chart that increases and reduce with respect to the vehicle Control oedema at each treatment group median claw volume.

Figure 23 A represents: with 2,6 and the N-(S)-(3 of 20mg/kg, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-acute stage of the rat of 1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide treatment in, the inhibition of swelling in the arthritis model that adjuvant causes.

Figure 23 B represents: with 2,6 and the N-(S)-(3 of 20mg/kg, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) in the period of delay of the rat of cyclopropane-1-sulfonamide treatment, the inhibition of swelling in the arthritis model that adjuvant causes.

Figure 24 represents: with 1,3 ﹠amp; Average arthritis score in arthritis (CAIA) mouse that the collagen-antibody of 10mg/kg QD N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide treatment causes.

Detailed Description Of The Invention

Chapter title used herein only should not be understood to limit described theme for the logic purpose. All documents that include, but are not limited to patent, patent application, article, books, handbook and paper or the part document quoted among the application are intactly clearly quoted adding hereby with any purpose.

Some technical terms of chemistry

Unless otherwise defined, whole technology used herein has the implication identical with the common understanding of the theme one of ordinary skill in the art of prescription with scientific terminology. Unless otherwise indicated, the material that runs through the whole disclosed whole patents that are cited, patent application, announcement is herein intactly quoted adding herein. If term herein has various definitions, to be defined as the master in these chapters and sections. In the situation to URL or other such identifiers or address reference, understand that such identifier may change and the specifying information on the internet may constantly change, but can find the information that is equal to by search internet or other suitable reference sources. Availability and the public propagation of the information that its list of references proof is such.

It only is exemplary and explanatory should understanding above-mentioned general introduction and following detailed description, is not any theme of requirement for restriction right. In this application, unless specifically describe in addition, the use of odd number comprises plural number. Clearly state in addition unless must be noted that context, the singulative that uses in this specification and the appended claims " a ", " an " and " should/this/described (the) " comprise the referent of plural number. Should also be noted that unless otherwise indicated, use "or" mean " and/or ". And term " comprises " and other forms of use is nonrestrictive.

(comprise Carey and Sundberg " A in reference works_DVANCED O _RGANIC C _HEMISTRYThe 4th edition " volume A (2000) and roll up B (2001), Plenum Press, New York) in can find the definition of standard chemical term. Unless otherwise indicated, use mass spectrum, NMR, HPLC, IR and UV/Vis spectroscopic methodology and pharmacological conventional method in the art technology. Unless specific definition is provided, the name relevant with analytical chemistry as herein described, synthetic organic chemistry and pharmaceutical chemistry of use and laboratory method and the technology in these fields are known in the art. Standard technique can be used to chemical synthesis, chemical analysis, medicine preparation, preparation and administration, and the treatment patient. For example, use manufacturer's kit specification, the mode of perhaps usually finishing according to this area, perhaps as described herein, can carry out reaction and purification technique. By conventional method well known in the art, and as run through various summaries that this specification quotes and discuss and more specifically as described in the list of references, usually can carry out above-mentioned technology and method. In whole specification, those skilled in the art can select its group and substituting group so that stable part and compound to be provided.

Illustrating in the substituted radical situation that by their the conventional chemical formula of writing from left to right they comprise equally writes the chemically identical substituting group that structure can produce from right to left. With-CH₂O-is equivalent to-OCH₂-as limiting examples.

Unless otherwise indicated, the generalization technics of use is equivalent to their randomly substituted form such as but not limited to " alkyl ", " amine ", " aryl ". For example, " alkyl " used herein comprises randomly substituted alkyl.

Compound as herein described can have one or more stereocenters, and each center can be with R or S configuration, or their combination exists. Similarly, compound as herein described can have one or more pairs of keys, and each pair key can be with E (trans) or Z (cis) configuration, or their combination exists. The description that should understand a kind of specific stereoisomer, regional isomer (regioisomer), diastereomer, enantiomer or epimer comprises all possible stereoisomer, regional isomer, diastereomer, enantiomer or epimer and their mixture. Therefore, compound as herein described comprises all independent configuration stereoisomeric forms in any ratio, position isomerism form, diastereomer form, enantiomeric form and epimer form and their corresponding mixtures. Should understand comprising one or more chiral centres but do not specify a kind of specific chemical constitution of concrete stereochemical compound or the description of chemical name to comprise all possible stereoisomer, it comprise might stereoisomer pure form or the pure form basically of mixture, a kind of particular stereoisomer, and the pure form of alternative stereoisomer or pure form basically. It is well known in the art making the technology of specific stereocenter upset or the technology that remains unchanged and fractionation stereoisomer, and selects suitable method fully within those skilled in the art's ability for particular case. Referring to 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 " mean specific part or the functional group of molecule. Chemical part usually is considered to be embedded in the molecule or is attached to chemical entities on the molecule.

Term " key " or " singly-bound " mean two chemical bonds between the atom, perhaps when the atom that is connected by described key is considered to the part of larger minor structure, mean two chemical bonds between the part.

Term " optional " or " randomly " mean subsequently described event or situation may occur or may not occur, and this description comprises the situation that described event or situation occur and do not occur. For example, " randomly substituted alkyl " means such as undefined " alkyl " or " substituted alkyl ". In addition, randomly substituted group can be unsubstituted (such as-CH₂CH ₃), replace fully (such as-CF₂CF ₃), mono-substituted (such as-CH₂CH ₂F), the perhaps fully replacement of any level between replacement and the single replacement (for example-CH₂CHF ₂、-CH ₂CF ₃、-CF ₂CH ₃、-CFHCHF ₂Deng). For comprising one or more substituent any groups, it will be understood by those skilled in the art that such group is not (to comprise randomly substituted group of naphthene base such as substituted alkyl in order to introduce on the solid unactual and/or synthetic infeasible any replacement or substitute mode, it is defined as comprising randomly substituted alkyl group successively, may be unlimited). Therefore, described any substituting group should be understood to have highest weight about 1 usually, 000 dalton, more typically, up to about 500 dalton (except meaning clearly in large molecule substituting group those situations such as polypeptide, polysaccharide, polyethylene glycol, DNA, RNA etc.).

Unless otherwise indicated, the generalization technics is unsubstituted such as but not limited to the use of " alkyl ", " amine ", " aryl ".

C used herein₁-C _xComprise C₁-C ₂、C ₁-C ₃……C ₁-C _x Only as example, be expressed as " C₁-C ₄" group show and in this part, have 1-4 carbon atom, namely comprise 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms, and scope C₁-C ₂And C₁-C ₃Group. Therefore, only as example, " C₁-C ₄Alkyl " show and in alkyl group, have 1-4 carbon atom that namely described alkyl group is selected from methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, sec-butyl and the tert-butyl group. Whenever number range for example " 1-10 " mean each integer in given range when occurring in this article; For example, " 1-10 carbon atom " means described group and can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.

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

The term that is used alone or in combination herein " hetero atom " or " mixing " mean the atom except carbon or hydrogen. Hetero atom can be independently selected from oxygen, nitrogen, sulphur, phosphorus, silicon, selenium and tin, but is not limited to these atoms. In having two or more heteroatomic embodiments, described two or more hetero atoms can be mutually the same, and perhaps some or all in described two or more hetero atom can be different from other hetero atoms separately.

The term that is used alone or in combination herein " alkyl " means to contain 1 to the straight or branched saturated hydrocarbons unit price base of about 10 carbon atoms or 1-6 carbon atom. Example includes but not limited to methyl, ethyl, n-pro-pyl, isopropyl, 2-methyl isophthalic acid-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 long alkyl group such as heptyl, octyl group etc. Whenever number range " C for example₁-C ₆Alkyl " or " C_1-6Alkyl " when occurring in this article, meaning described alkyl group can be comprised of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. In one embodiment, described " alkyl " is substituted. Unless otherwise indicated, described " alkyl " is unsubstituted.

The term that is used alone or in combination herein " thiazolinyl " means to have one or more carbon-carbon double bonds and has 2 to about 10 carbon atoms or 2 straight or branched hydrocarbon unit price bases to about 6 carbon atoms. Can be in cis or anti-configuration for the described group of two keys, and should understand described group and comprise two kinds of isomers. Example includes but not limited to vinyl (CH=CH₂), 1-acrylic (CH₂CH＝CH ₂), isopropenyl [C (CH₃)＝CH ₂], cyclobutenyl, 1,3-butadiene base etc. Whenever number range " C for example₂-C ₆Thiazolinyl " or " C_2-6Thiazolinyl " when occurring in this article, meaning described alkenyl group can be comprised of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. In one embodiment, described " thiazolinyl " is substituted. Unless otherwise indicated, described " thiazolinyl " is unsubstituted.

The term that is used alone or in combination herein " alkynyl " means to have one or more carbon-carbon triple bonds and has 2 to about 10 carbon atoms or 2 straight or branched hydrocarbon unit price bases to about 6 carbon atoms. Example includes but not limited to acetenyl, 2-propynyl, 2-butynyl, 1,3-diacetylene base etc. Whenever number range " C for example₂-C ₆Alkynyl " or " C_2-6Alkynyl " when occurring in this article, meaning described alkynyl group can be comprised of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. In one embodiment, described " alkynyl " is substituted. Unless otherwise indicated, described " alkynyl " is unsubstituted.

The term that is used alone or in combination herein " assorted alkyl ", " assorted thiazolinyl " and " assorted alkynyl " mean respectively aforesaid alkyl, thiazolinyl and alkynyl structure, wherein one or more skeletal chain carbon atoms (and any continuous suitable hydrogen atom) independently of one another by hetero atom (i.e. atom except carbon, such as but not limited to oxygen, nitrogen, sulphur, silicon, phosphorus, tin or their combination) 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-、-SnH ₂-etc.) substitute.

The term that is used alone or in combination herein " haloalkyl ", " haloalkenyl group " and " halo alkynyl " mean respectively as defined above alkyl, thiazolinyl and alkynyl group, and wherein one or more hydrogen atoms are replaced by fluorine atom, chlorine atom, bromine atoms or iodine atom or their combination. In some embodiments, two or more hydrogen atoms can be replaced (for example difluoromethyl) by mutually the same halogen atom; In other embodiments, two or more hydrogen atoms can be replaced (for example 1-chloro-1-fluoro-1-iodine ethyl) by incomplete same each other halogen atom. The limiting examples of halogenated alkyl group is methyl fluoride, chloromethyl and bromoethyl. The limiting examples of haloalkenyl group group is the bromine vinyl. The limiting examples of halo alkynyl group is the chloroethene alkynyl.

The term that is used alone or in combination herein " carbochain " means any alkyl, thiazolinyl, alkynyl, assorted alkyl, assorted thiazolinyl or assorted alkynyl group, they be straight chain, ring-type or their any combination. If described chain is a part that connects base, and this connection base comprises the one or more rings as core main chain part, in order to calculate chain length, described " chain " only comprises and consisting of to the two those carbon atoms of the bottom of fixed ring or top rather than bottom and top, and in the long situation about not waiting in the top and bottom of ring, should use short distance to determine chain length. If described chain comprises the hetero atom as main chain part, in those atoms are not calculated in as the part of carbon chain length.

The term that is used alone or in combination herein " ring (cycle) ", " ring-type ", " ring (ring) and " unit's ring " mean any covalence closed structure, comprise alicyclic ring as described herein, heterocycle, aromatics, heteroaromatic and encircle more condensing or the ring system of non-condensed. Ring can randomly be substituted. Ring can form the part that condenses ring system. Term " unit " means to consist of the skeletal atom number of ring. Therefore, only as example, cyclohexane, pyridine, pyrans and pyrimidine are hexatomic rings, and pentamethylene, pyrroles, oxolane and thiophene are five-membered rings.

The term that is used alone or in combination herein " condenses " and means the ring structure that two or more rings share one or more keys.

The term that is used alone or in combination herein " cycloalkyl " means saturated hydrocarbons unit price basic ring, it comprises 3 to about 15 ring carbon atoms or 3 to about 10 ring carbon atoms, but can comprise as substituent extra non-ring carbon atom (such as the methyl cyclopropyl). Whenever number range " C for example₃-C ₆Cycloalkyl " or " C_3-6Cycloalkyl " when occurring in this article; meaning described group of naphthene base can be comprised of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms; be cyclopropyl, cyclobutyl, cyclopenta or suberyl (cyclohepty), but the appearance of the term " cycloalkyl " of not specifying number range is also contained in this definition. This term comprise condense, non-condensed, bridge and tap bolt group. The fused rings alkyl can comprise 2-4 fused rings, and wherein connecting ring is cycloalkyl ring, and other each rings can be the ring of alicyclic ring, heterocycle, aromatics or heteroaromatic or their any combination. Example includes but not limited to cyclopropyl, cyclopenta, cyclohexyl, decahydronaphthalenes base and dicyclo [2.2.1] heptyl and adamantyl ring system. Illustrative examples includes but not limited to following part:

Deng.

In one embodiment, described " cycloalkyl " is substituted. Unless otherwise indicated, described " cycloalkyl " is unsubstituted.

The term that is used alone or in combination herein " non-aromatic heterocycle " and " heterolipid cyclic group " mean to comprise 3 to about 20 annular atomses saturated, part is undersaturated or the complete unit price base of undersaturated non-aromatic ring, one or more in the wherein said annular atoms are being independently selected from oxygen, nitrogen, sulphur, phosphorus, silicon, selenium and tin but being not limited to the atom of these atoms except carbon. Exist in two or more heteroatomic embodiments in ring, described two or more hetero atoms can be mutually the same, and perhaps some or all in described two or more hetero atom can be different from other hetero atoms separately. These terms comprise condense, non-condensed, bridge and tap bolt group. The non-aromatic heterocycle group that condenses can comprise 2-4 fused rings, and wherein connecting ring is non-aromatic heterocyclic, and other each rings can be the ring of alicyclic ring, heterocycle, aromatics or heteroaromatic or their any combination. Condensing ring system can condense by singly-bound or two key, also can condense by carbon-carbon bond, carbon-heteroatom bond or hetero atom-heteroatomic bond. These terms also comprise have 3 to about 12 framework ring atoms and have 3 groups to about 10 framework ring atoms. Non-aromatic heterocycle subunit can pass through hetero atom or carbon atom with being connected of its parent molecule. Similarly, other replacement can be passed through hetero atom or carbon atom. As limiting examples, the imidazolidine non-aromatic heterocyclic can be connected to parent molecule by its arbitrary N atom (imidazolidine-1-base or imidazolidine-3-yl) or its any carbon atom (imidazolidine-2-base, imidazolidine-4-base or imidazolidine-5-yl). In certain embodiments, non-aromatic heterocyclic comprises the group that one or more carbonyls or thiocarbonyl group for example contain oxo and contain sulfo-. Example includes but not limited to pyrrolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidino, morpholino, thiomorpholine generation, thioxane base, piperazinyl, azetidinyl, oxetanyl, Thietane base, homopiperidinyl, oxepane alkyl, thia cycloheptane base, oxygen azepine

Base, diazaBase, sulphur azepine

Base, 1,2,3,6-tetrahydro pyridyl, 2-pyrrolinyl, 3-pyrrolinyl, indoline base, 2H-pyranose, 4H-pyranose, alkyl dioxin, DOX base, pyrazolinyl, dithiane base, dithiolane base, dihydro pyranyl, dihydro-thiophene base, dihydrofuran base, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, 3H-indyl and quinolizine base. The illustrative examples that the heterocycle alkyl group is also referred to as non-aromatic heterocycle comprises:

Deng.

This term also comprises all loop types of carbohydrate, includes but not limited to monose, disaccharides and oligosaccharides. In one embodiment, described " non-aromatic heterocycle " or " heterolipid cyclic group " is substituted. Unless otherwise indicated, described " non-aromatic heterocycle " or " heterolipid cyclic group " is unsubstituted.

The term that is used alone or in combination herein " aryl " means 6 aromatic hydrocarbyls to about 20 ring carbon atoms, and comprises that condense and aryl rings non-condensed. The aryl rings group that condenses comprises 2-4 fused rings, and wherein connecting ring is aryl rings, and other each rings can be the ring of alicyclic ring, heterocycle, aromatics or heteroaromatic or their any combination. In addition, term aryl comprise comprise 6 to about 12 ring carbon atoms and comprise 6 condense and rings non-condensed to about 10 ring carbon atoms. The limiting examples of monocyclic aryl group comprises phenyl; The limiting examples of fused rings aromatic yl group comprises naphthyl, phenanthryl, anthryl, Azulene base; The limiting examples of the biaryl group of non-condensed comprises xenyl. In one embodiment, described " aryl " is substituted. Unless otherwise indicated, described " aryl " is unsubstituted.

The term that is used alone or in combination herein " heteroaryl " means to comprise about 5 aromatics unit price bases to about 20 framework ring atoms, wherein one or more in the annular atoms are independently selected from oxygen, nitrogen, sulphur, phosphorus, silicon, selenium and tin but the hetero atom that is not limited to these atoms, and condition is that the ring of described group does not comprise two adjacent O or S atom. Exist in two or more heteroatomic embodiments in ring, described two or more hetero atoms can be mutually the same, and perhaps some or all in described two or more hetero atom can be different from other hetero atoms separately. The term heteroaryl comprises the heteroaryl group with at least one heteroatomic that condense and non-condensed. The term heteroaryl also comprise have 5 to about 12 framework ring atoms and have 5 condense and heteroaryls non-condensed to about 10 framework ring atoms. Can pass through carbon atom or hetero atom and heteroaryl group Cheng Jian. Therefore, as limiting examples, imidazole group can be by its any carbon atom (imidazoles-2-base, imidazoles-4-base or imidazoles-5-yl), and perhaps its any nitrogen-atoms (imidazoles-1-base or imidazoles-3-yl) is connected with parent molecule. Similarly, the heteroaryl group can further be substituted by its any or all of carbon atom and/or its any or all of hetero atom. The heteroaryl group that condenses can comprise 2-4 fused rings, and wherein connecting ring is the heteroaromatic ring, and other each rings can be the ring of alicyclic ring, heterocycle, aromatics, heteroaromatic or their any combination. The limiting examples of bicyclic heteroaryl group comprises pyridine radicals; The limiting examples of fused ring heteroaryl group comprises benzimidazolyl, quinolyl, acridinyl; The limiting examples of non-condensed connection heteroaryl group comprises bipyridyl. Other examples of heteroaryl comprise furyl, thienyl, oxazolyl, acridinyl, phenazinyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, diazosulfide base, benzothienyl, Ben Bing oxadiazolyl, BTA base, imidazole radicals, indyl, isoxazolyl, isoquinolyl, indolizine base, isothiazolyl, iso-indoles oxadiazole base, indazolyl, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, pyrrole radicals, pyrazinyl, pyrazolyl, purine radicals, phthalazinyl, pteridyl, quinolyl, quinazolyl, quinoxalinyl, triazolyl, tetrazole radical, thiazolyl, triazine radical, thiadiazolyl group etc. without limitation, and their oxide, for example pyridine radicals-N-oxide. The illustrative examples of heteroaryl group comprises following part:

Deng.

In one embodiment, described " heteroaryl " is substituted. Unless otherwise indicated, described " heteroaryl " is unsubstituted.

The term that is used alone or in combination herein " heterocyclic radical " jointly means heterolipid cyclic group and heteroaryl group. Herein, (the C for example of the carbon number in specifying heterocycle₁-C ₆Heterocycle), must there be at least one non-carbon atom (hetero atom) in the ring. Title is " C for example₁-C ₆Heterocycle " in only meaning to encircle carbon number and be not total atom number in meaning to encircle. Title is " 4-6 unit heterocycle " total atom number of comprising in meaning to encircle (namely 4 yuan of rings, 5 yuan encircle or 6 yuan of rings, and wherein at least one atom is carbon atom, and at least one atom is hetero atom, and a remaining 2-4 atom is carbon atom or hetero atom) for example. For having two or more heteroatomic heterocycles, those two or more hetero atoms can be same to each other or different to each other. The non-aromatic heterocyclic group comprises the group that only has 3 atoms in the ring, and aromatic heterocyclic group must have at least 5 atoms in ring. Can be by hetero atom or carbon atom and heterocycle Cheng Jian (namely being connected to parent molecule or further replacement). It is in one embodiment, described that " heterocyclic radical " is substituted. It is unless otherwise indicated, described that " heterocyclic radical " is unsubstituted.

The term that is used alone or in combination herein " halogen ", " halo " or " halide " mean fluorine, chlorine, bromine and/or iodine.

The term that is used alone or in combination herein " amino " means unit price base-NH₂。

The term that is used alone or in combination herein " alkyl amino " means unit price base-NH (alkyl), and wherein alkyl as defined herein.

The term that is used alone or in combination herein " dialkyl amido " means unit price base-N (alkyl) (alkyl), and wherein each alkyl can be identical or different and as defined herein.

The term that is used alone or in combination herein " Diaminoalkyl " means to comprise the alkyl group of two amine groups, wherein said amine groups can be the substituting group on the alkyl group, it can be amino, alkyl amino or dialkyl amino group, perhaps one or two in the wherein said amine groups can the component part alkyl chain with formation-alkylidene-N (H or alkyl)-alkylidene-N (H or alkyl or alkylidene-) (H or alkyl or alkylidene-).

The term that is used alone or in combination herein " hydroxyl " means unit price base-OH.

The term that is used alone or in combination herein " cyano group " means unit price base-CN.

The term that is used alone or in combination herein " cyanogen methyl " means unit price base-CH₂CN。

The term that is used alone or in combination herein " nitro " means unit price base-NO₂。

The term that is used alone or in combination herein " oxygen base " means bilvalent radical-O-.

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

The term that is used alone or in combination herein " carbonyl " mean bilvalent radical-C (=O)-, also can write-C (O)-.

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

The term that is used alone or in combination herein " alkoxyl " means alkyl ether groups,-O-alkyl, it comprise group-O-aliphatic group and-the O-carbocylic radical, wherein said alkyl, aliphatic group and carbocylic radical group can randomly be substituted, and wherein term alkyl, aliphatic group and carbocylic radical be as defined herein. The limiting examples of alkoxyl comprises: methoxyl group, ethyoxyl, positive propoxy, isopropoxy, positive butoxy, isobutoxy, sec-butoxy, tert-butoxy etc.

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

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

The term that is used alone or in combination herein " sulfonamide ", " sulfonamido " and " amino-sulfonyl (sulfonamidyl) " mean diradical group-S (=O)₂-NH-and-NH-S (=O)₂-。

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

Term used herein " reactant " means for generation of the nucleophile of covalent bond or close electric body.

Should understand and defining with two or more groups continuously in the substituent situation that is connected with structure, it is terminal that first group of being named is considered to, and the group of being named at last is considered to be connected to the structure of being discussed. Therefore, for example, the group aryl alkyl is connected to the structure of discussing by alkyl group.

Some technical term of pharmacology

Term used herein " mek inhibitor " means to measure with the Mek1 kinase assay of general introduction herein, demonstrates about 100 μ M at the most or is no more than the IC of about 50 μ M for the MEK activity₅₀Compound. " IC₅₀" be to make the activity of enzyme (such as MEK) be reduced to the inhibitor concentration of maximum half level. Found that compound exhibits as herein described goes out the inhibitory action to MEK. Measure with Mek1 kinase assay as herein described, compound of the present invention preferably demonstrates the at the most IC of about 10 μ M for MEK₅₀, more preferably about 5 μ M at the most, even more preferably no more than about 1 μ M, and be most preferably not exceeding about 200nM.

Term about ill disease individuality used herein " experimenter ", " patient " or " individuality " etc. comprise mammal and nonmammalian. Mammiferous example includes but not limited to any member of class of mammals: human, such as non-human primate and other ape kinds and the monkey kind of chimpanzee; Domestic animal such as ox, horse, sheep, goat, pig; Domestic animal such as rabbit, dog and cat; Comprise the animal used as test of rodent such as rat, mouse and cavy etc. The example of nonmammalian includes, but not limited to bird, fish etc. In the embodiment of the method and composition that provides in this article, described mammal is human.

The word of equivalence on term used herein " treatment " and other grammers, comprise alleviation, alleviate or improve the symptom of disease or the patient's condition, prevent other symptoms, improve or prevent the potential metabolism cause of symptom, suppress disease or the patient's condition, for example contain the development of disease or the patient's condition, palliate a disease or the patient's condition, cause disappearing of disease or the patient's condition, palliate a disease or the caused situation of the patient's condition, perhaps stop the symptom of disease or the patient's condition, and in order to comprise prevention. This term also comprises obtains treatment benefit and/or prevention benefit. The treatment benefit means to eradicate or improve the potential illness of just receiving treatment. In addition, in the patient, observe improvement thereby reach the treatment benefit by elimination or improvement one or more physiological signs relevant with potential illness, but the patient may be tormented by potential illness still. For the prevention benefit, to the patient that the specified disease risk occurs is arranged, or to the patient of one or more physiological signs of report disease, even not yet make the diagnosis of this disease, also can the described composition of administration.

Term used herein " effective dose ", " treatment effective dose " or " pharmacy effective dose " mean to be enough to treat or prevent at least a reagent of specified disease or the patient's condition or the dosage of compound. Its result reduces and/or alleviates sign, symptom or the cause of disease of disease, the perhaps change of any other hope of biosystem. For example, " effective dose " for the treatment of use provides the amount of the required composition that comprises compound disclosed herein that significantly palliates a disease clinically. Operation technique for example dose escalation study can be determined " effectively " amount suitable in any individual case.

Term used herein " basically anhydrous " and " essentially no solvent " mean crystalline polymorph and comprise water or the solvent that is less than respectively 0.01,0.1,0.2,0.3,0.4,0.5,1 or 2 % by weight.

Term used herein " basic identical " means not to be equal to described figure herein, but the x-ray diffractogram of powder in the experimental error limit that those skilled in the art consider or means of differential scanning calorimetry figure.

Term used herein " administration " etc. means can be used for making compound or composition can be delivered to the method in the biological agent site of expectation. These methods include but not limited to oral route, intraduodenal route, parenteral injection (comprising administration in intravenous administration, subcutaneous administration, the peritonaeum, intramuscular administration, intravascular administration or infusion administration), topical and rectally. Those skilled in the art know the operable medicine-feeding technology of Compounds and methods for as herein described, for example, such as Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition; Pergamon; And Remington ' s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton discusses among the Pa. In preferred embodiments, oral administration compound as herein described and composition.

Term used herein " acceptable " with regard to preparation, composition or composition, means to align the experimenter's who receives treatment overall healthy adverse effect without continuing.

Term used herein " pharmacy is acceptable " means not eliminate biologically active or character and the relatively avirulent material such as carrier or diluent of compound described herein, namely can not cause bad biological effect to the described material of individual administration, perhaps not with any component interaction in the mode that is harmful to and the composition that comprises described material.

Term used herein " pharmaceutical composition " means bioactive compound, it randomly mixes with the acceptable chemical composition of at least a pharmacy (such as, but not limited to carrier, stabilizing agent, diluent, dispersant, suspending agent, thickener and/or excipient).

Term used herein " carrier " means to promote cell or tissue to include relatively avirulent chemical compound or the reagent of compound in.

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

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

Term used herein " adjusting " means to interact to change with target spot directly or indirectly the activity of target spot, comprises that (only as an example) strengthens the activity of target spot, suppresses the activity of target spot, the activity of restriction target spot, the activity that perhaps prolongs target spot.

Term used herein " conditioning agent " means directly or indirectly and the interactional molecule of target spot. Described interaction includes, but are not limited to the interaction of activator and antagonist.

Term used herein " pharmacy acceptable derivates or prodrug " means the acceptable salt of any pharmacy, the ester of formula I compound, salt or other derivatives of ester, when to recipient's administration, it can provide compound of the present invention or its pharmaceutical active metabolin or residue directly or indirectly. First-selected especially derivative or prodrug are when to the such compound of patient's administration, improve derivative or the prodrug (for example more easily being absorbed in the blood by the compound that makes oral administration) of the bioavilability of compound of the present invention, perhaps improve derivative or prodrug that parent compound is sent to biological compartment (such as brain or lymphatic system).

" prodrug " used herein is can be under physiological condition or change into the compound of the acceptable salt of pharmacy of appointed compound or such compound by lyolysis. Prodrug comprises such compound, and wherein the polypeptide chain of amino acid residue or two or more amino acid residues is by amido link or the covalently bound free amine group to formula I compound of ester bond, hydroxyl or carboxylic acid group. The amino acid residue that relates to includes but not limited to 20 kinds of naturally occurring amino acid. Other amino acid that are fit to comprise 4-hydroxy-proline, oxylysine, desmosine (demosine), isodensmosine (isodemosine), 3-Methyl histidine, norvaline, Beta-alanine, GABA, citrulling (cirtulline), homocysteine, homoserine, ornithine and methionine sulfone. The prodrug of other types is well known in the art.

The acceptable prodrug of the pharmacy of compound as herein described includes but not limited to quaternary ammonium derivative, N-Mannich base, schiff bases, amino acid conjugate, phosphate, slaine and the sulphonic acid ester of ester, carbonic ester, sulfocarbonate, N-acyl derivative, N-acyloxy alkyl derivative, tertiary amine. Various forms of prodrugs are known in this field. Referring to for example, Designof 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 " be at ATextbook of Drug Design and Development, Krosgaard-Larsen and H.Bundgaard, and Ed., 1991, the 5 chapters, p.113-191; And Bundgaard, H., Advanced Drug Delivery Review, 1992,8,1-38, it quotes adding herein. Prodrug as herein described includes but not limited to the combination of following group and these groups; The prodrug that amine is derived:

The hydroxyl prodrug includes but not limited to acyloxy Arrcostab, alkoxy-carbonyl oxy Arrcostab, Arrcostab, aryl ester and comprises the disulphide of ester.

Term used herein " the acceptable salt of pharmacy " comprises the biological effectiveness of the free acid that keeps appointed compound and free alkali and abiology is not optimum or other not optimum salt. Described compound can have acidity or basic group, and therefore can be with some inorganic or organic base and inorganic or organic acid reaction form the acceptable salt of pharmacy. The example of the acceptable salt of pharmacy comprises those salt by compound as herein described and inorganic acid or organic acid or inorganic base reaction preparation, such salt comprises acetate, acrylates, adipate, alginates, aspartate, benzoate, benzene sulfonate, disulfate, bisulfites, bromide, butyrate, butine-1, the 4-diacid salt, camphorate, camsilate, caproate, caprylate, chloride, chloro benzoate, chloride, citrate, cyclopentane propionate, caprate, digluconate, dihydric phosphate, dinitro-benzoate, lauryl sulfate, esilate, formates, fumarate, gluceptate (glucoheptanoate), glycerophosphate, glycollate, Hemisulphate, enanthate, caproate, hexin-1, the 6-diacid salt, hydroxybenzoic acid salt, gamma hydroxybutyrate, hydrochloride, hydrobromate, hydriodate, the 2-isethionate, iodide, isobutyrate, lactate, maleate, malonate, mesylate, mandelate, metaphosphate, mesylate, methoxy benzoic acid salt, methyl benzoic acid salt, hydrophosphate, 1-naphthalene sulfonic aicd salt, the 2-naphthalene sulfonate, the nicotinic acid cigarette, nitrate, oxalates, pamoate (palmoate), pectate (pectinate), persulfate, phenylacetate, phenpropionate, the 3-phenpropionate, phosphate, picrate, Pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, propionate, phthalate, benzenebutanoic acid salt, the propane sulfonic acid ester, pyrophosphate, salicylate, succinate, sulfate, sulphite, succinate, suberate, sebacate, sulfonate, tartrate, rhodanate, toluene fulfonate, hendecane hydrochlorate (undeconate) and xylenesulfonate. Other acid are oxalic acid for example, although they itself are not that pharmacy is acceptable, but can be for the preparation of the salt that is used as obtaining the intermediate in compound of the present invention and the acceptable acid-addition salts process of their pharmacy (referring to such as Berge etc., J.Pharm.Sci.1977,66,1-19.). In addition, those compounds that can comprise free acid group as herein described can with suitable for example hydroxide, carbonate, the bicarbonate reaction of the acceptable metal cation of pharmacy of alkali, with ammonia react, perhaps with the acceptable organic primary amine of pharmacy, secondary amine or reactive tertiary amine. Representational alkali metal salt or alkali salt comprise lithium salts, sodium salt, sylvite, calcium salt, magnesium salts and aluminium salt etc. The illustrative example of alkali comprises NaOH, potassium hydroxide, bursine, sodium carbonate, N⁺(C _1-4Alkyl)₄Deng. The representative organic amine that is used to form base addition salts comprises ethamine, diethylamine, ethylenediamine, monoethanolamine, diethanol amine, piperazine etc. Should understand the quaternized of any alkaline nitrogen-containing group that compound as herein described comprises that also they may comprise. Quaternizedly can obtain water-soluble or oil-soluble or water dispersible or oil-dispersing property product by such. Referring to for example, Berge etc. are on seeing. During the final separation of compound of the present invention and purifying, can prepare on the spot these salt, the perhaps purified compound by making respectively free alkali form and suitable organic or inorganic acid reaction, and separate the salt that forms thus and prepare these salt.

Term used herein " enhancing " means to improve or prolong effectiveness or the continuation of predictive role. Therefore, about strengthening the therapeutic agent effect, term " enhancing " means to improve or prolong the other treatment agent to the ability of the effect of system in effectiveness or continuation. " synergy amount " used herein means to be enough to strengthen the amount of the effect of another therapeutic agent in required system.

Term used herein " drug regimen ", " using other therapies ", " administration other therapeutic agent " etc. mean by mixing or merge the drug therapy that produces more than a kind of active component, and comprise fixing and revocable combination of active component. Term " fixed combination " means at least a compound as herein described and at least a auxiliary agent with the form of single entities or dosage simultaneously to patient's administration. Term " on-fixed combination " means with at least a compound as herein described and at least a auxiliary agent with the entity that separates to the patient side by side and deposit ground or in turn to limit administration variable blanking time, wherein such administration provides the level of significance of two or more compounds in patient body. These also are applicable to conjoint therapy, for example three kinds of administrations or more kinds of active component.

Term used herein " administering drug combinations ", " with ... administering drug combinations " and their grammer word of equal value etc., intention comprises to the selected therapeutic agent of single patient administration, and intention comprises by identical or different administration path or at the therapeutic scheme of the described medicament of identical or different time administration. In some embodiments, compound as herein described can with the simultaneously administration of other medicaments. These terms comprise to two or more medicaments of animals administer so that medicament and/or their metabolin are present in the animal simultaneously. The simultaneously administration of composition that they comprise separating, in the composition administration of different time to separate, and/or all be present in wherein composition administration with two kinds of medicaments. Therefore, in some embodiments, with single composition administration compound of the present invention and other medicaments. In some embodiments, compound of the present invention and other medicaments are mixed in the described composition.

Term used herein " metabolin " means the derivative of the compound that forms during by metabolism when compound.

Term used herein " active metabolite " means the biologically active derivatives of the compound that forms during by metabolism when compound.

Term used herein " by metabolism " means the biological summation (including but not limited to hydrolysis and enzymatic reaction) that changes the process of predetermined substance. Therefore, enzyme can make compound produce specific structural change. For example, the various oxidations of Cytochrome P450 catalysis and reduction reaction, and the glucuronic acid molecule of uridine diphosphate glucuronate transferase catalytic activation is to the transfer of aromatic alcohol, fatty alcohol, carboxylic acid, amine and free thiohydroxy group. From The PharmacologicalBasis of Therapeutics, the 9th edition, McGraw-Hill (1996) can obtain other about metabolic information.

Compound

Compound and the acceptable salt of pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or the prodrug of formula I have been described herein:

Formula I

Wherein

Z is H or F;

X is F, Cl, CH₃、CH ₂OH、CH ₂F、CHF ₂Or CF₃；

Y is I, Br, Cl, CF₃、C ₁-C ₃Alkyl, C₂-C ₃Thiazolinyl, C₂-C ₃Alkynyl, cyclopropyl, OMe, OEt, SMe, phenyl or Het, wherein Het is 5 to 10 yuan of monocyclic heterocycles groups or bicyclic heterocyclic groups that comprise 1-5 the ring hetero atom that is independently selected from N, O and S, and described heterocyclic group is saturated, olefinic or aromatic; Wherein

Whole described phenyl or Het group are randomly by F, Cl, Br, I, acetyl group, methyl, CN, NO₂、CO ₂H、C ₁-C ₃Alkyl, C₁-C ₃Alkoxyl, C₁-C ₃Alkyl-C (=O)-, C₁-C ₃Alkyl-C (=S)-, C₁-C ₃Alkoxy-C (=S)-, C₁-C ₃Alkyl-C (=O) O-, C₁-C ₃Alkyl-O-(C=O)-, C₁-C ₃Alkyl-C (=O) NH-, C₁-C ₃Alkyl-C (=NH) NH-, C₁-C ₃Alkyl-NH-(C=O)-, two-C₁-C ₃Alkyl-N-(C=O)-, C₁-C ₃Alkyl-C (=O) N (C₁-C ₃Alkyl)-, C₁-C ₃Alkyl-S (=O)₂NH-or trifluoromethyl replace;

Whole described methyl, ethyl, C₁-C ₃Alkyl and cyclopropyl group are randomly replaced by OH;

Whole described methyl groups are randomly by 1,2 or 3 F atoms replacements;

R ⁰Be: H, F, Cl, Br, I, CH₃NH-、(CH ₃) ₂N-、C ₁-C ₆Alkyl, C₁-C ₄Alkoxyl, C₃-C ₆Cycloalkyl, C₂-C ₆Thiazolinyl, C₂-C ₆Alkynyl, phenyl, mono-substituted phenyl, O (C₁-C ₄Alkyl), O-C (=O) (C₁-C ₄Alkyl) or C (=O) O (C₁-C ₄Alkyl); Wherein

1-3 the substituting group that described alkyl, alkoxyl, cycloalkyl, thiazolinyl, alkynyl and phenyl group randomly are independently selected from F, Cl, Br, I, OH, CN, cyano methyl, nitro, phenyl and trifluoromethyl replaces;

Described C₁-C ₆Alkyl and C₁-C ₄Alkoxy base is also randomly by OCH₃Or OCH₂CH ₃Replace;

G is G₁、G ₂、R _1a、R _1b、R _1c、R _1d、R _1e、Ar ₁、Ar ₂Or Ar₃ Wherein

G ₁Randomly by an amino, C₁-C ₃The C that alkyl amino or dialkyl amino group replace₁-C ₆Alkyl, described dialkyl amino group comprise 2 can be identical or different C₁-C ₄Alkyl group; Perhaps

G ₁C₃-C ₈The Diaminoalkyl group;

G ₂Be saturated, undersaturated or aromatic 5-or the 6-unit ring that comprises 1-3 the ring hetero atom that is independently selected from N, O and S, it randomly is independently selected from F, Cl, OH, O (C₁-C ₃Alkyl), OCH₃、OCH ₂CH ₃、CH ₃C(＝O)NH、CH ₃C(＝O)O、CN、CF ₃Replace with 1-3 substituting group of 5 yuan of aromatic heterocycle groups that comprise 1-4 the ring hetero atom that is independently selected from N, O and S;

R _1aMethyl, randomly by 1-3 fluorine atom or 1-3 chlorine atom, perhaps OH, ring propoxyl group or C₁-C ₃Alkoxyl replaces, wherein said ring propoxyl group group or described C₁-C ₃The C of alkoxy base₁-C ₃Moieties is randomly replaced by a hydroxyl or methoxy group, and wherein said C₁-C ₄Whole C in the alkoxyl₃-alkyl group is randomly further replaced by another OH group;

R _1bCH (CH₃)-C _1-3Alkyl or C₃-C ₆Cycloalkyl, described alkyl and group of naphthene base randomly are independently selected from F, Cl, Br, I, OH, OCH₃Replace with 1-3 the substituting group of CN;

R _1c(CH₂) _nO _mR '; Wherein

M is 0 or 1; And wherein

When m was 0, n was 1 or 2;

When m was 1, n was 2 or 3;

R ' is C₁-C ₆Alkyl, it randomly is independently selected from F, Cl, OH, OCH₃、OCH ₂CH ₃And C₃-C ₆The 1-3 of cycloalkyl substituting group replaces;

R _1dBe C (A) (A ') (B)-; Wherein

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

A and A ' are H or C independently_1-4Alkyl is randomly replaced by one or two OH group; Perhaps

A forms 3 yuan of-6 yuan of saturated rings with A ' with the carbon atom that links to each other with them;

R _1eBe

Wherein

Q is 1 or 2;

R ₂And R₃Be independently of one another: H, F, Cl, Br, CH₃、CH ₂F、CHF ₂、CF ₃OCH ₃、OCH ₂F、OCHF ₂、OCF ₃, ethyl, n-pro-pyl, isopropyl, cyclopropyl, isobutyl group, sec-butyl, the tert-butyl group or mesyl;

R ₄Be: H, F, Cl, Br, CH₃、CH ₂F、CHF ₂、CF ₃OCH ₃、OCH ₂F、OCHF ₂、OCF ₃, ethyl, n-pro-pyl, isopropyl, cyclopropyl, isobutyl group, sec-butyl, the tert-butyl group, mesyl, nitro, acetylamino, amidino groups, cyano group, carbamoyl, methylamino formoxyl, formyl-dimethylamino, 1,3,4-oxadiazole-2-base, 5-methyl isophthalic acid, 3,4-oxadiazole, 1,3,4-thiadiazoles, 5-methyl isophthalic acid, 3,4-thiadiazoles, 1H-TETRAZOLE base, N-morpholinyl carbonyl amino, N-morpholinyl sulfonyl and N-pyrrolidinyl carbonyl are amino;

R ₅H, F, Cl or methyl;

R ₆H, F, Cl or methyl;

Ar ₁Be

Wherein

U and V are N, CR independently₂Or CR₃；

R ₂、R ₃And R₄Be independently: H, F, Cl, Br, CH₃、CH ₂F、CHF ₂、CF ₃OCH ₃、OCH ₂F、OCHF ₂、OCF ₃, ethyl, n-pro-pyl, isopropyl, cyclopropyl, isobutyl group, sec-butyl, the tert-butyl group, acetylamino, amidino groups, cyano group, carbamoyl, methylamino formoxyl, formyl-dimethylamino, 1,3,4-oxadiazole-2-base, 5-methyl isophthalic acid, 3,4-oxadiazolyl, 1,3,4-thiadiazolyl group, 5-methyl isophthalic acid, 3,4-thiadiazolyl group, 1H-TETRAZOLE base, N-morpholinyl carbonyl amino, N-morpholinyl sulfonyl, N-pyrrolidinyl carbonyl amino, and mesyl;

R ₅And R₆Be H, F, Cl or methyl independently;

Ar ₂Be

Wherein

Dotted line represents the optional pro forma position of second two key of ring;

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

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

When U be-during N=, V is-CH=,-CCl=, or-N=;

R ₇H or methyl;

R ₈H, acetylamino, methyl, F or Cl;

Ar ₃Be

Wherein

U is-NH-,-NCH₃-or-O-;

R ₇And R₈Be H, F, Cl or methyl independently.

Except herein to group G, R⁰, outside the definition that provides of X, Y and Z, comprise that chemistry and pharmaceutical field technical staff can thinkable other replacements.

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

In some embodiments, the invention provides the compound of formula I, wherein G is R_1a、R _1b、R _1c、R _1d、R _1e、Ar ₁、Ar ₂Or Ar₃ Further or in other the embodiment, G is R_1a、R _1b、R _1c、R _1dOr R_1e Further or in other the embodiment, G is R_1a Further or in other the embodiment, G is R_1b Further or in other the embodiment, G is R_1c Further or in other the embodiment, G is R_1d Further or in other the embodiment, G is R_1e Further or in other the embodiment, G is Ar₁、Ar ₂Or Ar₃ Further or in other the embodiment, G is Ar₁ Further or in other the embodiment, G is Ar₂ Further or in other the embodiment, G is Ar₃。

Compound or the acceptable salt of their pharmacy of formula I are provided in some embodiments. Further or in other the embodiment, provide the compound of formula I or their solvate herein. Further or in other the embodiment, provide the compound of formula I or their polymorphs body herein. Further or in other the embodiment, provide the compound of formula I or their ester herein. Further or in other the embodiment, provide the compound of formula I or their acid amides herein. Further or in other the embodiment, provide the compound of formula I or their dynamic isomer herein. Further or in other the embodiment, provide the compound of formula I or their prodrug herein.

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. In some embodiments, X is CH₂F. In some embodiments, X is CHF₂ In some embodiments, X is CF₃ In some embodiments, 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、C ₁-C ₃Alkyl, phenyl, pyridine radicals, pyrrole radicals, pyrazolyl, described phenyl, pyridine radicals, pyrrole radicals and pyrazolyl group are randomly by F, Cl, Br, I, acetyl group, methyl, CN, NO₂、CO ₂H、C ₁-C ₃Alkyl, C₁-C ₃Alkoxyl, C₁-C ₃Alkyl-C (=O)-, C₁-C ₃Alkyl-C (=S)-, C₁-C ₃Alkoxy-C (=S)-, C₁-C ₃Alkyl-C (=O) O-, C₁-C ₃Alkyl-O-(C=O)-, C₁-C ₃Alkyl-C (=O) NH-, C₁-C ₃Alkyl-C (=NH) NH-, C₁-C ₃Alkyl-NH-(C=O)-, two-C₁-C ₃Alkyl-N-(C=O)-, C₁-C ₃Alkyl-C (=O) N (C₁-C ₃Alkyl)-, C₁-C ₃Alkyl-S (=O)₂NH-or trifluoromethyl replace; And Z is H or F. Further or in other the embodiment, G is G₁Or G₂, and R⁰F, Cl, C₁-C ₄Alkyl or C₁-C ₄Alkoxyl, described C₁-C ₄Alkyl group and described C₁-C ₄The C of alkoxy base₁-C ₄Moieties is randomly by F, Cl, OCH₃Or OCH₂CH ₃Replace. Further or in other the embodiment, G is G₁Or G₂, and R⁰H, F, Cl, C₁-C ₄Alkyl, methoxyl group, ethyoxyl or 2-methoxyl group-ethyoxyl.

In some embodiments, G₁It is N-methyl-2-amino ethyl. Further or in other the embodiment, G₁(CH₃) ₂N-CH ₂CH ₂-NH-(CH ₂) _n-, wherein n is 1,2 or 3. Further or in other the embodiment, G₁(CH₃) ₂N-CH ₂CH ₂-NH-(CH ₂) _n-, wherein n is 1,2 or 3, and X is F. Further or in other the embodiment, G₁(CH₃) ₂N-CH ₂CH ₂-NH-(CH ₂) _n-, wherein n be 1,2 or 3, X be F, and Z is F.

In some embodiments, G₂1-piperidyl, 2-piperidyl, 3-piperidyl or 4-piperidyl. Further or in other the embodiment, G₂Morpholinyl, 1-piperazinyl or 2-piperazinyl.

In some embodiments, G is R_1a、R _1b、R _1c、R _1d、R _1e、Ar ₁、Ar ₂Or Ar₃, and X is F, Cl or CH₃ Further or in other the embodiment, G is R_1a、R _1b、R _1c、R _1d、R _1e、Ar ₁、Ar ₂Or Ar₃, X is F, Cl or CH₃, and Y is I, Br, Cl, CF₃Or C₁-C ₃Alkyl. Further or in other the embodiment, G is R_1a、R _1b、R _1c、R _1d、R _1e、Ar ₁、Ar ₂Or Ar₃, X is F, Cl or CH₃, Y is I, Br, Cl, CF₃Or C₁-C ₃Alkyl, and Z is H or F.

Further or in other the embodiment, G is R_1a、R _1b、R _1c、R _1d、R _1e、Ar ₁、Ar ₂Or Ar₃, and R⁰F, Cl, C₁-C ₄Alkyl or C₁-C ₄Alkoxyl, described C₁-C ₄Alkyl group and described C₁-C ₄The C of alkoxy base₁-C ₄Moieties is randomly by F, Cl, OCH₃Or OCH₂CH ₃Replace. Further or in other the embodiment, G is R_1a、R _1b、R _1c、R _1d、R _1e、Ar ₁、Ar ₂Or Ar₃, and R⁰H, F, Cl, C₁-C ₄Alkyl, methoxyl group, ethyoxyl or 2-methoxyl group-ethyoxyl.

In some embodiments, G is R_1a And Z is F. Further or in other the embodiment, G is R_1a, R wherein_1aCH₃，R ⁰H; And Y is Br, I, CF₃Or CH₃ In some embodiments, G is R_1bAnd Z is F. Further or in other the embodiment, G is R_1b, Z is F, and R⁰H, F or OCH₃ Further or in other the embodiment, G is R_1b, Z is F, R⁰H, F or OCH₃, and X is F or CH₃ Further or in other the embodiment, G is R_1b, Z is F, R⁰H, F or OCH₃, X is F or CH₃, and Y is Br, I or CH₃ Further or in other the embodiment, G is R_1b, R wherein_1bC₃-C ₆Cycloalkyl. Further or in other the embodiment, G is R_1b, R wherein_1bSubstituted C₃-C ₆Cycloalkyl. Further or in other the embodiment, G is R_1b, R wherein_1bUnsubstituted C₃-C ₆Cycloalkyl. Further or in other the embodiment, G is R_1b, R wherein_1bUnsubstituted C₃-C ₆Cycloalkyl and R⁰H. Further or in other the embodiment, G is R_1b, R wherein_1bIsopropyl or cyclopropyl.

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

In some embodiments, G is R_1d, and R⁰Fluorine, chlorine, methyl, ethyl, propyl group, isopropyl, sec-butyl, isobutyl group, the tert-butyl group, cyclopropyl, cyclobutyl, methyl fluoride, methoxyl group, fluorine methoxyl group, methylamino or dimethylamino. Further or in other the embodiment, G is R_1d，R ⁰Be fluorine, chlorine, methyl, ethyl, propyl group, isopropyl, sec-butyl, isobutyl group, the tert-butyl group, cyclopropyl, cyclobutyl, methyl fluoride, methoxyl group, fluorine methoxyl group, methylamino or dimethylamino, and X is F, Cl, CH₃Perhaps single methyl fluoride, difluoromethyl or trifluoromethyl. Further or in other the embodiment, G is R_1d，R ⁰Be fluorine, chlorine, methyl, ethyl, propyl group, isopropyl, sec-butyl, isobutyl group, the tert-butyl group, cyclopropyl, cyclobutyl, methyl fluoride, methoxyl group, fluorine methoxyl group, methylamino or dimethylamino, X is F, Cl, CH₃Perhaps single methyl fluoride, difluoromethyl or trifluoromethyl, and Y is I, Br, Cl or single methyl fluoride, difluoromethyl or trifluoromethyl. Further or in other the embodiment, G is R_1d，R ⁰Be fluorine, chlorine, methyl, ethyl, propyl group, isopropyl, sec-butyl, isobutyl group, the tert-butyl group, cyclopropyl, cyclobutyl, methyl fluoride, methoxyl group, fluorine methoxyl group, methylamino or dimethylamino, X is F, Cl, CH₃Perhaps 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 the embodiment, G is R_1dAnd R⁰F, Cl, methyl, ethyl, methoxyl group, ethyoxyl or 2-methoxyl group-ethyoxyl.

Further or in other the embodiment, G is R_1d，R ⁰Be F, Cl, methyl, ethyl, methoxyl group, ethyoxyl or 2-methoxyl group-ethyoxyl, and X is F, Cl or CH₃ Further or in other the embodiment, G is R_1d，R ⁰Be F, Cl, methyl, ethyl, methoxyl group, ethyoxyl or 2-methoxyl group-ethyoxyl, X is F, Cl or CH₃, and Y is I, Br, Cl or single methyl fluoride, difluoromethyl or trifluoromethyl. Further or in other the embodiment, G is R_1d，R ⁰Be F, Cl, methyl, ethyl, methoxyl group, ethyoxyl or 2-methoxyl group-ethyoxyl, X is F, Cl or CH₃, Y is I, Br, Cl or single methyl fluoride, difluoromethyl or trifluoromethyl, and Z is H or F. Further or in other the embodiment, G is R_1dAnd R⁰H; X is F, Cl, CH₃Perhaps single methyl fluoride, difluoromethyl or trifluoromethyl. Further or in other the embodiment, G is R_1d，R ⁰H; X is F, Cl, CH₃Perhaps single methyl fluoride, difluoromethyl or trifluoromethyl, and Y is I, Br, Cl or single methyl fluoride, difluoromethyl or trifluoromethyl. Further or in other the embodiment, G is R_1d，R ⁰H; X is F, Cl, CH₃Perhaps 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 the embodiment, G is R_1d, R wherein_1dThat C (A) (A ') is C₁-C ₆The group of cycloalkyl. Further or in other the embodiment, G is R_1d, R wherein_1dThat C (A) (A ') is C₁-C ₆Cycloalkyl and B are the group of H. Further or in other the embodiment, G is R_1d, R wherein_1dThat C (A) (A ') is C₁-C ₆Cycloalkyl and B are methyl, ethyl, 2-hydroxyl ethyl, n-pro-pyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 3, the group of 4-dihydroxy butyl, isopropyl, 1-methyl-2-hydroxyl ethyl, normal-butyl, sec-butyl, isobutyl group or 2-hydroxymethyl-3-hydroxypropyl.

Further or in other the embodiment, G is R_1d, R wherein_1dThat C (A) (A ') is C₁-C ₆Cycloalkyl and B are the group of 2,3-dihydroxypropyl or 3,4-dihydroxy butyl. Further or in other the embodiment, G is R_1d, R wherein_1dThat C (A) (A ') is C₁-C ₆Cycloalkyl and B are the group of 2,3-dihydroxypropyl or 3,4-dihydroxy butyl, and wherein the chiral carbon among the B is in the R configuration. Further or in other the embodiment, G is R_1d, R wherein_1dThat C (A) (A ') is C₁-C ₆Cycloalkyl and B are the group of 2,3-dihydroxypropyl or 3,4-dihydroxy butyl, and wherein the chiral carbon among the B is in the S configuration. Further or in other the embodiment, G is R_1d, R wherein_1dThat C (A) (A ') is C₁-C ₆Cycloalkyl and B are the methyl that is randomly replaced by an OH group, the C that is perhaps randomly replaced by one or two OH group₂-C ₄The group of alkyl. Further or in other the embodiment, G is R_1d, R wherein_1dThat C (A) (A ') is C₁-C ₆The group of cycloalkyl and R⁰Fluorine, chlorine, methyl, ethyl, propyl group, isopropyl, sec-butyl, isobutyl group, the tert-butyl group, cyclopropyl, cyclobutyl, methyl fluoride, methoxyl group, fluorine methoxyl group, methylamino or dimethylamino. Further or in other the embodiment, G is R_1d, R wherein_1dThat C (A) (A ') is C₁-C ₆The group of cycloalkyl and R⁰F, Cl, methyl, ethyl, methoxyl group, ethyoxyl or 2-methoxyl group-ethyoxyl. Further or in other the embodiment, G is R_1d, R wherein_1dThat C (A) (A ') is C₁-C ₆The group of cycloalkyl and R⁰H; X is F, Cl, CH₃Perhaps single methyl fluoride, difluoromethyl or trifluoromethyl.

Further or in other the embodiment, the invention provides the composition that comprises formula I compound, wherein G is R_1d, R wherein_1dThat C (A) (A ') is C₁-C ₆Cycloalkyl and B are the group of 2,3-dihydroxypropyl or 3,4-dihydroxy butyl, and wherein the chiral carbon among the B is in the R configuration, the essentially no S isomers of described composition. Further or in other the embodiment, the invention provides the composition that comprises formula I compound, wherein G is R_1d, R wherein_1dThat C (A) (A ') is C₁-C ₆Cycloalkyl and B are the group of 2,3-dihydroxypropyl, and wherein the chiral carbon among the B is in the R configuration, the essentially no S isomers of described composition. Further or in other the embodiment, the invention provides the composition that comprises formula I compound, wherein G is R_1d, R wherein_1dThat C (A) (A ') is C₁-C ₆Cycloalkyl and B are the group of 3,4-dihydroxy butyl, and wherein the chiral carbon among the B is in the R configuration, the essentially no S isomers of described composition. Further or in other the embodiment, the invention provides the composition that comprises formula I compound, wherein G is R_1d, R wherein_1dThat C (A) (A ') is C₁-C ₆Cycloalkyl and B are the group of 2,3-dihydroxypropyl or 3,4-dihydroxy butyl, and wherein the chiral carbon among the B is in the S configuration, the essentially no R isomers of described composition. Further or in other the embodiment, the invention provides the composition that comprises formula I compound, wherein G is R_1d, R wherein_1dThat C (A) (A ') is C₁-C ₆Cycloalkyl and B are the group of 2,3-dihydroxypropyl, and wherein the chiral carbon among the B is in the S configuration, the essentially no R isomers of described composition. Further or in other the embodiment, the invention provides the composition that comprises formula I compound, wherein G is R_1d, R wherein_1dThat C (A) (A ') is C₁-C ₆Cycloalkyl and B are the group of 3,4-dihydroxy butyl, and wherein the chiral carbon among the B is in the S configuration, the essentially no R isomers of described composition.

Further or in other the embodiment, G is R_1d, R wherein_1dThat C (A) (A ') is the group of cyclopropyl. Further or in other the embodiment, G is R_1d, R wherein_1dThat C (A) (A ') is that cyclopropyl and B are the group of H. Further or in other the embodiment, G is R_1d, R wherein_1dThat C (A) (A ') is that cyclopropyl and B are methyl, ethyl, 2-hydroxyl ethyl, n-pro-pyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 3, the group of 4-dihydroxy butyl, isopropyl, 1-methyl-2-hydroxyl ethyl, normal-butyl, sec-butyl, isobutyl group or 2-hydroxymethyl-3-hydroxypropyl. Further or in other the embodiment, G is R_1d, R wherein_1dThat C (A) (A ') is that cyclopropyl and B are 2,3-dihydroxypropyl or 3, the group of 4-dihydroxy butyl. Further or in other the embodiment, G is R_1d, R wherein_1dThat C (A) (A ') is that cyclopropyl and B are 2,3-dihydroxypropyl or 3, the group of 4-dihydroxy butyl, wherein the chiral carbon among the B is in the R configuration. Further or in other the embodiment, G is R_1d, R wherein_1dThat C (A) (A ') is that cyclopropyl and B are 2,3-dihydroxypropyl or 3, the group of 4-dihydroxy butyl, wherein the chiral carbon among the B is in the S configuration. Further or in other the embodiment, G is R_1d, R wherein_1dThat C (A) (A ') is cyclopropyl and the methyl of B for randomly being replaced by an OH group, the C that is perhaps randomly replaced by one or two OH group₂-C ₄The group of alkyl. Further or in other the embodiment, G is R_1d, R wherein_1dThat C (A) (A ') is the group of cyclopropyl and R⁰It is the group of fluorine, chlorine, methyl, ethyl, propyl group, isopropyl, sec-butyl, isobutyl group, the tert-butyl group, cyclopropyl, cyclobutyl, methyl fluoride, methoxyl group, fluorine methoxyl group, methylamino or dimethylamino. Further or in other the embodiment, G is R_1d, R wherein_1dThat C (A) (A ') is the group of cyclopropyl and R⁰F, Cl, methyl, ethyl, methoxyl group, ethyoxyl or 2-methoxyl group-ethyoxyl. Further or in other the embodiment, G is R_1d, R wherein_1dThat C (A) (A ') is the group of cyclopropyl and R⁰H; X is F, Cl, CH₃Perhaps single methyl fluoride, difluoromethyl or trifluoromethyl.

Further or in other the embodiment, the invention provides the composition that comprises formula I compound, wherein G is R_1d, R wherein_1dThat C (A) (A ') is that cyclopropyl and B are 2,3-dihydroxypropyl or 3, the group of 4-dihydroxy butyl, wherein the chiral carbon among the B is in the R configuration, the essentially no S isomers of described composition. Further or in other the embodiment, the invention provides the composition that comprises formula I compound, wherein G is R_1d, R wherein_1dThat C (A) (A ') is that cyclopropyl and B are 2, the group of 3-dihydroxypropyl, wherein the chiral carbon among the B is in the R configuration, the essentially no S isomers of described composition. Further or in other the embodiment, the invention provides the composition that comprises formula I compound, wherein G is R_1d, R wherein_1dThat C (A) (A ') is that cyclopropyl and B are 3, the group of 4-dihydroxy butyl, wherein the chiral carbon among the B is in the R configuration, the essentially no S isomers of described composition. Further or in other the embodiment, the invention provides the composition that comprises formula I compound, wherein G is R_1d, R wherein_1dThat C (A) (A ') is that cyclopropyl and B are 2,3-dihydroxypropyl or 3, the group of 4-dihydroxy butyl, wherein the chiral carbon among the B is in the S configuration, the essentially no R isomers of described composition. Further or in other the embodiment, the invention provides the composition that comprises formula I compound, wherein G is R_1d, R wherein_1dThat C (A) (A ') is that cyclopropyl and B are 2, the group of 3-dihydroxypropyl, wherein the chiral carbon among the B is in the S configuration, the essentially no R isomers of described composition. Further or in other the embodiment, the invention provides the composition that comprises formula I compound, wherein G is R_1d, R wherein_1dThat C (A) (A ') is that cyclopropyl and B are 3, the group of 4-dihydroxy butyl, wherein the chiral carbon among the B is in the S configuration, the essentially no R isomers of described composition.

In some embodiments, G is R_1eAnd n is 1. Further or in other the embodiment, G is R_1e，R ⁰H, R_4-6H, R₂And R₃Be H, F, Cl, Br, CH independently₃、CH ₂F、CHF ₂、CF ₃、OCH ₃、OCH ₂F、OCHF ₂、OCF ₃, ethyl, n-pro-pyl, isopropyl, cyclopropyl, isobutyl group, sec-butyl, the tert-butyl group and mesyl, X is that F and Y are I.

In some embodiments, G is Ar₁, Ar wherein₁It is phenyl; described phenyl randomly is selected from acetylamino, amidino groups, cyano group, carbamyl, methylcarbamoyl, dimethylamino formoxyl, 1; 3,4-oxadiazole-2-base, 5-methyl isophthalic acid, 3; 4-oxadiazolyl, 1; 3,4-thiadiazolyl group, 5-methyl isophthalic acid, 3; a group of 4-thiadiazolyl group, 1H-TETRAZOLE base, N-morpholinyl carbonyl amino, N-morpholinyl sulfonyl, N-pyrrolidinyl carbonyl amino and mesyl replaces, and randomly is independently selected from F, Cl and CH₃1-3 substituting group replace. Further or in other the embodiment, G is Ar₁, Ar wherein₁It is phenyl; described phenyl randomly is selected from acetylamino, amidino groups, cyano group, carbamyl, methylcarbamoyl, dimethylamino formoxyl, 1; 3,4-oxadiazole-2-base, 5-methyl isophthalic acid, 3; 4-oxadiazolyl, 1; 3,4-thiadiazolyl group, 5-methyl isophthalic acid, 3; a group of 4-thiadiazolyl group, 1H-TETRAZOLE base, N-morpholinyl carbonyl amino, N-morpholinyl sulfonyl, N-pyrrolidinyl carbonyl amino and mesyl replaces, and randomly is independently selected from F, Cl and CH₃1-3 substituting group replace R⁰Be H, X is that F, Cl or methyl and Y are Br, I, CF₃、C ₁-C ₃Alkyl, C₂-C ₃Thiazolinyl, C₂-C ₃Alkynyl, cyclopropyl, OCH₃、OCH ₂CH ₃Or SCH₃ In some embodiments, G is Ar₁, Ar wherein₁Be

And R wherein₂And R₃Be H, F, Cl, CH independently₃、CF ₃、OCH ₃ Further or in other the embodiment, G is Ar₁, Ar wherein₁BeAnd R wherein₂And R₃Be H, F, Cl, CH independently₃、CF ₃、OCH ₃, X is F or CH₃, Y is I, Br or Cl; And Z is F. Further or in other the embodiment, G is Ar₁, Ar wherein₁Phenyl or monosubstituted phenyl. Further or in other the embodiment, G is Ar₁, Ar wherein₁Be phenyl or monosubstituted phenyl, X is F or CH₃, Y is I, Br or Cl, Z is F; And R⁰F, methyl, ethyl, methoxyl group or 2-methoxyl group-ethyoxyl. Further or in other the embodiment, G is Ar₁, wherein U is N or CR₂And V is N. Further or in other the embodiment, G is Ar₁, wherein U is N or CR₂And V is CR. Further or in other the embodiment, G is Ar₁, wherein U is N or CR₂, V is CR, R⁰Be H, X is that F, Cl or methyl and Y are Br, I, CF₃、C ₁-C ₃Alkyl, C₂-C ₃Thiazolinyl, C₂-C ₃Alkynyl, cyclopropyl, OCH₃、OCH ₂CH ₃Or SCH₃。

In some embodiments, G is Ar₂, Ar wherein₂Be

R wherein₇H or methyl and R₈H, acetylamino, methyl, F or Cl. Further or in other the embodiment, G is Ar₂, Ar wherein₂Be

R wherein₇H or methyl, R₈H, acetylamino, methyl, F or Cl, R⁰Be H, X is F, Cl or methyl, and Y is Br, I, CF₃、C ₁-C ₃Alkyl, C₂-C ₃Thiazolinyl, C₂-C ₃Alkynyl, cyclopropyl, OCH₃、OCH ₂CH ₃Or SCH₃, and Z is F. Further or in other the embodiment, G is Ar₂, Ar wherein₂Be

Wherein U is S or O, and V is CH=, and R₈H or CH₃，R ₇H or methyl, R₈H, acetylamino, methyl, F or Cl, R⁰Be H, X is F, Cl or methyl, and Y is Br, I, CF₃、C ₁-C ₃Alkyl, C₂-C ₃Thiazolinyl, C₂-C ₃Alkynyl, cyclopropyl, OCH₃、OCH ₂CH ₃Or SCH₃And Z is F. Further or in other the embodiment, R⁰H. Further or in other the embodiment, R⁰Be H, X is that F or Cl and Y are Br, I, CH₂CH ₃Or SCH₃。

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

Further or in other the embodiment, G is R_1a, R wherein_1aAs above definition. Further or in other the embodiment, G is R_1a, and R⁰H, R wherein_1aAs above definition. Further or in other the embodiment, G is R_1aAnd R⁰As above definition except H, and R_1aAs above definition. Further or in other the embodiment, G is R_1a, R wherein_1aMethyl, single halogenated methyl, C₁-C ₃Alkoxy methyl or ring propoxyl group methyl. Further or in other the embodiment, G is R_1a, R wherein_1aMethyl, single halogenated methyl, C₁-C ₃Alkoxy methyl or ring propoxyl group methyl and R wherein⁰F, Cl, C₁-C ₃Alkyl, monochloro are for C₁-C ₃Alkyl, C₁-C ₃Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl.

Further or in other the embodiment, G is R_1b, R wherein_1bAs above definition. Further or in other the embodiment, G is R_1b, and R⁰H, R wherein_1bAs above definition. Further or in other the embodiment, G is R_1b，R ⁰That H and Z are F, R wherein_1bAs above definition. Further or in other the embodiment, G is R_1bAnd R⁰As above definition except H, and R_1bAs above definition. Further or in other the embodiment, G is R_1b, R wherein_1bBe isopropyl, 2-butyl, 2-amyl group, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl, all randomly be independently selected from F, Cl, OH and

OCH

₃1 or 2 substituting groups replace; Y is Br, I, methyl or trifluoromethyl. Further or in other the embodiment, G is R_1b, R wherein_1bBe isopropyl, 2-butyl, 2-amyl group, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl, randomly be independently selected from F, Cl, OH and

OCH

₃1 or 2 substituting groups replace; Y is Br, I, methyl or trifluoromethyl; And R⁰Be: F, Cl, C₁-C ₃Alkyl, monochloro are for C₁-C ₃Alkyl, C₁-C ₃Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl. Further or in other the embodiment, G is R_1b, R wherein_1bIsopropyl, 2-butyl, 2-amyl group, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl, all randomly by 1 Cl or by 1 or 2 OH groups replacements; And Y is Br, I, methyl or trifluoromethyl. Further or in other the embodiment, G is R_1b, R wherein_1bIsopropyl, 2-butyl, 2-amyl group, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl, all randomly by 1 Cl or by 1 or 2 OH groups replacements; Y is Br, I, methyl or trifluoromethyl; And R⁰F, Cl, C₁-C ₃Alkyl, monochloro are for C₁-C ₃Alkyl, C₁-C ₃Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl.

Further or in other the embodiment, G is R_1c, R wherein_1cAs above definition. Further or in other the embodiment, G is R_1c, and R⁰H, R wherein_1cAs above definition. Further or in other the embodiment, G is R_1cAnd R⁰As above definition except H, and R_1cAs above definition. Further or in other the embodiment, G is R_1c, and R⁰H, R wherein_1c(CH₂) _nO _mR ', wherein m is 0 or 1, and when m was 1, n was 2 or 3, and when m was 0, n was 1 or 2, and R ' is C₁-C ₆Alkyl, it randomly is independently selected from F, Cl, OH, OCH₃、OCH ₂CH ₃And C₃-C ₆The 1-3 of cycloalkyl substituting group replaces. More specifically in the embodiment of subgenus, m is that 0, n is 1 or 2, and R ' is C at another₁-C ₄Alkyl, it randomly is substituted as mentioned above. More specifically in the embodiment of subgenus, m is that 1, n is 2 or 3, and R ' is C at another₁-C ₄Alkyl, it randomly is substituted as mentioned above. At one also more specifically in the embodiment of subgenus, m is that 0, n is 1 or 2, and R ' is C₁-C ₄Alkyl, it randomly is selected from OH, OCH₃, Cl and cyclopropyl 1-3 group replace.

Further or in other the embodiment, G is R_1d, R wherein_1dAs above definition. Further or in other the embodiment, G is R_1d, and R⁰H, R wherein_1dAs above definition. Further or in other the embodiment, G is R_1dAnd R⁰As above definition except H, and R_1dAs above definition. Further or in other the embodiment, G is R_1d, and R⁰H, R wherein_1dBe C (A) (A ') (B)-, wherein B, A and A ' are H or the C that randomly replaced by one or two OH group or halogen atom independently_1-4Alkyl, perhaps the carbon atom that is attached thereto with them of A and A ' forms 3-6 unit saturated rings, described ring randomly comprises one or two hetero atom that is independently selected from O, N and S, and randomly is independently selected from one or two group replacement of methyl, ethyl, fluorine, chlorine, bromine and iodine.

Further or in other the embodiment, G is R_1e, R wherein_1eAs above definition. Further or in other the embodiment, G is R_1e, and R⁰H, R wherein_1eAs above definition. Further or in other the embodiment, G is R_1eAnd R⁰As above definition except H, and R_1eAs above definition.

Further or in other the embodiment, G is Ar₁, Ar wherein₁As above definition. Further or in other the embodiment, G is Ar₁, and R⁰H, Ar wherein₁As above definition. Further or in other the embodiment, G is Ar₁And R⁰As above definition except H, and Ar₁As above definition.

Further or in other the embodiment, G is Ar₂, Ar wherein₂As above definition. Further or in other the embodiment, G is Ar₂, and R⁰H, Ar wherein₂As above definition. Further or in other the embodiment, G is Ar₂And R⁰As above definition except H, and Ar₂As above definition.

Further or in other the embodiment, X is F, Cl or CH₃ Y is I, Br, Cl, CF₃Or C₁-C ₃Alkyl, and Z is H or F. Further or in other the embodiment, X is F, Cl or CH₃ Y is I, Br, Cl, CF₃Or C₁-C ₃Alkyl, Z are H or F, and R⁰Halogen, C₁-C ₆Alkyl, single halo C₁-C ₆Alkyl, C₃-C ₆Cycloalkyl, C₂-C ₆Thiazolinyl, C₂-C ₆Alkynyl, phenyl, monosubstituted phenyl, OR₃、O-C(＝O)R ₄Or C (=O) OR₅ Further or in other the embodiment, X is F, Cl or CH₃ Y is I, Br, Cl, CF₃Or C₁-C ₃Alkyl, Z are H or F, and R⁰Furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrole radicals or pyrazolyl. Further or in other the embodiment, X is F, Cl or CH₃ Y is I, Br, Cl, CF₃Or C₁-C ₃Alkyl, Z are H or F, and R⁰F, Cl, C₁-C ₄Alkyl, C₁-C ₃Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl.

At another more specifically in the embodiment of subgenus, R_1dBe cycloalkyl or 1-alkyl-cycloalkyl, wherein said 1-alkyl group randomly replaces by one or two OH group or by one or two halogen atom.

At another more specifically in the embodiment of subgenus, R⁰Halogen, C₁-C ₆Alkyl, single halo C₁-C ₆Alkyl, C₃-C ₆Cycloalkyl, C₂-C ₆Thiazolinyl, C₂-C ₆Alkynyl, phenyl, monosubstituted phenyl, OR₃、O-C(＝O)R ₄Or C (=O) OR₅ And R_1dBe cycloalkyl or 1-alkyl-cycloalkyl, wherein said 1-alkyl group randomly replaces by one or two OH group or by one or two halogen atom.

At another more specifically in the embodiment of subgenus, R⁰Furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrole radicals or pyrazolyl; And R_1dBe cycloalkyl or 1-alkyl-cycloalkyl, wherein said 1-alkyl group randomly replaces by one or two OH group or by one or two halogen atom.

At another more specifically in the embodiment of subgenus, R_1dBe cycloalkyl or 1-alkyl-cycloalkyl, wherein said 1-alkyl group is randomly replaced by one or two OH group, and wherein Y is Br, I, methyl or trifluoromethyl. At another more specifically in the embodiment of subgenus, R_1dBe cycloalkyl or 1-alkyl-cycloalkyl, wherein said 1-alkyl group is randomly replaced by one or two fluorine atom or chlorine atom, and wherein Y is Br, I, methyl or trifluoromethyl. At another more specifically in the embodiment of subgenus, R_1dBe cycloalkyl or (1-alkyl (alleyl))-cycloalkyl, wherein said 1-alkyl group is randomly replaced by one or two OH group, and R wherein⁰' be: F, Cl, C₁-C ₃Alkyl, monochloro are for C₁-C ₃Alkyl, C₁-C ₃Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl. At another more specifically in the embodiment of subgenus, R_1dBe tetrahydrofuran base, tetrahydro-thienyl, pyrrolidinyl, piperidyl, piperazinyl or morpholinyl, randomly be substituted as mentioned above separately, and wherein Y is Br, I, methyl or trifluoromethyl. At another more specifically in the embodiment of subgenus, R_1dOxazole alkyl, thiazolidinyl, isoxazole alkyl, isothiazole alkyl, tetrahydrofuran base, tetrahydro-thienyl, pyrrolidinyl, piperidyl, piperazinyl or morpholinyl, randomly be substituted as mentioned above separately, and wherein Y is Br, I, methyl or trifluoromethyl. At another more specifically in the embodiment of subgenus, R_1dBe cyclopropyl or 1-alkyl-cyclopropyl, wherein said 1-alkyl group is randomly replaced by one or two OH group, and R wherein⁰' be F, Cl, methyl, ethyl, chloromethyl, C₁-C ₂Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl. In one even more particular embodiment, R_1dIt is 1-(monohydroxy alkyl) cycloalkyl. In another more particular embodiment, R_1d1-(monohydroxy alkyl) cycloalkyl, wherein R⁰' be F, Cl, methyl, ethyl, chloromethyl, C₁-C ₂Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl. In one even more particular embodiment, R_1dIt is 1-(dihydroxy alkyl) cycloalkyl. In another more particular embodiment, R_1d1-(dihydroxy alkyl) cycloalkyl, wherein R⁰' be F, Cl, methyl, ethyl, chloromethyl, C₁-C ₂Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl.

At one more specifically in the embodiment of subgenus, U is CR₂And V is N. More specifically in the embodiment of subgenus, U and V are N at another. At one more specifically in the embodiment of subgenus, U is CR₂And V is CR₃。

The invention provides the compound of formula I at one also more specifically in the embodiment of subgenus, wherein G is Ar₁And Ar₁Phenyl or monosubstituted phenyl, R⁰F, methyl, ethyl, C₁-C ₃Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl; X is F, Cl or CH₃ Y is I; And Z is F. In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is Ar₁, Ar wherein₁Phenyl or monosubstituted phenyl, R⁰Halogen, C₁-C ₆Alkyl, C₃-C ₆Cycloalkyl, C₂-C ₆Thiazolinyl, C₂-C ₆Alkynyl, all such alkyl, cycloalkyl, thiazolinyl and alkynyl group randomly is independently selected from 1-3 substituting group replacement of halogen, OH, CN, cyanogen methyl, nitro, phenyl and trifluoromethyl; Perhaps R⁰Phenyl, OR₃, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrole radicals or pyrazolyl. The invention provides the compound of formula I at one more specifically in the embodiment of subgenus, wherein A is Ar₁, Ar wherein₁Phenyl or monosubstituted phenyl, R⁰F, Cl, C₁-C ₃Alkyl, C₁-C ₃Alkoxyl, 2-methoxy ethoxy, C₂-C ₃Thiazolinyl, C₂-C ₃Alkynyl, 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-C ₃Alkyl; And Z is F.

Also more specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is Ar₁, Ar wherein₁Phenyl or monosubstituted phenyl, R⁰H; X is F, Cl or CH₃ Y is Br or I; And Z is F.

In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is Ar₂, Ar wherein₂Be 2-thienyl, 2-furyl, 3-thienyl, 3-furyl, 2-pyrrole radicals or 3-pyrrole radicals, all randomly replaced by methoxycarbonyl, methylcarbamoyl, acetylamino, acetyl group, methyl, ethyl, trifluoromethyl or halogen. The invention provides the compound of formula I at one more specifically in the embodiment of subgenus, wherein G is Ar₂, Ar wherein₂Be 2-thienyl, 2-furyl, 3-thienyl, 3-furyl, 2-pyrrole radicals or 3-pyrrole radicals, all randomly replaced by methoxycarbonyl, methylcarbamoyl, acetylamino, acetyl group, methyl, ethyl, trifluoromethyl or halogen; R⁰Not H; X is F, Cl or CH₃ Y is I, Br, Cl, CF₃Or C₁-C ₃Alkyl, and Z is H or F. In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is Ar₂, Ar wherein₂Be 2-thienyl, 2-furyl, 3-thienyl, 3-furyl, 2-pyrrole radicals or 3-pyrrole radicals, all randomly replaced by methoxycarbonyl, methylcarbamoyl, acetylamino, acetyl group, methyl, ethyl, trifluoromethyl or halogen; R⁰F, Cl, C₁-C ₃Alkyl, monochloro are for C₁-C ₃Alkyl, C₁-C ₃Alkoxyl, trifluoromethoxy, methoxyl group-methoxyl group or 2-methoxyl group-ethyoxyl; X is F, Cl or CH₃ Y is I, Br, Cl, CF₃Or C₁-C ₃Alkyl, and Z is H or F. In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is Ar₂, Ar wherein₂Be 2-thienyl, 2-furyl, 3-thienyl, 3-furyl, 2-pyrrole radicals or 3-pyrrole radicals, all randomly replaced by methoxycarbonyl, methylcarbamoyl, acetylamino, acetyl group, methyl, ethyl, trifluoromethyl or halogen; R⁰H; X is F, Cl or CH₃ Y is I, Br, Cl, CF₃Or C₁-C ₃Alkyl, and Z is H or F. In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is Ar₂, Ar wherein₂Be thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrole radicals or pyrazolyl, all randomly replaced by methoxycarbonyl, methylcarbamoyl, acetylamino, acetyl group, methyl, ethyl, trifluoromethyl or halogen; R⁰H or methoxyl group; X is F, Cl or CH₃ Y is I, Br, Cl, CF₃Or C₁-C ₃Alkyl, 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 invention provides the compound or pharmaceutically acceptable salt thereof of formula I, it is selected from:

Wherein 2-OH carbon is in the R configuration.

Wherein 2-OH carbon is in the S configuration.

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

In some embodiments, the invention provides the composition that comprises the formula I compound that is selected from compound shown below, wherein 2-OH carbon is in the R configuration, the essentially no S-isomers of described composition.

In some embodiments, the invention provides the composition that comprises the formula I compound that is selected from compound shown below, wherein 2-OH carbon is in the S configuration, the essentially no R-isomers of described composition.

In some embodiments, the invention provides the compound of formula I, wherein Y is phenyl, pyridine radicals or pyrazolyl. In the embodiment of another subgenus, the invention provides the compound of formula I, wherein Y is substituted phenyl, pyridine radicals or pyrazolyl. In the embodiment of another subgenus, the invention provides the compound of formula I, wherein Y is Br or I. In the embodiment of a subgenus, the invention provides the compound of formula I, wherein G is 1-piperidyl, 2-piperidyl, 3-piperidyl or 4-piperidyl. In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is 1-piperazinyl or 2-piperazinyl. In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is morpholinyl. In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is N-methyl-2-amino ethyl. In the embodiment of a subgenus, the invention provides the compound of formula I, wherein G is N-methyl-3-amino-n-pro-pyl. In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is (CH₃) ₂N-CH ₂CH ₂-NH-(CH ₂) _n-, wherein n is 1,2 or 3. In the embodiment of another subgenus, the invention provides the compound of formula I, wherein G is (CH₃CH ₂) ₂N-CH ₂CH ₂-NH-(CH ₂) _n-, wherein n is 1 or 2. The invention provides the compound of formula I at one more specifically in the embodiment of subgenus, wherein G is 1-piperidyl, 2-piperidyl, 3-piperidyl or 4-piperidyl; R⁰H, halogen or methoxyl group; X is F; And Y is I. More specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is 1-piperazinyl or 2-piperazinyl; R⁰H, halogen or methoxyl group; X is F; And Y is I. More specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is morpholinyl; R⁰H, halogen or methoxyl group; X is F; And Y is I. More specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is N-methyl-2-amino ethyl; R⁰H, halogen or methoxyl group; X is F; And Y is I. More specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is N-methyl-3-amino-n-pro-pyl; R⁰H, halogen or methoxyl group; X is F; And Y is I. More specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is (CH₃) ₂N-CH ₂CH ₂-NH-(CH ₂) _n-, wherein n is 1,2 or 3; R⁰H, halogen or methoxyl group; X is F; And Y is I. More specifically in the embodiment of subgenus, the invention provides the compound of formula I at another, wherein G is (CH₃CH ₂) ₂N-CH ₂CH ₂-NH-(CH ₂) _n-, wherein n is 1 or 2; R⁰H, halogen or methoxyl group; X is F; And Y is I.

In some embodiments, the invention provides pharmaceutical composition, it comprises compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or the prodrug of formula I. In some embodiments, described pharmaceutical composition also comprises at least a pharmaceutically acceptable carrier.

In some embodiments, the invention provides pharmaceutical composition, it comprises and is selected from:

Compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug. In some embodiments, described pharmaceutical composition also comprises at least a pharmaceutically acceptable carrier. In some embodiments, described compound is in the R configuration. In some embodiments, described compound is in the R configuration, its essentially no S-isomers. In some embodiments, described compound is in the S configuration.

In some embodiments, described compound is in the S configuration, essentially no R-isomers. In some embodiments, described compound is:

In some embodiments, described compound is:

In some embodiments, described compound is:

In some embodiments, described compound is:

The tabulation of the limiting examples of formula I compound

Following table is depicted as the example of each compound that the invention provides or relate to. Never these examples should be interpreted as limitative examples.

Table 1 is depicted as the embodiment of formula I compound of the present invention, wherein R⁰As defined herein, G is R_1a, R wherein_1aSuch as definition in this table, and in this table, define X, Y and Z.

Table 1

Table 2 is depicted as the embodiment of formula I compound of the present invention, wherein R⁰As defined herein, G is R_1b, R wherein_1bSuch as definition in this table, and in this table, define X, Y and Z.

Table 2

Table 3 is depicted as the embodiment of formula I compound of the present invention, wherein R⁰As defined herein, G is R_1c, R wherein_1cSuch as definition in this table, and in this table, define X, Y and Z.

Table 3

R _1c	X	Y	Z
R _1c	X	Y	Z			3-(CH ₃-SO ₂-NH)-phenyl
CH ₂CH ₂OH	F	3-(CH ₃-SO ₂-NH)-phenyl	F			3-(CH ₃-SO ₂-NH)-phenyl
CH ₂CH ₂OH	F	3-(CH ₃-SO ₂-NH)-phenyl	F	CH ₂CH ₂OH	Cl	3-(CH ₃-SO ₂-NH)-phenyl	F
CH ₂CH ₂OH	F	Phenyl	F	CH ₂CH ₂OH	Cl	3-(CH ₃-SO ₂-NH)-phenyl	F
CH ₂CH ₂OH	F	Phenyl	F	CH ₂CH ₂OH	Cl	Phenyl	F
CH ₂CH ₂OH	F	Phenyl	F	CH ₂CH ₂OH	Cl	Phenyl	F
CH ₂CH ₂OH	F	Phenyl	F	CH ₂CH ₂OH	Cl	The 3-pyridine radicals	F
CH ₂CH ₂OH	F	The 3-pyridine radicals	F	CH ₂CH ₂OH	Cl	The 3-pyridine radicals	F
CH ₂CH ₂OH	F	The 3-pyridine radicals	F	CH ₂CH ₂OH	Cl	The 4-pyridine radicals	F
		Pyrazolyl		CH ₂CH ₂OH	Cl	The 4-pyridine radicals	F
		Pyrazolyl		CH ₂CH ₂CH ₂O H	F	Pyrazolyl	F
CH ₂CH ₂CH ₂O H	Cl	The 4-pyridine radicals	F	CH ₂CH ₂CH ₂O H	F	Pyrazolyl	F
CH ₂CH ₂CH ₂O H	Cl	The 4-pyridine radicals	F	CH ₂CH ₂CH ₂O H	F	The 4-pyridine radicals	F
CH ₂CH ₂CH ₂O H	Cl	2-(CH ₃-SO ₂-NH)-phenyl	F	CH ₂CH ₂CH ₂O H	F	The 4-pyridine radicals	F
CH ₂CH ₂CH ₂O H	Cl	2-(CH ₃-SO ₂-NH)-phenyl	F	CH ₂CH ₂CH ₂O H	F	3-(CH ₃-SO ₂-NH)-phenyl	F

R _1c	X	Y	Z
R _1c	X	Y	Z	CH ₂CH ₂CH ₂O H	Cl	3-(CH ₃-SO ₂-NH)-phenyl	F
CH ₂CH ₂CH ₂O H	F	3-(CH ₃-SO ₂-NH)-phenyl	F	CH ₂CH ₂CH ₂O H	Cl	3-(CH ₃-SO ₂-NH)-phenyl	F
CH ₂CH ₂CH ₂O H	F	3-(CH ₃-SO ₂-NH)-phenyl	F	CH ₂CH ₂CH ₂O H	Cl	Phenyl	F
		Phenyl		CH ₂CH ₂CH ₂O H	Cl	Phenyl	F
		Phenyl		(CH ₂) ₄OH	F	Phenyl	F
(CH ₂) ₄OH	Cl	The 3-pyridine radicals	F	(CH ₂) ₄OH	F	Phenyl	F
(CH ₂) ₄OH	Cl	The 3-pyridine radicals	F	(CH ₂) ₄OH	F	The 3-pyridine radicals	F
(CH ₂) ₄OH	Cl	The 4-pyridine radicals	F	(CH ₂) ₄OH	F	The 3-pyridine radicals	F
(CH ₂) ₄OH	Cl	The 4-pyridine radicals	F	(CH ₂) ₄OH	F	Pyrazolyl	F
(CH ₂) ₄OH	Cl	Pyrazolyl	F	(CH ₂) ₄OH	F	Pyrazolyl	F
(CH ₂) ₄OH	Cl	Pyrazolyl	F	(CH ₂) ₄OH	F	The 4-pyridine radicals	F
(CH ₂) ₄OH	Cl	The 4-pyridine radicals	F	(CH ₂) ₄OH	F	The 4-pyridine radicals	F
(CH ₂) ₄OH	Cl	The 4-pyridine radicals	F			2-(CH ₃-SO ₂-NH)-phenyl
CH ₂CH ₂OCH ₃	F	3-(CH ₃-SO ₂-NH)-phenyl	F			2-(CH ₃-SO ₂-NH)-phenyl

R _1c	X	Y	Z
R _1c	X	Y	Z	CH ₂CH ₂OCH ₃	Cl	3-(CH ₃-SO ₂-NH)-phenyl	F

R _1c	X	Y	Z
R _1c	X	Y	Z	CH ₂CH ₂OCH ₃	F	3-(CH ₃-SO ₂-NH)-phenyl	F
CH ₂CH ₂OCH ₃	Cl	Phenyl	F	CH ₂CH ₂OCH ₃	F	3-(CH ₃-SO ₂-NH)-phenyl	F
CH ₂CH ₂OCH ₃	Cl	Phenyl	F	CH ₂CH ₂OCH ₃	F	Phenyl	F
CH ₂CH ₂OCH ₃	Cl	Phenyl	F	CH ₂CH ₂OCH ₃	F	Phenyl	F
CH ₂CH ₂OCH ₃	Cl	Phenyl	F	CH ₂CH ₂OCH ₃	F	The 3-pyridine radicals	F
CH ₂CH ₂OCH ₃	Cl	The 3-pyridine radicals	F	CH ₂CH ₂OCH ₃	F	The 3-pyridine radicals	F
CH ₂CH ₂OCH ₃	Cl	The 3-pyridine radicals	F			The 4-pyridine radicals
(CH ₂) ₃OCH ₃	F	Pyrazolyl	F			The 4-pyridine radicals
(CH ₂) ₃OCH ₃	F	Pyrazolyl	F	(CH ₂) ₃OCH ₃	Cl	Pyrazolyl	F
(CH ₂) ₃OCH ₃	F	The 4-pyridine radicals	F	(CH ₂) ₃OCH ₃	Cl	Pyrazolyl	F
(CH ₂) ₃OCH ₃	F	The 4-pyridine radicals	F	(CH ₂) ₃OCH ₃	Cl	The 4-pyridine radicals	F
(CH ₂) ₃OCH ₃	F	2-(CH ₃-SO ₂-NH)-phenyl	F	(CH ₂) ₃OCH ₃	Cl	The 4-pyridine radicals	F
(CH ₂) ₃OCH ₃	F	2-(CH ₃-SO ₂-NH)-phenyl	F	(CH ₂) ₃OCH ₃	Cl	3-(CH ₃-SO ₂-NH)-phenyl	F
(CH ₂) ₃OCH ₃	F	3-(CH ₃-SO ₂-NH)-phenyl	F	(CH ₂) ₃OCH ₃	Cl	3-(CH ₃-SO ₂-NH)-phenyl	F
(CH ₂) ₃OCH ₃	F	3-(CH ₃-SO ₂-NH)-phenyl	F	(CH ₂) ₃OCH ₃	Cl	3-(CH ₃-SO ₂-NH)-phenyl	F
		Phenyl		(CH ₂) ₃OCH ₃	Cl	3-(CH ₃-SO ₂-NH)-phenyl	F
		Phenyl		CH ₂CH ₂OEt	F	Phenyl	F

R _1c	X	Y	Z
R _1c	X	Y	Z	CH ₂CH ₂OEt	Cl	Phenyl	F
CH ₂CH ₂OEt	F	The 3-pyridine radicals	F	CH ₂CH ₂OEt	Cl	Phenyl	F
CH ₂CH ₂OEt	F	The 3-pyridine radicals	F	CH ₂CH ₂OEt	Cl	The 3-pyridine radicals	F
CH ₂CH ₂OEt	F	The 4-pyridine radicals	F	CH ₂CH ₂OEt	Cl	The 3-pyridine radicals	F
CH ₂CH ₂OEt	F	The 4-pyridine radicals	F	CH ₂CH ₂OEt	Cl	Pyrazolyl	F
CH ₂CH ₂OEt	F	Pyrazolyl	F	CH ₂CH ₂OEt	Cl	Pyrazolyl	F
CH ₂CH ₂OEt	F	Pyrazolyl	F	CH ₂CH ₂OEt	Cl	The 4-pyridine radicals	F

Table 4a and 4b are depicted as the embodiment of formula I compound of the present invention, wherein G=R_1d, Z is F, X is F, and defines R in this table_1dAnd R⁰ Every row is corresponding to different five kinds of materials in the Y position only in this table.

Table 4a

Y _a＝CH ₃；Y _b＝Br；Y _c＝I；Y _d＝Cl；

CMPD #	A，A′	B	R ⁰
CMPD #	A，A′	B	R ⁰	1(a-d)	H，H	H	OCH ₃
2(a-d)	H，H	H	NHCH ₃	1(a-d)	H，H	H	OCH ₃
2(a-d)	H，H	H	NHCH ₃	3(a-d)	H，H	H	CH ₂CH ₃
4(a-d)	H，H	H	CH ₂CH＝CH ₂	3(a-d)	H，H	H	CH ₂CH ₃
4(a-d)	H，H	H	CH ₂CH＝CH ₂	5(a-d)	H，H	H	CN
6(a-d)	H，H	H	CF ₃	5(a-d)	H，H	H	CN

CMPD #	A，A′	B	R ⁰
CMPD #	A，A′	B	R ⁰	7(a-d)	H，H	H	F
8(a-d)	H，H	H	C ₆H ₆	7(a-d)	H，H	H	F
8(a-d)	H，H	H	C ₆H ₆	9(a-d)	H，H	-CH ₂CH(OH)CH ₂OH	OCH ₃
10(a-d)	H，H	-CH ₂CH(OH)CH ₂OH	NHCH ₃	9(a-d)	H，H	-CH ₂CH(OH)CH ₂OH	OCH ₃
10(a-d)	H，H	-CH ₂CH(OH)CH ₂OH	NHCH ₃	11(a-d)	H，H	-CH ₂CH(OH)CH ₂OH	CH ₂CH ₃
12(a-d)	-(CH ₂) ₂-	-CH ₂(C ₃H ₅)	OCH ₃	11(a-d)	H，H	-CH ₂CH(OH)CH ₂OH	CH ₂CH ₃
12(a-d)	-(CH ₂) ₂-	-CH ₂(C ₃H ₅)	OCH ₃	13(a-d)	-(CH ₂) ₂-	-CH ₂(C ₃H ₅)	NHCH ₃
14(a-d)	-(CH ₂) ₂-	-CH ₂(C ₃H ₅)	CH ₂CH ₃	13(a-d)	-(CH ₂) ₂-	-CH ₂(C ₃H ₅)	NHCH ₃
14(a-d)	-(CH ₂) ₂-	-CH ₂(C ₃H ₅)	CH ₂CH ₃	15(a-d)	-(CH ₂) ₂-	CH ₃	F
16(a-d)	-(CH ₂) ₂-	-CH ₂CH ₂OH	F	15(a-d)	-(CH ₂) ₂-	CH ₃	F
16(a-d)	-(CH ₂) ₂-	-CH ₂CH ₂OH	F	17(a-d)	-(CH ₂) ₂-	-(CH ₂) ₂CH(OH)CH ₂OH	F
18(a-d)	CH ₃，H	-(CH ₂) ₂CH(OH)CH ₂OH	F	17(a-d)	-(CH ₂) ₂-	-(CH ₂) ₂CH(OH)CH ₂OH	F
18(a-d)	CH ₃，H	-(CH ₂) ₂CH(OH)CH ₂OH	F	19(a-d)	-(CH ₂) ₂-	CH ₃	OCH ₃
20(a-d)	-(C H ₂) ₂-	-CH ₂CH ₂OH	OCH ₃	19(a-d)	-(CH ₂) ₂-	CH ₃	OCH ₃
20(a-d)	-(C H ₂) ₂-	-CH ₂CH ₂OH	OCH ₃	21(a-d)	-(CH ₂) ₂-	-(CH ₂) ₂CH(OH)CH ₂OH	OCH ₃
22(a-d)	CH ₃，H	-(CH ₂) ₂CH(OH)CH ₂OH	OCH ₃	21(a-d)	-(CH ₂) ₂-	-(CH ₂) ₂CH(OH)CH ₂OH	OCH ₃
22(a-d)	CH ₃，H	-(CH ₂) ₂CH(OH)CH ₂OH	OCH ₃	23(a-d)	-(CH ₂) ₂-	CH ₃	H
24(a-d)	-(CH ₂) ₂-	-CH ₂CH ₂OH	H	23(a-d)	-(CH ₂) ₂-	CH ₃	H
24(a-d)	-(CH ₂) ₂-	-CH ₂CH ₂OH	H	25(a-d)	-(CH ₂) ₂-	-(CH ₂) ₂CH(OH)CH ₂OH	H
26(a-d)	CH ₃，H	-(CH ₂) ₂CH(OH)CH ₂OH	H	25(a-d)	-(CH ₂) ₂-	-(CH ₂) ₂CH(OH)CH ₂OH	H

CMPD #	A，A′	B	R ⁰
CMPD #	A，A′	B	R ⁰	27(a-d)	H，H	H	OCH ₃
28(a-d)	H，H	H	NHCH ₃	27(a-d)	H，H	H	OCH ₃
28(a-d)	H，H	H	NHCH ₃	29(a-d)	H，H	H	CH ₂CH ₃
30(a-d)	H，H	H	CH ₂CH＝CH ₂	29(a-d)	H，H	H	CH ₂CH ₃
30(a-d)	H，H	H	CH ₂CH＝CH ₂	31(a-d)	H，H	H	CN
32(a-d)	H，H	H	CF ₃	31(a-d)	H，H	H	CN
32(a-d)	H，H	H	CF ₃	33(a-d)	H，H	H	F
CMPD #	A，A′	B	R ⁰	33(a-d)	H，H	H	F
CMPD #	A，A′	B	R ⁰	34(a-d)	H，H	H	C ₆H ₆
35(a-d)	H，H	-CH ₂CH(OH)CH ₂OH	OCH ₃	34(a-d)	H，H	H	C ₆H ₆
35(a-d)	H，H	-CH ₂CH(OH)CH ₂OH	OCH ₃	36(a-d)	H，H	-CH ₂CH(OH)CH ₂OH	NHCH ₃
37(a-d)	H，H	-CH ₂CH(OH)CH ₂OH	CH ₂CH ₃	36(a-d)	H，H	-CH ₂CH(OH)CH ₂OH	NHCH ₃
37(a-d)	H，H	-CH ₂CH(OH)CH ₂OH	CH ₂CH ₃	38(a-d)	-(CH ₂) ₂-	-CH ₂(C ₃H ₅)	OCH ₃
39(a-d)	-(CH ₂) ₂-	-CH ₂(C ₃H ₅)	NHCH ₃	38(a-d)	-(CH ₂) ₂-	-CH ₂(C ₃H ₅)	OCH ₃
39(a-d)	-(CH ₂) ₂-	-CH ₂(C ₃H ₅)	NHCH ₃	40(a-d)	-(CH ₂) ₂-	-CH ₂(C ₃H ₅)	CH ₂CH ₃
41(a-d)	-(CH ₂) ₂-	CH ₃	F	40(a-d)	-(CH ₂) ₂-	-CH ₂(C ₃H ₅)	CH ₂CH ₃
41(a-d)	-(CH ₂) ₂-	CH ₃	F	42(a-d)	-(CH ₂) ₂-	-CH ₂CH ₂OH	F
43(a-d)	-(CH ₂) ₂-	-(CH ₂) ₂CH(OH)CH ₂OH	F	42(a-d)	-(CH ₂) ₂-	-CH ₂CH ₂OH	F
43(a-d)	-(CH ₂) ₂-	-(CH ₂) ₂CH(OH)CH ₂OH	F	44(a-d)	CH ₃，H	-(CH ₂) ₂CH(OH)CH ₂OH	F
45(a-d)	-(CH ₂) ₂-	CH ₃	OCH ₃	44(a-d)	CH ₃，H	-(CH ₂) ₂CH(OH)CH ₂OH	F

CMPD #	A，A′	B	R ⁰
CMPD #	A，A′	B	R ⁰	46(a-d)	-(CH ₂) ₂-	-CH ₂CH ₂OH	OCH ₃
47(a-d)	-(CH ₂) ₂-	-(CH ₂) ₂CH(OH)CH ₂OH	OCH ₃	46(a-d)	-(CH ₂) ₂-	-CH ₂CH ₂OH	OCH ₃
47(a-d)	-(CH ₂) ₂-	-(CH ₂) ₂CH(OH)CH ₂OH	OCH ₃	48(a-d)	CH ₃，H	-(CH ₂) ₂CH(OH)CH ₂OH	OCH ₃
49(a-d)	-(CH ₂) ₂-	CH ₃	H	48(a-d)	CH ₃，H	-(CH ₂) ₂CH(OH)CH ₂OH	OCH ₃
49(a-d)	-(CH ₂) ₂-	CH ₃	H	50(a-d)	-(CH ₂) ₂-	-CH ₂CH ₂OH	H
51(a-d)	-(CH ₂) ₂-	-(CH ₂) ₂CH(OH)CH ₂OH	H	50(a-d)	-(CH ₂) ₂-	-CH ₂CH ₂OH	H
51(a-d)	-(CH ₂) ₂-	-(CH ₂) ₂CH(OH)CH ₂OH	H	52(a-d)	CH ₃，H	-(CH ₂) ₂CH(OH)CH ₂OH	H

Table 4b

CMPD #	A，A′	B	R ⁰
CMPD #	A，A′	B	R ⁰	1(a-d)	H，H	H	The 2-furyl
2(a-d)	H， H	H		1(a-d)	H，H	H	The 2-furyl	1,2,3-triazoles-4-base
2(a-d)	H， H	H		3(a-d)	H，H	H	The 4-imidazole radicals	1,2,3-triazoles-4-base
4(a-d)	H，H	H	The 2-furyl	3(a-d)	H，H	H	The 4-imidazole radicals
4(a-d)	H，H	H	The 2-furyl	5(a-d)	H， H	H		1,2,3-triazoles-4-base
6(a-d)	H，H	H	The 4-imidazole radicals	5(a-d)	H， H	H		1,2,3-triazoles-4-base
6(a-d)	H，H	H	The 4-imidazole radicals	7(a-d)	H，H	-(CH ₂) ₂CH(OH)CH ₂OH	The 2-furyl
8(a-d)	H，H	-(CH ₂) ₂CH(OH)CH ₂OH	1,2,3-triazoles-4-base	7(a-d)	H，H	-(CH ₂) ₂CH(OH)CH ₂OH	The 2-furyl
8(a-d)	H，H	-(CH ₂) ₂CH(OH)CH ₂OH	1,2,3-triazoles-4-base	9(a-d)	H，H	-(CH ₂) ₂CH(OH)CH ₂OH	The 4-imidazole radicals
10(a-d)	-(CH ₂) ₂-	-CH ₂(C ₃H ₅)	The 2-furyl	9(a-d)	H，H	-(CH ₂) ₂CH(OH)CH ₂OH	The 4-imidazole radicals

CMPD #	A，A′	B	R ⁰
CMPD #	A，A′	B	R ⁰	11(a-d)	-(CH ₂) ₂-	-CH ₂(C ₃H ₅)	1,2,3-triazoles-4-base
12(a-d)	-(CH ₂) ₂-	-CH ₂(C ₃H ₅)	The 4-imidazole radicals	11(a-d)	-(CH ₂) ₂-	-CH ₂(C ₃H ₅)	1,2,3-triazoles-4-base
12(a-d)	-(CH ₂) ₂-	-CH ₂(C ₃H ₅)	The 4-imidazole radicals	13(a-d)	-(CH ₂) ₂-	CH ₃	The 4-thiazolyl
14(a-d)	-(CH ₂) ₂-	-CH ₂CH ₂OH	The 4-thiazolyl	13(a-d)	-(CH ₂) ₂-	CH ₃	The 4-thiazolyl
14(a-d)	-(CH ₂) ₂-	-CH ₂CH ₂OH	The 4-thiazolyl	15(a-d)	-(CH ₂) ₂-	-(CH ₂) ₂CH(OH)CH ₂OH	The 4-thiazolyl
16(a-d)	CH ₃，H	-(CH ₂) ₂CH(OH)CH ₂OH	The 4-thiazolyl	15(a-d)	-(CH ₂) ₂-	-(CH ₂) ₂CH(OH)CH ₂OH	The 4-thiazolyl
16(a-d)	CH ₃，H	-(CH ₂) ₂CH(OH)CH ₂OH	The 4-thiazolyl	17(a-d)	-(CH ₂) ₂-	CH ₃	The 2-oxazolyl
18(a-d)	-(CH ₂) ₂-	-CH ₂CH ₂OH	The 2-oxazolyl	17(a-d)	-(CH ₂) ₂-	CH ₃	The 2-oxazolyl
18(a-d)	-(CH ₂) ₂-	-CH ₂CH ₂OH	The 2-oxazolyl	19(a-d)	-(CH ₂) ₂-	-(CH ₂) ₂CH(OH)CH ₂OH	The 2-oxazolyl
CMPD #	A，A′	B	R ⁰	19(a-d)	-(CH ₂) ₂-	-(CH ₂) ₂CH(OH)CH ₂OH	The 2-oxazolyl
CMPD #	A，A′	B	R ⁰	20(a-d)	CH ₃，H	-(CH ₂) ₂CH(OH)CH ₂OH	The 2-oxazolyl
21(a-d)	H，H	H	The 2-furyl	20(a-d)	CH ₃，H	-(CH ₂) ₂CH(OH)CH ₂OH	The 2-oxazolyl
21(a-d)	H，H	H	The 2-furyl	22(a-d)	H，H	H	1,2,3-triazoles-4-base
23(a-d)	H，H	H	The 4-imidazole radicals	22(a-d)	H，H	H	1,2,3-triazoles-4-base
23(a-d)	H，H	H	The 4-imidazole radicals	24(a-d)	H，H	H	The 2-furyl
25(a-d)	H，H	H	1,2,3-triazoles-4-base	24(a-d)	H，H	H	The 2-furyl
25(a-d)	H，H	H	1,2,3-triazoles-4-base	26(a-d)	H，H	H	The 4-imidazole radicals
27(a-d)	H，H	-CH ₂CH(OH)CH ₂OH	The 2-furyl	26(a-d)	H，H	H	The 4-imidazole radicals
27(a-d)	H，H	-CH ₂CH(OH)CH ₂OH	The 2-furyl	28(a-d)	H，H	-CH ₂CH(OH)CH ₂OH	1,2,3-triazoles-4-base
29(a-d)	H，H	-CH ₂CH(OH)CH ₂OH	The 4-imidazole radicals	28(a-d)	H，H	-CH ₂CH(OH)CH ₂OH	1,2,3-triazoles-4-base

CMPD #	A，A′	B	R ⁰
CMPD #	A，A′	B	R ⁰	30(a-d)	-(CH ₂) ₂-	-CH ₂(C ₃H ₅)	The 2-furyl
31(a-d)	-(CH ₂) ₂-	-CH ₂(C ₃H ₅)	1,2,3-triazoles-4-base	30(a-d)	-(CH ₂) ₂-	-CH ₂(C ₃H ₅)	The 2-furyl
31(a-d)	-(CH ₂) ₂-	-CH ₂(C ₃H ₅)	1,2,3-triazoles-4-base	32(a-d)	-(CH ₂) ₂-	-CH ₂(C ₃H ₅)	The 4-imidazole radicals
33(a-d)	-(CH ₂) ₂-	CH ₃	The 4-thiazolyl	32(a-d)	-(CH ₂) ₂-	-CH ₂(C ₃H ₅)	The 4-imidazole radicals
33(a-d)	-(CH ₂) ₂-	CH ₃	The 4-thiazolyl	34(a-d)	-(CH ₂) ₂-	-CH ₂CH ₂OH	The 4-thiazolyl
35(a-d)	-(CH ₂) ₂-	-(CH ₂) ₂CH(OH)CH ₂OH	The 4-thiazolyl	34(a-d)	-(CH ₂) ₂-	-CH ₂CH ₂OH	The 4-thiazolyl
35(a-d)	-(CH ₂) ₂-	-(CH ₂) ₂CH(OH)CH ₂OH	The 4-thiazolyl	36(a-d)	CH ₃，H	-(CH ₂) ₂CH(OH)CH ₂OH	The 4-thiazolyl
37(a-d)	-(CH ₂) ₂-	CH ₃	The 2-oxazolyl	36(a-d)	CH ₃，H	-(CH ₂) ₂CH(OH)CH ₂OH	The 4-thiazolyl
37(a-d)	-(CH ₂) ₂-	CH ₃	The 2-oxazolyl	38(a-d)	-(CH ₂) ₂-	-CH ₂CH ₂OH	The 2-oxazolyl
39(a-d)	-(CH ₂) ₂-	-(CH ₂) ₂CH(OH)CH ₂OH	The 2-oxazolyl	38(a-d)	-(CH ₂) ₂-	-CH ₂CH ₂OH	The 2-oxazolyl
39(a-d)	-(CH ₂) ₂-	-(CH ₂) ₂CH(OH)CH ₂OH	The 2-oxazolyl	40(a-d)	CH ₃，H	-(CH ₂) ₂CH(OH)CH ₂OH	The 2-oxazolyl

Table 5a is depicted as the embodiment of formula I compound of the present invention, and wherein G is Ar ₁, Ar ₂Or R _1d, and R ⁰Be H, Z is F, and defines G and X in this table.Every row is corresponding to different five kinds of material (Y in the Y position only in this table _a, Y _b, Y _c, Y _dAnd Y _e), Y wherein _a=SCH ₃Y _b=Br; Y _c=I; Y _d=Cl; Y _e=CH ₃

Table 5a

Y _a＝SCH ₃；Y _b＝Br；Y _c＝I；Y _d＝Cl；Y _e＝CH ₃

Compound #	G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	G＝R _1d、Ar ₁Or Ar ₂	??X	??1(a-e)	Phenyl	??Cl

Compound #	G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	G＝R _1d、Ar ₁Or Ar ₂	??X	??2(a-e)	Phenyl	??F
??3(a-e)	The 2-F-phenyl	??Cl	??2(a-e)	Phenyl	??F
??3(a-e)	The 2-F-phenyl	??Cl	??4(a-e)	The 2-F-phenyl	??F
??5(a-e)	The 3-F-phenyl	??Cl	??4(a-e)	The 2-F-phenyl	??F
??5(a-e)	The 3-F-phenyl	??Cl	??6(a-e)	The 3-F-phenyl	??F

Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??7(a-e)	The 4-F-phenyl	??Cl
??8(a-e)	The 4-F-phenyl	??F	??7(a-e)	The 4-F-phenyl	??Cl
??8(a-e)	The 4-F-phenyl	??F	??9(a-e)	2,4-two-F-phenyl	??Cl
??10(a-e)	2,4-two-F-phenyl	??F	??9(a-e)	2,4-two-F-phenyl	??Cl
??10(a-e)	2,4-two-F-phenyl	??F	??11(a-e)	2,5-two-F-phenyl	??Cl
??12(a-e)	2,5-two-F-phenyl	??F	??11(a-e)	2,5-two-F-phenyl	??Cl
??12(a-e)	2,5-two-F-phenyl	??F	Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
??13(a-e)	2,6-two-F-phenyl	??Cl	Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
??13(a-e)	2,6-two-F-phenyl	??Cl	??14(a-e)	2,6-two-F-phenyl	??F
??15(a-e)	3,4-two-F-phenyl	??Cl	??14(a-e)	2,6-two-F-phenyl	??F
??15(a-e)	3,4-two-F-phenyl	??Cl	??16(a-e)	3,4-two-F-phenyl	??F
??17(a-e)	3,5-two-F-phenyl	??Cl	??16(a-e)	3,4-two-F-phenyl	??F
??17(a-e)	3,5-two-F-phenyl	??Cl	??18(a-e)	3,5-two-F-phenyl	??F
??19(a-e)	2,6-two-F-phenyl	??Cl	??18(a-e)	3,5-two-F-phenyl	??F
??19(a-e)	2,6-two-F-phenyl	??Cl	??20(a-e)	2,6-two-F-phenyl	??F
??21(a-e)	2,3,4-three-F-phenyl	??Cl	??20(a-e)	2,6-two-F-phenyl	??F

Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??22(a-e)	2,3,4-three-F-phenyl	??F
??23(a-e)	3,4,5-three-F-phenyl	??Cl	??22(a-e)	2,3,4-three-F-phenyl	??F
??23(a-e)	3,4,5-three-F-phenyl	??Cl	??24(a-e)	3,4,5-three-F-phenyl	??F
??25(a-e)	Five-F-phenyl	??Cl	??24(a-e)	3,4,5-three-F-phenyl	??F
??25(a-e)	Five-F-phenyl	??Cl	??26(a-e)	Five-F-phenyl	??F
??27(a-e)	The 3-Cl-4-F-phenyl	??Cl	??26(a-e)	Five-F-phenyl	??F
??27(a-e)	The 3-Cl-4-F-phenyl	??Cl	??28(a-e)	The 3-Cl-4-F-phenyl	??F
??29(a-e)	The 2-Cl-4-F-phenyl	??Cl	??28(a-e)	The 3-Cl-4-F-phenyl	??F
??29(a-e)	The 2-Cl-4-F-phenyl	??Cl	??30(a-e)	The 2-Cl-4-F-phenyl	??F
??31(a-e)	The 2-F-3-Cl-phenyl	??Cl	??30(a-e)	The 2-Cl-4-F-phenyl	??F
??31(a-e)	The 2-F-3-Cl-phenyl	??Cl	??32(a-e)	The 2-F-3-Cl-phenyl	??F
??33(a-e)	The 2-F-4-Cl-phenyl	??Cl	??32(a-e)	The 2-F-3-Cl-phenyl	??F
??33(a-e)	The 2-F-4-Cl-phenyl	??Cl	??34(a-e)	The 2-F-4-Cl-phenyl	??F
??35(a-e)	The 2-F-5-Cl-phenyl	??Cl	??34(a-e)	The 2-F-4-Cl-phenyl	??F
??35(a-e)	The 2-F-5-Cl-phenyl	??Cl	??36(a-e)	The 2-F-5-Cl-phenyl	??F
??37(a-e)	3-cyano group-4-F-phenyl	??Cl	??36(a-e)	The 2-F-5-Cl-phenyl	??F
??37(a-e)	3-cyano group-4-F-phenyl	??Cl	??38(a-e)	3-cyano group-4-F-phenyl	??F
??39(a-e)	The 2-Cl-phenyl	??Cl	??38(a-e)	3-cyano group-4-F-phenyl	??F
??39(a-e)	The 2-Cl-phenyl	??Cl	??40(a-e)	The 2-Cl-phenyl	??F
??41(a-e)	The 3-Cl-phenyl	??Cl	??40(a-e)	The 2-Cl-phenyl	??F
??41(a-e)	The 3-Cl-phenyl	??Cl	??42(a-e)	The 3-Cl-phenyl	??F
??43(a-e)	The 4-Cl-phenyl	??Cl	??42(a-e)	The 3-Cl-phenyl	??F

Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??44(a-e)	The 4-Cl-phenyl	??F
??45(a-e)	2,3-two-Cl-phenyl	??Cl	??44(a-e)	The 4-Cl-phenyl	??F
??45(a-e)	2,3-two-Cl-phenyl	??Cl	??46(a-e)	2,3-two-Cl-phenyl	??F
??47(a-e)	2,5-two-Cl-phenyl	??Cl	??46(a-e)	2,3-two-Cl-phenyl	??F
??47(a-e)	2,5-two-Cl-phenyl	??Cl	??48(a-e)	2,5-two-Cl-phenyl	??F
??49(a-e)	2,6-two-Cl-phenyl	??Cl	??48(a-e)	2,5-two-Cl-phenyl	??F
??49(a-e)	2,6-two-Cl-phenyl	??Cl	??50(a-e)	2,6-two-Cl-phenyl	??F
??51(a-e)	3,5-two-Cl-phenyl	??Cl	??50(a-e)	2,6-two-Cl-phenyl	??F

Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??52(a-e)	3,5-two-Cl-phenyl	??F
??53(a-e)	2,4-two-Cl-phenyl	??Cl	??52(a-e)	3,5-two-Cl-phenyl	??F
??53(a-e)	2,4-two-Cl-phenyl	??Cl	??54(a-e)	2,4-two-Cl-phenyl	??F
??55(a-e)	3,4-two-Cl-phenyl	??Cl	??54(a-e)	2,4-two-Cl-phenyl	??F
??55(a-e)	3,4-two-Cl-phenyl	??Cl	??56(a-e)	3,4-two-Cl-phenyl	??F
??57(a-e)	2,4,6-three-Cl-phenyl	??Cl	??56(a-e)	3,4-two-Cl-phenyl	??F
??57(a-e)	2,4,6-three-Cl-phenyl	??Cl	??58(a-e)	2,4,6-three-Cl-phenyl	??F
??59(a-e)	??2-Cl-4-CF ₃-phenyl	??Cl	??58(a-e)	2,4,6-three-Cl-phenyl	??F
??59(a-e)	??2-Cl-4-CF ₃-phenyl	??Cl	??60(a-e)	??2-Cl-4-CF ₃-phenyl	??F
??61(a-e)	??2-CF ₃-phenyl	??Cl	??60(a-e)	??2-Cl-4-CF ₃-phenyl	??F
??61(a-e)	??2-CF ₃-phenyl	??Cl	??62(a-e)	??2-CF ₃-phenyl	??F

Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??63(a-e)	??3-CF ₃-phenyl	??Cl
??64(a-e)	??3-CF ₃-phenyl	??F	??63(a-e)	??3-CF ₃-phenyl	??Cl
??64(a-e)	??3-CF ₃-phenyl	??F	??65(a-e)	??4-CF ₃-phenyl	??Cl
??66(a-e)	??4-CF ₃-phenyl	??F	??65(a-e)	??4-CF ₃-phenyl	??Cl
??66(a-e)	??4-CF ₃-phenyl	??F	??67(a-e)	??2-CF ₃The O-phenyl	??Cl
??68(a-e)	??2-CF ₃The O-phenyl	??F	??67(a-e)	??2-CF ₃The O-phenyl	??Cl
??68(a-e)	??2-CF ₃The O-phenyl	??F	??69(a-e)	??3-CF ₃The O-phenyl	??Cl
??70(a-e)	??3-CF ₃The O-phenyl	??F	??69(a-e)	??3-CF ₃The O-phenyl	??Cl
??70(a-e)	??3-CF ₃The O-phenyl	??F	??71(a-e)	??4-CF ₃The O-phenyl	??Cl
??72(a-e)	??4-CF ₃The O-phenyl	??F	??71(a-e)	??4-CF ₃The O-phenyl	??Cl
??72(a-e)	??4-CF ₃The O-phenyl	??F	??73(a-e)	??2-CHF ₂The O-phenyl	??Cl
??74(a-e)	??2-CHF ₂The O-phenyl	??F	??73(a-e)	??2-CHF ₂The O-phenyl	??Cl
??74(a-e)	??2-CHF ₂The O-phenyl	??F	??75(a-e)	2-methyl-5-nitro-phenyl	??Cl
??76(a-e)	2-methyl-5-nitro-phenyl	??F	??75(a-e)	2-methyl-5-nitro-phenyl	??Cl
??76(a-e)	2-methyl-5-nitro-phenyl	??F	??77(a-e)	2-cyano group-phenyl	??Cl
??78(a-e)	2-cyano group-phenyl	??F	??77(a-e)	2-cyano group-phenyl	??Cl
??78(a-e)	2-cyano group-phenyl	??F	??79(a-e)	3-cyano group-phenyl	??Cl
??80(a-e)	3-cyano group-phenyl	??F	??79(a-e)	3-cyano group-phenyl	??Cl
??80(a-e)	3-cyano group-phenyl	??F	??81(a-e)	4-cyano group-phenyl	??Cl
??82(a-e)	4-cyano group-phenyl	??F	??81(a-e)	4-cyano group-phenyl	??Cl

Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??83(a-e)	4-methoxyl group-phenyl	??Cl
??84(a-e)	4-methoxyl group-phenyl	??F	??83(a-e)	4-methoxyl group-phenyl	??Cl
??84(a-e)	4-methoxyl group-phenyl	??F	??85(a-e)	3,4-dimethoxy-phenyl	??Cl
??86(a-e)	3,4-dimethoxy-phenyl	??F	??85(a-e)	3,4-dimethoxy-phenyl	??Cl
??86(a-e)	3,4-dimethoxy-phenyl	??F	??87(a-e)	3-carbamyl-phenyl	??Cl
??88(a-e)	3-carbamyl-phenyl	??F	??87(a-e)	3-carbamyl-phenyl	??Cl
??88(a-e)	3-carbamyl-phenyl	??F	??89(a-e)	3-carboxyl-phenyl	??Cl
??90(a-e)	3-carboxyl-phenyl	??F	??89(a-e)	3-carboxyl-phenyl	??Cl
??90(a-e)	3-carboxyl-phenyl	??F	Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
??91(a-e)	3-(N, N-dimethylamino formoxyl) phenyl	??Cl	Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
??91(a-e)	3-(N, N-dimethylamino formoxyl) phenyl	??Cl	??92(a-e)	3-(N, N-dimethylamino formoxyl) phenyl	??F
??93(a-e)	4-mesyl-phenyl	??Cl	??92(a-e)	3-(N, N-dimethylamino formoxyl) phenyl	??F
??93(a-e)	4-mesyl-phenyl	??Cl	??94(a-e)	4-mesyl-phenyl	??F
??95(a-e)	3-(1,3,4-oxadiazole-2-yl) phenyl	??Cl	??94(a-e)	4-mesyl-phenyl	??F
??95(a-e)	3-(1,3,4-oxadiazole-2-yl) phenyl	??Cl	??96(a-e)	3-(1,3,4-oxadiazole-2-yl) phenyl	??F
??97(a-e)	3-(1,3,4-thiadiazoles-2-yl) phenyl	??Cl	??96(a-e)	3-(1,3,4-oxadiazole-2-yl) phenyl	??F
??97(a-e)	3-(1,3,4-thiadiazoles-2-yl) phenyl	??Cl	??98(a-e)	3-(1,3,4-thiadiazoles-2-yl) phenyl	??F

Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??99(a-e)	3-(5-methyl isophthalic acid-1,3,4-oxadiazole) phenyl	??Cl
??100(a-e)	3-(5-methyl isophthalic acid-1,3,4-oxadiazole) phenyl	??F	??99(a-e)	3-(5-methyl isophthalic acid-1,3,4-oxadiazole) phenyl	??Cl
??100(a-e)	3-(5-methyl isophthalic acid-1,3,4-oxadiazole) phenyl	??F	??101(a-e)	3-(5-methyl isophthalic acid-1,3,4-thiadiazoles) phenyl	??Cl
??102(a-e)	3-(5-methyl isophthalic acid-1,3,4-thiadiazoles) phenyl	??F	??101(a-e)	3-(5-methyl isophthalic acid-1,3,4-thiadiazoles) phenyl	??Cl
??102(a-e)	3-(5-methyl isophthalic acid-1,3,4-thiadiazoles) phenyl	??F	??103(a-e)	3-amidino groups-phenyl	??Cl
??104(a-e)	3-amidino groups-phenyl	??F	??103(a-e)	3-amidino groups-phenyl	??Cl
??104(a-e)	3-amidino groups-phenyl	??F	??105(a-e)	3-(1H-tetrazole radical) phenyl	??Cl
??106(a-e)	3-(1H-tetrazole radical) phenyl	??F	??105(a-e)	3-(1H-tetrazole radical) phenyl	??Cl
??106(a-e)	3-(1H-tetrazole radical) phenyl	??F	??107(a-e)	4-acetylaminohydroxyphenylarsonic acid phenyl	??Cl
??108(a-e)	4-acetylaminohydroxyphenylarsonic acid phenyl	??F	??107(a-e)	4-acetylaminohydroxyphenylarsonic acid phenyl	??Cl
??108(a-e)	4-acetylaminohydroxyphenylarsonic acid phenyl	??F	??109(a-e)	The 3-Cl-4-[(N-morpholinyl carbonyl) amino] phenyl	??Cl
??110(a-e)	The 3-Cl-4-[(N-morpholinyl carbonyl) amino] phenyl	??F	??109(a-e)	The 3-Cl-4-[(N-morpholinyl carbonyl) amino] phenyl	??Cl
??110(a-e)	The 3-Cl-4-[(N-morpholinyl carbonyl) amino] phenyl	??F	??111(a-e)	3-Cl-4-[(N-pyrrolidinyl carbonyl) amino] phenyl	??Cl
??112(a-e)	3-Cl-4-[(N-pyrrolidinyl carbonyl) amino] phenyl	??F	??111(a-e)	3-Cl-4-[(N-pyrrolidinyl carbonyl) amino] phenyl	??Cl
??112(a-e)	3-Cl-4-[(N-pyrrolidinyl carbonyl) amino] phenyl	??F	??113(a-e)	3,5-dimethyl isoxazole base	??Cl
??114(a-e)	3,5-dimethyl isoxazole base	??F	??113(a-e)	3,5-dimethyl isoxazole base	??Cl

Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??115(a-e)	4-(N-morpholinyl sulfonyl) phenyl	??Cl

Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??116(a-e)	4-(N-morpholinyl sulfonyl) phenyl	??F
??117(a-e)	The 3-F-benzyl	??Cl	??116(a-e)	4-(N-morpholinyl sulfonyl) phenyl	??F
??117(a-e)	The 3-F-benzyl	??Cl	??118(a-e)	The 3-F-benzyl	??F
??119(a-e)	The 4-F-benzyl	??Cl	??118(a-e)	The 3-F-benzyl	??F
??119(a-e)	The 4-F-benzyl	??Cl	??120(a-e)	The 4-F-benzyl	??F
??121(a-e)	3-F-phenyl-ethyl	??Cl	??120(a-e)	The 4-F-benzyl	??F
??121(a-e)	3-F-phenyl-ethyl	??Cl	??122(a-e)	3-F-phenyl-ethyl	??F
??123(a-e)	4-F-phenyl-ethyl	??Cl	??122(a-e)	3-F-phenyl-ethyl	??F
??123(a-e)	4-F-phenyl-ethyl	??Cl	??124(a-e)	4-F-phenyl-ethyl	??F
??125(a-e)	The 8-quinolyl	??Cl	??124(a-e)	4-F-phenyl-ethyl	??F
??125(a-e)	The 8-quinolyl	??Cl	??126(a-e)	The 8-quinolyl	??F
??127(a-e)	The 2-thienyl	??Cl	??126(a-e)	The 8-quinolyl	??F
??127(a-e)	The 2-thienyl	??Cl	??128(a-e)	The 2-thienyl	??F
??129(a-e)	2,3-two-Cl-thiophene-5-base	??Cl	??128(a-e)	The 2-thienyl	??F
??129(a-e)	2,3-two-Cl-thiophene-5-base	??Cl	??130(a-e)	2,3-two-Cl-thiophene-5-base	??F

Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??131(a-e)	1,3,5-trimethyl-1H-pyrazolyl	??Cl
??132(a-e)	1,3,5-trimethyl-1H-pyrazolyl	??F	??131(a-e)	1,3,5-trimethyl-1H-pyrazolyl	??Cl
??132(a-e)	1,3,5-trimethyl-1H-pyrazolyl	??F	??133(a-e)	1,3-dimethyl-5-Cl-1H-pyrazolyl	??Cl
??134(a-e)	1,3-dimethyl-5-Cl-1H-pyrazolyl	??F	??133(a-e)	1,3-dimethyl-5-Cl-1H-pyrazolyl	??Cl
??134(a-e)	1,3-dimethyl-5-Cl-1H-pyrazolyl	??F	??135(a-e)	1-methyl-3-CF ₃-1H-pyrazoles-4-base	??Cl
??136(a-e)	1-methyl-3-CF ₃-1H-pyrazoles-4-base	??F	??135(a-e)	1-methyl-3-CF ₃-1H-pyrazoles-4-base	??Cl
??136(a-e)	1-methyl-3-CF ₃-1H-pyrazoles-4-base	??F	??137(a-e)	2-acetylaminohydroxyphenylarsonic acid 4-methyl-thiazole-5-Ji	??Cl
??138(a-e)	2-acetylaminohydroxyphenylarsonic acid 4-methyl-thiazole-5-Ji	??F	??137(a-e)		??Cl
??138(a-e)		??F	??139(a-e)	2,4-dimethyl-thiazole-5-base	??Cl
??140(a-e)	2,4-dimethyl-thiazole-5-base	??F	??139(a-e)	2,4-dimethyl-thiazole-5-base	??Cl
??140(a-e)	2,4-dimethyl-thiazole-5-base	??F	??141(a-e)	1,2-dimethyl-1H-imidazoles-4-base	??Cl
??142(a-e)	1,2-dimethyl-1H-imidazoles-4-base	??F	??141(a-e)	1,2-dimethyl-1H-imidazoles-4-base	??Cl

Table 5b is depicted as the embodiment of formula I compound of the present invention, and wherein G is Ar ₁, Ar ₂Or R _1d, and R ⁰Be H, Z is F, and defines G and X in this table.Every row is corresponding to different five kinds of material (Y in the Y position only in this table _a, Y _b, Y _c, Y _dAnd Y _e), Y wherein _a=phenyl; Y _b=3-substituted-phenyl; Y _c=3-pyridine radicals; Y _d=4-pyridine radicals; Y _e=3-pyrazolyl.

Table 5b

Y _a=phenyl; Y _b=3-substituted-phenyl; Y _c=3-pyridine radicals; Y _d=4-pyridine radicals; Y _e=3-pyrazolyl

Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??1(a-e)	Phenyl	??Cl
??2(a-e)	Phenyl	??F	??1(a-e)	Phenyl	??Cl
??2(a-e)	Phenyl	??F	??3(a-e)	The 2-F-phenyl	??Cl
??4(a-e)	The 2-F-phenyl	??F	??3(a-e)	The 2-F-phenyl	??Cl
??4(a-e)	The 2-F-phenyl	??F	??5(a-e)	The 3-F-phenyl	??Cl
??6(a-e)	The 3-F-phenyl	??F	??5(a-e)	The 3-F-phenyl	??Cl
??6(a-e)	The 3-F-phenyl	??F	??7(a-e)	The 4-F-phenyl	??Cl
??8(a-e)	The 4-F-phenyl	??F	??7(a-e)	The 4-F-phenyl	??Cl
??8(a-e)	The 4-F-phenyl	??F	??9(a-e)	2,4-two-F-phenyl	??Cl
??10(a-e)	2,4-two-F-phenyl	??F	??9(a-e)	2,4-two-F-phenyl	??Cl
??10(a-e)	2,4-two-F-phenyl	??F	??11(a-e)	2,5-two-F-phenyl	??Cl
??12(a-e)	2,5-two-F-phenyl	??F	??11(a-e)	2,5-two-F-phenyl	??Cl
??12(a-e)	2,5-two-F-phenyl	??F	??13(a-e)	2,6-two-F-phenyl	??Cl
??14(a-e)	2,6-two-F-phenyl	??F	??13(a-e)	2,6-two-F-phenyl	??Cl
??14(a-e)	2,6-two-F-phenyl	??F	??15(a-e)	3,4-two-F-phenyl	??Cl

Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??16(a-e)	3,4-two-F-phenyl	??F
??17(a-e)	3,5-two-F-phenyl	??Cl	??16(a-e)	3,4-two-F-phenyl	??F
??17(a-e)	3,5-two-F-phenyl	??Cl	??18(a-e)	3,5-two-F-phenyl	??F
??19(a-e)	2,6-two-F-phenyl	??Cl	??18(a-e)	3,5-two-F-phenyl	??F
??19(a-e)	2,6-two-F-phenyl	??Cl	??20(a-e)	2,6-two-F-phenyl	??F
??21(a-e)	2,3,4-three-F-phenyl	??Cl	??20(a-e)	2,6-two-F-phenyl	??F
??21(a-e)	2,3,4-three-F-phenyl	??Cl	??22(a-e)	2,3,4-three-F-phenyl	??F
??23(a-e)	3,4,5-three-F-phenyl	??Cl	??22(a-e)	2,3,4-three-F-phenyl	??F
??23(a-e)	3,4,5-three-F-phenyl	??Cl	??24(a-e)	3,4,5-three-F-phenyl	??F
??25(a-e)	Five-F-phenyl	??Cl	??24(a-e)	3,4,5-three-F-phenyl	??F
??25(a-e)	Five-F-phenyl	??Cl	??26(a-e)	Five-F-phenyl	??F
??27(a-e)	The 3-Cl-4-F-phenyl	??Cl	??26(a-e)	Five-F-phenyl	??F
??27(a-e)	The 3-Cl-4-F-phenyl	??Cl	??28(a-e)	The 3-Cl-4-F-phenyl	??F
??29(a-e)	The 2-Cl-4-F-phenyl	??Cl	??28(a-e)	The 3-Cl-4-F-phenyl	??F
??29(a-e)	The 2-Cl-4-F-phenyl	??Cl	??30(a-e)	The 2-Cl-4-F-phenyl	??F
??31(a-e)	The 2-F-3-Cl-phenyl	??Cl	??30(a-e)	The 2-Cl-4-F-phenyl	??F

Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??32(a-e)	The 2-F-3-Cl-phenyl	??F

Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??33(a-e)	The 2-F-4-Cl-phenyl	??Cl
??34(a-e)	The 2-F-4-Cl-phenyl	??F	??33(a-e)	The 2-F-4-Cl-phenyl	??Cl
??34(a-e)	The 2-F-4-Cl-phenyl	??F	??35(a-e)	The 2-F-5-Cl-phenyl	??Cl
??36(a-e)	The 2-F-5-Cl-phenyl	??F	??35(a-e)	The 2-F-5-Cl-phenyl	??Cl
??36(a-e)	The 2-F-5-Cl-phenyl	??F	??37(a-e)	3-cyano group-4-F-phenyl	??Cl
??38(a-e)	3-cyano group-4-F-phenyl	??F	??37(a-e)	3-cyano group-4-F-phenyl	??Cl
??38(a-e)	3-cyano group-4-F-phenyl	??F	??39(a-e)	The 2-Cl-phenyl	??Cl
??40(a-e)	The 2-Cl-phenyl	??F	??39(a-e)	The 2-Cl-phenyl	??Cl
??40(a-e)	The 2-Cl-phenyl	??F	??41(a-e)	The 3-Cl-phenyl	??Cl
??42(a-e)	The 3-Cl-phenyl	??F	??41(a-e)	The 3-Cl-phenyl	??Cl
??42(a-e)	The 3-Cl-phenyl	??F	??43(a-e)	The 4-Cl-phenyl	??Cl
??44(a-e)	The 4-Cl-phenyl	??F	??43(a-e)	The 4-Cl-phenyl	??Cl
??44(a-e)	The 4-Cl-phenyl	??F	??45(a-e)	2,3-two-Cl-phenyl	??Cl
??46(a-e)	2,3-two-Cl-phenyl	??F	??45(a-e)	2,3-two-Cl-phenyl	??Cl
??46(a-e)	2,3-two-Cl-phenyl	??F	??47(a-e)	2,5-two-Cl-phenyl	??Cl
??48(a-e)	2,5-two-Cl-phenyl	??F	??47(a-e)	2,5-two-Cl-phenyl	??Cl
??48(a-e)	2,5-two-Cl-phenyl	??F	??49(a-e)	2,6-two-Cl-phenyl	??Cl
??50(a-e)	2,6-two-Cl-phenyl	??F	??49(a-e)	2,6-two-Cl-phenyl	??Cl
??50(a-e)	2,6-two-Cl-phenyl	??F	??51(a-e)	3,5-two-Cl-phenyl	??Cl

Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??52(a-e)	3,5-two-Cl-phenyl	??F
??53(a-e)	2,4-two-Cl-phenyl	??Cl	??52(a-e)	3,5-two-Cl-phenyl	??F
??53(a-e)	2,4-two-Cl-phenyl	??Cl	??54(a-e)	2,4-two-Cl-phenyl	??F
??55(a-e)	3,4-two-Cl-phenyl	??Cl	??54(a-e)	2,4-two-Cl-phenyl	??F
??55(a-e)	3,4-two-Cl-phenyl	??Cl	??56(a-e)	3,4-two-Cl-phenyl	??F
??57(a-e)	2,4,6-three-Cl-phenyl	??Cl	??56(a-e)	3,4-two-Cl-phenyl	??F
??57(a-e)	2,4,6-three-Cl-phenyl	??Cl	??58(a-e)	2,4,6-three-Cl-phenyl	??F
??59(a-e)	??2-Cl-4-CF ₃-phenyl	??Cl	??58(a-e)	2,4,6-three-Cl-phenyl	??F
??59(a-e)	??2-Cl-4-CF ₃-phenyl	??Cl	??60(a-e)	??2-Cl-4-CF ₃-phenyl	??F
??61(a-e)	??2-CF ₃-phenyl	??Cl	??60(a-e)	??2-Cl-4-CF ₃-phenyl	??F
??61(a-e)	??2-CF ₃-phenyl	??Cl	??62(a-e)	??2-CF ₃-phenyl	??F
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??62(a-e)	??2-CF ₃-phenyl	??F
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??63(a-e)	??3-CF ₃-phenyl	??Cl
??64(a-e)	??3-CF ₃-phenyl	??F	??63(a-e)	??3-CF ₃-phenyl	??Cl
??64(a-e)	??3-CF ₃-phenyl	??F	??65(a-e)	??4-CF ₃-phenyl	??Cl
??66(a-e)	??4-CF ₃-phenyl	??F	??65(a-e)	??4-CF ₃-phenyl	??Cl
??66(a-e)	??4-CF ₃-phenyl	??F	??67(a-e)	??2-CF ₃The O-phenyl	??Cl
??68(a-e)	??2-CF ₃The O-phenyl	??F	??67(a-e)	??2-CF ₃The O-phenyl	??Cl
??68(a-e)	??2-CF ₃The O-phenyl	??F	??69(a-e)	??3-CF ₃The O-phenyl	??Cl

Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??70(a-e)	??3-CF ₃The O-phenyl	??F
??71(a-e)	??4-CF ₃The O-phenyl	??Cl	??70(a-e)	??3-CF ₃The O-phenyl	??F
??71(a-e)	??4-CF ₃The O-phenyl	??Cl	??72(a-e)	??4-CF ₃The O-phenyl	??F
??73(a-e)	??4-CHF ₂The O-phenyl	??Cl	??72(a-e)	??4-CF ₃The O-phenyl	??F
??73(a-e)	??4-CHF ₂The O-phenyl	??Cl	??74(a-e)	??4-CHF ₂The O-phenyl	??F
??75(a-e)	2-methyl-5-nitro-phenyl	??Cl	??74(a-e)	??4-CHF ₂The O-phenyl	??F
??75(a-e)	2-methyl-5-nitro-phenyl	??Cl	??76(a-e)	2-methyl-5-nitro-phenyl	??F
??77(a-e)	2-cyano group-phenyl	??Cl	??76(a-e)	2-methyl-5-nitro-phenyl	??F
??77(a-e)	2-cyano group-phenyl	??Cl	??78(a-e)	2-cyano group-phenyl	??F
??79(a-e)	3-cyano group-phenyl	??Cl	??78(a-e)	2-cyano group-phenyl	??F
??79(a-e)	3-cyano group-phenyl	??Cl	??80(a-e)	3-cyano group-phenyl	??F
??81(a-e)	4-cyano group-phenyl	??Cl	??80(a-e)	3-cyano group-phenyl	??F
??81(a-e)	4-cyano group-phenyl	??Cl	??82(a-e)	4-cyano group-phenyl	??F
??83(a-e)	4-methoxyl group-phenyl	??Cl	??82(a-e)	4-cyano group-phenyl	??F
??83(a-e)	4-methoxyl group-phenyl	??Cl	??84(a-e)	4-methoxyl group-phenyl	??F
??85(a-e)	3,4-dimethoxy-phenyl	??Cl	??84(a-e)	4-methoxyl group-phenyl	??F
??85(a-e)	3,4-dimethoxy-phenyl	??Cl	??86(a-e)	3,4-dimethoxy-phenyl	??F

Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??87(a-e)	3-carbamyl-phenyl	??Cl
??88(a-e)	3-carbamyl-phenyl	??F	??87(a-e)	3-carbamyl-phenyl	??Cl
??88(a-e)	3-carbamyl-phenyl	??F	??89(a-e)	3-carboxyl-phenyl	??Cl
??90(a-e)	3-carboxyl-phenyl	??F	??89(a-e)	3-carboxyl-phenyl	??Cl
??90(a-e)	3-carboxyl-phenyl	??F	??91(a-e)	3-(N, N-dimethylamino formoxyl) phenyl	??Cl
??92(a-e)	3-(N, N-dimethylamino formoxyl) phenyl	??F	??91(a-e)	3-(N, N-dimethylamino formoxyl) phenyl	??Cl
??92(a-e)	3-(N, N-dimethylamino formoxyl) phenyl	??F	??93(a-e)	4-mesyl-phenyl	??Cl
??94(a-e)	4-mesyl-phenyl	??F	??93(a-e)	4-mesyl-phenyl	??Cl
??94(a-e)	4-mesyl-phenyl	??F	??95(a-e)	3-(1,3,4-oxadiazole-2-yl) phenyl	??Cl
??96(a-e)	3-(1,3,4-oxadiazole-2-yl) phenyl	??F	??95(a-e)	3-(1,3,4-oxadiazole-2-yl) phenyl	??Cl

Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??97(a-e)	3-(1,3,4-thiadiazoles-2-yl) phenyl	??Cl
??98(a-e)	3-(1,3,4-thiadiazoles-2-yl) phenyl	??F	??97(a-e)	3-(1,3,4-thiadiazoles-2-yl) phenyl	??Cl
??98(a-e)	3-(1,3,4-thiadiazoles-2-yl) phenyl	??F	??99(a-e)	3-(5-methyl isophthalic acid, 3,4-Evil diazole) phenyl	??Cl

Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??100(a-e)	3-(5-methyl isophthalic acid, 3,4-Evil diazole) phenyl	??F
??101(a-e)	3-(5-methyl isophthalic acid, 3,4-thiadiazoles) phenyl	??Cl	??100(a-e)	3-(5-methyl isophthalic acid, 3,4-Evil diazole) phenyl	??F
??101(a-e)	3-(5-methyl isophthalic acid, 3,4-thiadiazoles) phenyl	??Cl	??102(a-e)	3-(5-methyl isophthalic acid, 3,4-thiadiazoles) phenyl	??F
??103(a-e)	3-amidino groups-phenyl	??Cl	??102(a-e)	3-(5-methyl isophthalic acid, 3,4-thiadiazoles) phenyl	??F
??103(a-e)	3-amidino groups-phenyl	??Cl	??104(a-e)	3-amidino groups-phenyl	??F
??105(a-e)	3-(1H-tetrazole radical) phenyl	??Cl	??104(a-e)	3-amidino groups-phenyl	??F
??105(a-e)	3-(1H-tetrazole radical) phenyl	??Cl	??106(a-e)	3-(1H-tetrazole radical) phenyl	??F
??107(a-e)	4-acetylaminohydroxyphenylarsonic acid phenyl	??Cl	??106(a-e)	3-(1H-tetrazole radical) phenyl	??F
??107(a-e)	4-acetylaminohydroxyphenylarsonic acid phenyl	??Cl	??108(a-e)	4-acetylaminohydroxyphenylarsonic acid phenyl	??F
??109(a-e)	The 3-Cl-4-[(N-morpholinyl carbonyl) amino] phenyl	??Cl	??108(a-e)	4-acetylaminohydroxyphenylarsonic acid phenyl	??F
??109(a-e)	The 3-Cl-4-[(N-morpholinyl carbonyl) amino] phenyl	??Cl	??110(a-e)	The 3-Cl-4-[(N-morpholinyl carbonyl) amino] phenyl	??F
??111(a-e)	3-Cl-4-[(N-pyrrolidinyl carbonyl) amino] phenyl	??Cl	??110(a-e)	The 3-Cl-4-[(N-morpholinyl carbonyl) amino] phenyl	??F
??111(a-e)	3-Cl-4-[(N-pyrrolidinyl carbonyl) amino] phenyl	??Cl	??112(a-e)	3-Cl-4-[(N-pyrrolidinyl carbonyl) amino] phenyl	??F
??113(a-e)	3,5-dimethyl isoxazole base	??Cl	??112(a-e)	3-Cl-4-[(N-pyrrolidinyl carbonyl) amino] phenyl	??F

Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??114(a-e)	3,5-dimethyl isoxazole base	??F
??115(a-e)	4-(N-morpholinyl sulfonyl) phenyl	??Cl	??114(a-e)	3,5-dimethyl isoxazole base	??F
??115(a-e)	4-(N-morpholinyl sulfonyl) phenyl	??Cl	??116(a-e)	4-(N-morpholinyl sulfonyl) phenyl	??F
??117(a-e)	The 3-F-benzyl	??Cl	??116(a-e)	4-(N-morpholinyl sulfonyl) phenyl	??F
??117(a-e)	The 3-F-benzyl	??Cl	??118(a-e)	The 3-F-benzyl	??F
??119(a-e)	The 4-F-benzyl	??Cl	??118(a-e)	The 3-F-benzyl	??F
??119(a-e)	The 4-F-benzyl	??Cl	??120(a-e)	The 4-F-benzyl	??F
??121(a-e)	3-F-phenyl-ethyl	??Cl	??120(a-e)	The 4-F-benzyl	??F
??121(a-e)	3-F-phenyl-ethyl	??Cl	??122(a-e)	3-F-phenyl-ethyl	??F
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??122(a-e)	3-F-phenyl-ethyl	??F
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??123(a-e)	4-F-phenyl-ethyl	??Cl
??124(a-e)	4-F-phenyl-ethyl	??F	??123(a-e)	4-F-phenyl-ethyl	??Cl
??124(a-e)	4-F-phenyl-ethyl	??F	??125(a-e)	The 8-quinolyl	??Cl
??126(a-e)	The 8-quinolyl	??F	??125(a-e)	The 8-quinolyl	??Cl
??126(a-e)	The 8-quinolyl	??F	??127(a-e)	The 2-thienyl	??Cl
??128(a-e)	The 2-thienyl	??F	??127(a-e)	The 2-thienyl	??Cl
??128(a-e)	The 2-thienyl	??F	??129(a-e)	2,3-two-Cl-thiophene-5-base	??Cl

Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??130(a-e)	2,3-two-Cl-thiophene-5-base	??F
??131(a-e)	1,3,5-trimethyl-1H-pyrazolyl	??Cl	??130(a-e)	2,3-two-Cl-thiophene-5-base	??F
??131(a-e)	1,3,5-trimethyl-1H-pyrazolyl	??Cl	??132(a-e)	1,3,5-trimethyl-1H-pyrazolyl	??F
??133(a-e)	1,3-dimethyl-5-Cl-1H-pyrazolyl	??Cl	??132(a-e)	1,3,5-trimethyl-1H-pyrazolyl	??F
??133(a-e)	1,3-dimethyl-5-Cl-1H-pyrazolyl	??Cl	??134(a-e)	1,3-dimethyl-5-Cl-1H-pyrazolyl	??F
??135(a-e)	1-methyl-3-CF ₃-1H-pyrazoles-4-base	??Cl	??134(a-e)	1,3-dimethyl-5-Cl-1H-pyrazolyl	??F
??135(a-e)	1-methyl-3-CF ₃-1H-pyrazoles-4-base	??Cl	??136(a-e)	1-methyl-3-CF ₃-1H-pyrazoles-4-base	??F
??137(a-e)	2-acetylaminohydroxyphenylarsonic acid 4-methyl-thiazole-5-Ji	??Cl	??136(a-e)	1-methyl-3-CF ₃-1H-pyrazoles-4-base	??F

Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??138(a-e)	2-acetylaminohydroxyphenylarsonic acid 4-methyl-thiazole-5-Ji	??F
??139(a-e)	2,4-dimethyl-thiazole-5-base	??Cl	??138(a-e)		??F
??139(a-e)	2,4-dimethyl-thiazole-5-base	??Cl	??140(a-e)	2,4-dimethyl-thiazole-5-base	??F

Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X
Compound #	??G＝R _1d、Ar ₁Or Ar ₂	??X	??141(a-e)	1,2-dimethyl-1H-imidazol-4 yl	??Cl
??142(a-e)	1,2-dimethyl-1H-imidazol-4 yl	??F	??141(a-e)	1,2-dimethyl-1H-imidazol-4 yl	??Cl
??142(a-e)	1,2-dimethyl-1H-imidazol-4 yl	??F	??143(a-e)	1-(2-hydroxyethyl) cyclopropyl	??F
??144(a-e)	1-(3-hydroxypropyl) cyclopropyl	??F	??143(a-e)	1-(2-hydroxyethyl) cyclopropyl	??F
??144(a-e)	1-(3-hydroxypropyl) cyclopropyl	??F	??145(a-e)	1-(2, the 3-dihydroxypropyl) cyclopropyl	??F
??146(a-e)	1-(3,4-dihydroxy butyl) cyclopropyl	??F	??145(a-e)	1-(2, the 3-dihydroxypropyl) cyclopropyl	??F
??146(a-e)	1-(3,4-dihydroxy butyl) cyclopropyl	??F	??147(a-e)	1-(2, the 3-dihydroxypropyl) cyclobutyl	??F

Synthesis step

The method of synthetic compound as herein described is provided on the other hand.In some embodiments, compound as herein described can be by following method preparation.Following steps and embodiment are intended to illustrate those methods.Described step and embodiment should not be interpreted as restriction the present invention by any way.Use standard synthetic method well known by persons skilled in the art, perhaps use methods known in the art, also can synthesize compound as herein described in conjunction with method as herein described.In addition, solvent as herein described, temperature and other reaction conditions can change according to those skilled in the art's practice and knowledge.

The raw material that is used for synthetic compound described herein can obtain from commercial source, for example Aldrich Chemical Co. (Milwaukee, Wis.), Sigma Chemical Co. (St.Louis, Mo.), perhaps can synthesis material.Use method known to those skilled in the art and material, for example at March, A _DVANCEDO _RGANICC _HEMISTRYThe 4th edition, (Wiley 1992); Carey and Sundberg, A _DVANCEDO _RGANICC _HEMISTRYThe 4th edition, volume A and B (Plenum2000,2001) and Green and Wuts, P _ROTECTIVEG _{ROUPS IN}O _RGANICS _YNTHESISThe 3rd edition, (Wiley1999) described in (it all intactly quotes adding), other relevant compounds that can synthesize compound as herein described and have different substituents.The universal method that is used to prepare compound disclosed herein may come from reaction known in the art, and, in order to introduce the various groups of being found as in the formula provided herein, known to the technical staff, can change described reaction by using suitable reagent and condition.Can use following synthetic method as guidance.

Form covalent bond by electric body of parent and nucleophile reaction

Use electric body of various parents or nucleophile, can modify compound as herein described to form new functional group or substituting group.Title is listed the covalent bond that generated and the selected example of precursor functional group for the following table of " example of covalent bond and precursor thereof ", and can be as the guidance of various close electric bodies that get and nucleophile combination.Precursor functional group is expressed as electrophilic group and nucleophilic group.

The example of covalent bond and precursor thereof

The covalent bond product	The electric body of parent	Nucleophile
The covalent bond product	The electric body of parent	Nucleophile	Amide-type	Active ester	Amine/phenyl amines
Amide-type	Acyl azide	Amine/phenyl amines	Amide-type	Active ester	Amine/phenyl amines
Amide-type	Acyl azide	Amine/phenyl amines	Amide-type	Carboxylic acid halides	Amine/phenyl amines
The ester class	Carboxylic acid halides	Alcohols/phenol	Amide-type	Carboxylic acid halides	Amine/phenyl amines
The ester class	Carboxylic acid halides	Alcohols/phenol	The ester class	The acyl group nitrile	Alcohols/phenol
Amide-type	The acyl group nitrile	Amine/phenyl amines	The ester class	The acyl group nitrile	Alcohols/phenol
Amide-type	The acyl group nitrile	Amine/phenyl amines	The imines class	Aldehydes	Amine/phenyl amines
The hydrazone class	Aldehydes or ketone	The hydrazine class	The imines class	Aldehydes	Amine/phenyl amines
The hydrazone class	Aldehydes or ketone	The hydrazine class	Oximes	Aldehydes or ketone	The azanol class
Alkyl amine	Alkyl halide	Amine/phenyl amines	Oximes	Aldehydes or ketone	The azanol class
Alkyl amine	Alkyl halide	Amine/phenyl amines	The ester class	Alkyl halide	Carboxylic acids
The thioether class	Alkyl halide	Thio-alcohol	The ester class	Alkyl halide	Carboxylic acids
The thioether class	Alkyl halide	Thio-alcohol	Ethers	Alkyl halide	Alcohols/phenol
The thioether class	Alkyl sulfonates	Thio-alcohol	Ethers	Alkyl halide	Alcohols/phenol
The thioether class	Alkyl sulfonates	Thio-alcohol	The ester class	Alkyl sulfonates	Carboxylic acids
Ethers	Alkyl sulfonates	Alcohols/phenol	The ester class	Alkyl sulfonates	Carboxylic acids
Ethers	Alkyl sulfonates	Alcohols/phenol	The ester class	Anhydrides	Alcohols/phenol
Amide-type	Anhydrides	Amine/phenyl amines	The ester class	Anhydrides	Alcohols/phenol
Amide-type	Anhydrides	Amine/phenyl amines	The thio phenyl phenols	The aryl halides	Thio-alcohol

The covalent bond product	The electric body of parent	Nucleophile
The covalent bond product	The electric body of parent	Nucleophile	The aryl amine	The aryl halides	Amine
The thioether class	The ethylene imine class	Thio-alcohol	The aryl amine	The aryl halides	Amine
The thioether class	The ethylene imine class	Thio-alcohol	Borate ester	Borate	Glycols
Amide-type	Carboxylic acid	Amine/phenyl amines	Borate ester	Borate	Glycols
Amide-type	Carboxylic acid	Amine/phenyl amines	The ester class	Carboxylic acid	Alcohols
The hydrazine class	Hydrazides	Carboxylic acid	The ester class	Carboxylic acid	Alcohols
The hydrazine class	Hydrazides	Carboxylic acid	N-acylureas or acid anhydrides	Carbodiimide	Carboxylic acid
The ester class	Diazoparaffins	Carboxylic acid	N-acylureas or acid anhydrides	Carbodiimide	Carboxylic acid
The ester class	Diazoparaffins	Carboxylic acid	The thioether class	Epoxides	Thio-alcohol
The thioether class	Halogen acid amide	Thio-alcohol	The thioether class	Epoxides	Thio-alcohol
The thioether class	Halogen acid amide	Thio-alcohol	Amino triazine class (ammotriazine)	The halo triazine	Amine/phenyl amines
Triazinyl ether	The halo triazine	Alcohols/phenol	Amino triazine class (ammotriazine)	The halo triazine	Amine/phenyl amines
Triazinyl ether	The halo triazine	Alcohols/phenol	The amidine class	Imino-ester	Amine/phenyl amines
Urea	Isocyanates	Amine/phenyl amines	The amidine class	Imino-ester	Amine/phenyl amines
Urea	Isocyanates	Amine/phenyl amines	Carbamate	Isocyanates	Alcohols/phenol
Thiocarbamide	Isothiocyanates	Amine/phenyl amines	Carbamate	Isocyanates	Alcohols/phenol
Thiocarbamide	Isothiocyanates	Amine/phenyl amines	The thioether class	Maleimide	Thio-alcohol
Phosphorous acid esters	Phosphoramidite	Alcohols	The thioether class	Maleimide	Thio-alcohol
Phosphorous acid esters	Phosphoramidite	Alcohols	Silyl ether	Silicyl halo thing	Alcohols
Alkyl amine	Sulfonic acid esters	Amine/phenyl amines	Silyl ether	Silicyl halo thing	Alcohols
Alkyl amine	Sulfonic acid esters	Amine/phenyl amines	The thioether class	Sulfonic acid esters	Thio-alcohol
The ester class	Sulfonic acid esters	Carboxylic acid	The thioether class	Sulfonic acid esters	Thio-alcohol

The covalent bond product	The electric body of parent	Nucleophile
The covalent bond product	The electric body of parent	Nucleophile	Ethers	Sulfonic acid esters	Alcohols
Sulfonamides	Sulfonic acid halide	Amine/phenyl amines	Ethers	Sulfonic acid esters	Alcohols
Sulfonamides	Sulfonic acid halide	Amine/phenyl amines	Sulfonic acid esters	Sulfonic acid halide	Phenol/alcohols

The use of protecting group

In described reaction, the reactive functional groups that may need protection (in end product, needing under the situation of these groups), for example hydroxyl, amino, imino group, thio group (thio) or carboxylic group unnecessarily participate in reaction to avoid them.Protecting group is used to block some or all of reactive groups and stops such group to participate in chemical reaction be removed until described protecting group.In some embodiments, each protecting group can be removed by diverse ways.The protecting group of cutting off under diverse reaction condition satisfies the needs that otherness is removed.Can remove protecting group by acid, alkali and hydrogenolysis.Group for example trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl is unsettled to acid; and; with Cbz group (it can be removed through hydrogenolysis) with in the presence of to the amino group of alkali labile Fmoc radical protection, they can be used to protect carboxyl and hydroxyl reactive group.Use to acid unsettled group for example t-butyl carbamate or use bronsted lowry acids and bases bronsted lowry all stablized but in the presence of the amine of the removable carbamate blocking-up of hydrolysis, uses and can block carboxylic acid and hydroxyl reactive group such as but not limited to methyl, ethyl and acetyl group alkali labile group.

Carboxylic acid and hydroxyl reactive group can also be used through for example benzyl group blocking-up of the removable protecting group of hydrolysis, and can use for example Fmoc blocking-up of alkali labile group with the amine groups that acid forms hydrogen bond.As this paper example; by changing into simple ester compounds; can protect the carboxylic acid reaction group; perhaps they can be used through the removable protecting group of oxidation for example 2; the blocking-up of 4-dimethoxy-benzyl, and the amino group of coexistence can be used the unsettled silicyl carbamate blocking-up of fluoride.

Allyl-based protection is used to because it is stable, and can remove with metal or π acid catalyst subsequently under the situation of acid and alkaline protecting group existence.For example, to acid unsettled t-butyl carbamate or to alkali labile acetic acid esters amine protecting group in the presence of, the carboxylic acid of pi-allyl blocking-up can be with the reaction deprotection of Pd catalysis.The another form of protecting group is the resin that compound or intermediate can be attached thereto.As long as residue is connected with resin, this functional group just is blocked and can not reacts.In case discharge from resin, described functional group can be in order to reaction.

Protecting group or blocking group can be selected from:

Other protecting groups, and be applicable to that producing protecting group is described in detail in Greene and Wuts, Protective Groups in Organic Synthesis, the 3rd edition, John Wiley ﹠amp with the technology of removing them; Sons, New York, NY, 1999, and Kocienski, Protecting Groups, Thieme Verlag, New York, NY is described in 1994, and it intactly quotes adding herein.

The compound of preparation formula I

Can prepare compound of the present invention by the whole bag of tricks.Following steps are intended to illustrate those methods, and the embodiment that provides is intended to illustrate scope of the present invention.These methods and embodiment all should not be interpreted as restriction the present invention by any way.

I. the preparation of formula VI compound is summarized as follows

Above route I has illustrated the method for the sulfamide derivative of preparation formula VI.Can easily prepare 1,2-diamine derivative (formula IV) from the nitro-derivative (formula I) of expectation through two steps.The compound of formula IV can form the sulfonamide of expectation with sulfonyl chloride derivatives (formula V is referring to next route) reaction.Perhaps, before reacting with corresponding sulfonic acid chloride, can be with 1,2-diamine derivative IV protection is imidazolidinone (formula VII).Deprotection 1 under alkali condition, the raw material (formula VI) that 2-diamines VIII obtains expecting.

II. the general routes outlined of synthetic general formula V compound is summarized as follows

Above route II represents to prepare an example of complicated sulfonic acid chloride.Can synthetic compound XX from IX, it can and be converted to sylvite XII by alkylation.Use SOCl ₂Or POCl ₃Handle this salt and obtain desired compounds.Other that reported sulfonyl chloride derivatives that preparation is unique at experimental section are method more specifically.

III. route 3 has been summarized the general routes outlined of synthetic general formula X III compound.

Above route III has illustrated the preparation of the sulfamide derivative of general formula X III.For example, under the Suzuki condition, use palladium catalyst, can easily obtain these compounds by making compound VI and acid reaction.

IV. route 4 has been summarized the general routes outlined of synthetic general formula X III compound.

Above route IV has illustrated the preparation of the sulfamide derivative of general formula X V.Vinyl sulfonamide (XIV) reacts the derivative that forms general formula X V with amine.

Other forms of formula I compound

The isomer of formula I compound

Compound as herein described can exist with geometric isomer.Compound as herein described may have one or more pairs of keys.The given compound of this paper comprises all cis, trans, anti-(E) and suitable (Z) isomer and their corresponding mixture.In some cases, compound can exist with dynamic isomer.Compound as herein described comprises all possible dynamic isomer in the molecular formula described herein.Compound as herein described can have one or more chiral centres, and each center can exist with R or S configuration.Compound as herein described comprises all diastereomer forms, enantiomeric form and epimer form, and their corresponding mixture.In other embodiments of Compounds and methods for provided herein, by single preparation process, merging or transform the enantiomer of gained mutually and/or the mixture of diastereoisomer, also can be used for application as herein described.Racemic mixture by making described compound and the reaction of the resolving agent of optical activity form a pair of diastereomeric compound, separating obtained diastereomer also reclaims optically pure enantiomer, and compound as herein described can be prepared into their stereoisomer separately.Use the non-enantiomer derivative of the covalency of compound as herein described, perhaps can use dissociable complex compound (as the diastereoisomeric salt of crystallization), can carry out enantiomer and split.Diastereomer has different physical property (as fusing point, boiling point, solvability, reactivity etc.), can be easily separated by utilizing these differences.By chiral chromatography or based on the separation/disassemble technique of dissolubility difference, can separate diastereomer.Then, reclaim optically pure enantiomer and resolving agent by any feasible method that can not cause racemization.At Jean Jacques, Andre Collet, Samuel H.Wilen, " Enantiomers, Racemates andResolutions, " John Wiley and Sons, Inc., in 1981, can find to be applicable to the more detailed description that from the compound racemic mixture, splits their alloisomerism body method, intactly quote adding herein.

The formula I compound of mark

Isotope-labeled formula I compound and sanatory method are also described herein.For example, the invention provides method by the isotope-labeled formula I compounds for treating of administration disease.Can be with the described isotope-labeled formula I compound of the mode administration of pharmaceutical composition.Therefore, the compound of formula I also comprises isotope-labeled compound, it is identical with those compounds that this paper enumerates, but in fact one or more atom is had the atomic mass different with common atomic mass of finding of occurring in nature or mass number or the atom of mass number substitutes.Can be contained in isotopic example in the compound of the present invention and comprise the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, respectively for example ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl.Comprise other isotopic compounds as herein described of above-mentioned isotope and/or other atoms or the acceptable salt of its pharmacy within the scope of the invention.Some isotope-labeled formula I compound, for example radioisotope for example ³H and ¹⁴C is contained in those compounds wherein, is useful in medicine and/or substrate tissue distribution mensuration.Tritium promptly ³H and carbon-14 are promptly ¹⁴The C isotope is easy to preparation usually and detects.In addition, for example deuterium is promptly with heavier isotope ²H replaces some the treatment advantage can generate because of due to the better metabolic stability, for example, increases in the body half life period or reduces the dosage demand, and so may need in some cases.By using method as herein described, replace the heterotope labelled reagent with the isotope labeling reagent that is easy to get, generally can prepare the acceptable salt of isotope-labeled compound and pharmacy thereof.

Compound as herein described can pass through the additive method mark, and described additive method includes but not limited to use chromophore or fluorophor, bioluminescence marker or chemiluminescent labeling.

The acceptable salt of the pharmacy of formula I compound

The acceptable salt of pharmacy and the sanatory method of formula I compound have also been described herein.For example, the invention provides method by the acceptable salts for treating disease of pharmacy of Medicine-feeding type I compound.Can be with the acceptable salt of pharmacy of the mode Medicine-feeding type I compound of pharmaceutical composition.

Therefore, compound as herein described can be prepared into the acceptable salt of pharmacy, and for example alkali metal ion, alkaline-earth metal ions or aluminium ion substitute the acid proton that exists in parent compound by metal ion; During perhaps with the organic base coordination, form the acceptable salt of described pharmacy.By free acid form and acceptable inorganic base of pharmacy or the organic base reaction that makes compound as herein described, also can prepare base addition salts, described inorganic base or organic base include but not limited to for example for example aluminium hydroxide, slaked lime, potassium hydroxide, sodium carbonate, sodium hydroxide etc. of monoethanolamine, diethanol amine, triethanolamine, tromethamine, N-methylglucosamine etc. and inorganic base of organic base.In addition, use the salt of raw material or intermediate, can prepare the salt form of compound disclosed herein.

In addition, compound as herein described can be prepared into the acceptable salt of pharmacy, the acceptable inorganic or organic acid reaction of its free alkali form by described compound and pharmacy forms, and described inorganic or organic acid includes but not limited to: inorganic acid is hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid etc. for example; With organic acid acetate for example; propionic acid; caproic acid; the pentamethylene propionic acid; glycolic acid; pyruvic acid; lactic acid; malonic acid; succinic acid; malic acid; maleic acid; fumaric acid; the Q-toluenesulfonic acid; tartaric acid; trifluoroacetic acid; citric acid; benzoic acid; 3-(4-hydroxy benzoyl) benzoic acid; cinnamic acid; mandelic acid; aryl sulfonic acid; methanesulfonic acid; ethyl sulfonic acid; 1; the 2-ethane disulfonic acid; the 2-ethylenehydrinsulfonic acid; benzene sulfonic acid; the 2-naphthalene sulfonic acids; 4-methyl bicycle-[2.2.2] oct-2-ene-1-carboxylic acid; glucoheptonic acid; 4,4 '-di-2-ethylhexylphosphine oxide-(3-hydroxyl-2-alkene-1-carboxylic acid); the 3-phenylpropionic acid; trimethylace tonitric; butylacetic acid; dodecyl sulphate; gluconic acid; glutamic acid; hydroxynaphthoic acid; salicylic acid; stearic acid and muconic acid.

The solvate of the compound of formula I

This paper has also described the solvate and the method for the treatment of disease of the compound of formula I.For example, the invention provides the method for the treatment of disease by the solvate of Medicine-feeding type I compound.Can be with the solvate of the mode Medicine-feeding type I compound of pharmaceutical composition.

Solvate comprises stoichiometric or non-stoichiometric quantity of solvent, and can for example form in the process of crystallization such as water, ethanol with the pharmacy acceptable solvent.When described solvent is water, form hydrate, perhaps when described solvent is alcohol, form alcohol adduct.In method as described herein, can prepare or form the solvate of compound as herein described easily.Only as example, by the mixture recrystallization from water/organic solvent, can prepare the hydrate of compound as herein described easily, the organic solvent of use includes but not limited to diox, oxolane or methyl alcohol.In addition, the compound that this paper provided can exist with form solvation and solvation.Generally speaking, for the purpose of the Compounds and methods for that this paper provided, think that described solvation form is equivalent to the not form of solvation.

The polymorph of the compound of formula I

The polymorph and the sanatory method of the compound of formula I are also described herein.For example, the polymorph that the invention provides the compound by Medicine-feeding type I is treated the method for disease.Can be with the polymorph of the mode Medicine-feeding type I compound of pharmaceutical composition.

Therefore, compound as herein described comprises all their crystal types, is called polymorph.Polymorph comprises the different crystal accumulation arrangement that the identical element of compound is formed.Polymorph may have different X-ray diffractograms, infrared spectrum, fusing point, density, hardness, crystalline form, optics and electrical properties, stability and dissolubility.Various factors for example recrystallization solvent, crystallization rate and reserve temperature may to cause that single crystal form accounts for leading.

The crystalline polymorph of N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide

The invention still further relates to N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide that demonstrates the particular powder X-ray diffractogram:

Crystalline polymorph A.In some embodiments, described x-ray diffractogram of powder comprises at least about the peak shown in Fig. 5 of 50%.In some embodiments, described x-ray diffractogram of powder comprises at least about the peak shown in Fig. 5 of 70%.In some embodiments, described x-ray diffractogram of powder comprises at least about the peak shown in Fig. 5 of 90%.In some embodiments, the x-ray diffractogram of powder shown in described x-ray diffractogram of powder and Fig. 5 is basic identical.

The invention still further relates to the crystalline polymorph A of N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide, it demonstrates specific differential scanning calorimetric figure.In some embodiments, described specific differential scanning calorimetric figure and the differential scanning calorimetric figure shown in Fig. 6 are basic identical.In some embodiments, described crystalline polymorph A has and is about 143 ℃ fusing point starting point through determine with dsc method.

The invention still further relates to N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) polymorph of cyclopropane-1-sulfonamide, it makes unbodied N-(S)-(3 by comprising from solvent, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the method preparation of the step of 1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide crystallization.The invention still further relates to N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) polymorph of cyclopropane-1-sulfonamide, it makes unbodied N-(S)-(3 by comprising from the mixture of hexane and ethyl acetate, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the method preparation of the step of 1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide crystallization.

The invention still further relates to pharmaceutical composition, it comprises the N-(S)-(3 of effective dose, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-crystalline polymorph A and the pharmaceutically acceptable carrier or the carrier of 1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide.Other aspects of the present invention relate to pharmaceutical composition, and it comprises described crystalline polymorph A and at least a excipient or carrier.

The crystalline polymorph A of N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide is used to treatment or prophylaxis of cancer or inflammatory disease.The invention further relates to the method for treatment or prophylaxis of cancer or inflammatory disease, it comprises to the N-of experimenter's effective dosage that these needs are arranged (S)-(3, the crystalline polymorph A of 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide.Other other aspects of the present invention relate to the method for the treatment of or preventing inflammatory disease, and it comprises the crystalline polymorph to experimenter's effective dosage that these needs are arranged.Further aspect of the present invention relates to the method for the treatment of or preventing proliferative diseases, and it comprises the crystalline polymorph to experimenter's effective dosage that these needs are arranged.

The prodrug of formula I compound

This paper has also described the prodrug and the sanatory method of formula I compound.For example, the invention provides the method for the treatment of disease by the prodrug of Medicine-feeding type I compound.Can be with the prodrug of the mode Medicine-feeding type I compound of pharmaceutical composition.

Prodrug generally is the precursor of medicine, and to patient's administration and after absorbing subsequently, it is converted into active or active stronger material through some process, for example the conversion by metabolic pathway.Some prodrugs have chemical group on prodrug, described chemical group makes the prodrug activity lower and/or give described medicine dissolution or some other character.When described chemical group when described prodrug is cut off and/or modifies, produce active medicine.Because prodrug may be easier to administration than parent drug in some cases, all they normally useful.For example, prodrug may be biological available by oral administration, and its parent is not biological available.Than parent drug, prodrug also may have better dissolubility in pharmaceutical composition.The limiting examples of prodrug can be a compound as described herein, administration promotes to pass through the transportation of cell membrane as ester (" prodrug ") with it, water-soluble unfavorable at the cell membrane place to mobility, but, in case it enters cell (water-soluble therein is favourable), just be hydrolyzed into the active entity of carboxylic acid through metabolism.Other examples of prodrug may be and the small peptide (polyaminoacid) of acid groups Cheng Jian, state peptide in this key place and discharge active part through metabolism.

In order to be used as dressing agent, prodrug can be designed to reversible medicaments derivative to promote drug transport to site-specific sex organization.So far, thus the design of prodrug be for effective water solubility of improving the treatment compound be that targeting is carried out in the zone of primary solvent to water.Referring to 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 the 14th volume; With Edward B.Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, intactly add herein.

In addition, (for example, more details are referring to Saulnier etc. can to prepare the prodrug derivant of compound as described herein by method known to those skilled in the art, (1994), Bioorganic and Medicinal Chemistry Letters, Vol.4, p.1985).Only as example; formula I compound by making non-derivative and suitable carbamoyl reagent are such as but not limited to 1; 1-acyloxy alkyl chloride formic acid esters (1,1-acyloxyalkylcarbanochloridate), reaction such as p-nitrophenyl carbonic ester, can prepare suitable prodrug.Produce derivative as described herein through metabolism in the prodrug forms of compound described herein, wherein said prodrug body, be included in the scope of claim.In fact, some compound described herein may be the prodrug of another derivative or reactive compound.

In some embodiments, prodrug comprises compound, and wherein the polypeptide chain of amino acid residue or two or more (as 2,3 or 4) amino acid residue is by amido link or covalently bound free amino, hydroxyl or the hydroxy-acid group to compound of the present invention of ester bond.Described amino acid residue includes but not limited to use usually 20 kinds of naturally occurring amino acid of trigram symbolic representation, also comprises 4-hydroxy-proline, oxylysine, desmosine, isodensmosine, 3-Methyl histidine, norvaline, Beta-alanine, γ-An Jidingsuan, citrulling, homocysteine, homoserine, ornithine and methionine sulfone.The prodrug that also comprises other types.

Formula I compound with free amino, hydroxyl or carboxylic group can change into prodrug.For example, the free carboxy group can be derived and changed into acid amides or Arrcostab.As at Advanced Drug Delivery Reviews 1996,19, summarize in 115, the free hydroxyl group group can be changed into the group that includes but not limited to hemisuccinic acid ester, phosphate, dimethylamino acetic acid esters and phosphinylidyne oxygen ylmethyl oxygen base carbonyl by deriving.The carbamate prodrugs of hydroxyl and amino group, and in carbonic ester prodrug, sulphonic acid ester and the sulfuric ester of oh group be also included within.

Comprising also that oh group is derived changes into (acyloxy) methyl ether and (acyloxy) ethyl ether; wherein said acyl group can be an Arrcostab; its group that is randomly included but not limited to ether, amine and carboxylic acid functional replaces, and perhaps wherein said carboxyl groups is aforesaid amino-acid ester.This type of prodrug is described in J.Med.Chem.1996, in 39,10.Unhindered amina can also be derived turns to acid amides, sulfonamide or phosphamide.All these prodrug moieties can be introduced the group that includes but not limited to ether, amine or carboxylic acid functional.

Site on the aromatic ring part of formula I compound may be easy to take place various metabolic responses, therefore introduces suitable substituting group and can reduce, minimize or eliminate this metabolic pathway on described aromatic ring structure.

Pharmaceutical composition

This paper describes pharmaceutical composition.In some embodiments, described pharmaceutical composition comprises the formula I compound or the acceptable salt of its pharmacy of effective dose.In some embodiments, described pharmaceutical composition comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative and at least a pharmaceutically acceptable carrier of effective dose.In some embodiments, described pharmaceutical composition is used for the treatment of illness.In some embodiments, described pharmaceutical composition is used for the treatment of the illness in the mammal.In some embodiments, described pharmaceutical composition is used for the treatment of the illness among the mankind.

Further, the present invention relates to pharmaceutical composition, it comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug.In some embodiments, described pharmaceutical composition also comprises pharmaceutically acceptable carrier.Such composition can comprise assistant agent, excipient and preservative, be used to reagent, filler, adhesive, adsorbent, buffer, disintegrant, solubilizer, other carriers of postponing to absorb, and other inert fractions.The compound method of such composition is well known in the art.

In some embodiments, described pharmaceutical composition is the form that is suitable for oral administration.Further or in other the embodiment, described pharmaceutical composition is the form of tablet, capsule, pill, powder, sustained release preparation, solution, supensoid agent, for parenteral injection is aseptic solution, supensoid agent or emulsion, for topical is ointment or cream, is suppository for rectally perhaps.

Further or in other the embodiment, described pharmaceutical composition adopts the unit dosage forms that is suitable for the accurate dosage of single-dose.Further or in other the embodiment, the amount of formula I compound about 0.001 to the scope of about 1000mg/kg body weight/day.Further or in other the embodiment, the amount of formula I compound is in the scope of about 0.5 to about 50mg/kg/ day.Further or in other the embodiment, the amount of formula I compound is about 0.001 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.01 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.02 to about 5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.05 to about 2.5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.1 to about 1g/ day.Further or in other the embodiment, the dosage level that is lower than above-mentioned scope lower limit may enough be had a surplus.Further or in other the embodiment, the dosage level that is higher than above-mentioned range limit may be necessary.

Further or in other the embodiment, with the single dose compound of Medicine-feeding type I once a day.Further or in other the embodiment, with compound multiple dose every day more than single administration formula I.Further or in other the embodiment, every day twice Medicine-feeding type I compound.Further or in other the embodiment, every day three Medicine-feeding type I compound.Further or in other the embodiment, the compound of four times a day Medicine-feeding type I.Further or in other the embodiment, every day is more than the compound of four Medicine-feeding type I.In some embodiments, described pharmaceutical composition is used for to the mammal administration.Further or in other the embodiment, described mammal is human.

Further or in other the embodiment, described pharmaceutical composition also comprises pharmaceutical carriers, excipient and/or assistant agent.Further or in other the embodiment, described pharmaceutical composition also comprises at least a therapeutic agent.Further or in other the embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic.Further or in other the embodiment, described antineoplastic is selected from by alkylating agent, antimetabolite, epidophylltoxin, antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibitor, hormone/antihormones therapeutic agent and hemopoieticgrowth factor.Further or in other the embodiment, described therapeutic agent is taxol, bortezomib or the two.Further or in other the embodiment, the described pharmaceutical composition of administration is with other therapy couplings.Further or in other the embodiment, described other therapies are radiotherapy, chemotherapy, operation or their any combination.Further or in other the embodiment, described pharmaceutical composition comprises the pharmaceutically acceptable salt of formula I compound.

The invention still further relates to and comprise

Composition.In some embodiments, the 2-OH carbon on the described compound is in the R configuration.In some embodiments, the S-isomer of the essentially no described compound of composition.In some embodiments, described compound comprises the S-isomer that is less than 10% described compound.In some embodiments, described compound comprises the S-isomer that is less than 5% described compound.In some embodiments, described compound comprises the S-isomer that is less than 1% described compound.In some embodiments, described compound is in the R configuration.

In some embodiments, the 2-OH carbon on the described compound is in the S configuration.In some embodiments, the R-isomer of the essentially no described compound of composition.In some embodiments, described compound comprises the R-isomer that is less than 10% described compound.In some embodiments, described compound comprises the R-isomer that is less than 5% described compound.In some embodiments, described compound comprises the R-isomer that is less than 1% described compound.In some embodiments, described compound is the S configuration.

In some embodiments, described composition comprises the compound at least about 50%, and described compound exhibits goes out to comprise the x-ray diffractogram of powder at the peak of being identified in the x-ray diffractogram of powder shown in Fig. 5 of at least 50%.In some embodiments, described x-ray diffractogram of powder comprises the peak of being identified in the x-ray diffractogram of powder shown in Fig. 5 of at least 70%.In some embodiments, described x-ray diffractogram of powder comprises the peak of being identified in the x-ray diffractogram of powder shown in Fig. 5 of at least 90%.In some embodiments, the x-ray diffractogram of powder shown in described x-ray diffractogram of powder and Fig. 5 is basic identical.

In some embodiments, described composition comprises the compound at least about 75%, and described compound exhibits goes out to comprise the powder x-ray diffraction figure at the peak of being identified in the x-ray diffractogram of powder shown in Fig. 5 of at least 50%.In some embodiments, described x-ray diffractogram of powder comprises the peak of being identified in the x-ray diffractogram of powder shown in Fig. 5 of at least 70%.In some embodiments, described x-ray diffractogram of powder comprises the peak of being identified in the x-ray diffractogram of powder shown in Fig. 5 of at least 90%.In some embodiments, the x-ray diffractogram of powder shown in described x-ray diffractogram of powder and Fig. 5 is basic identical.

In some embodiments, described composition comprises the compound at least about 90%, and described compound exhibits goes out to comprise the powder x-ray diffraction figure at the peak of being identified in the x-ray diffractogram of powder shown in Fig. 5 of at least 50%.In some embodiments, described x-ray diffractogram of powder comprises the peak of being identified in the x-ray diffractogram of powder shown in Fig. 5 of at least 70%.In some embodiments, described x-ray diffractogram of powder comprises the peak of being identified in the x-ray diffractogram of powder shown in Fig. 5 of at least 90%.In some embodiments, the x-ray diffractogram of powder shown in described x-ray diffractogram of powder and Fig. 5 is basic identical.

In some embodiments, whole basically described compounds all demonstrate the powder x-ray diffraction figure that comprises the peak of being identified in the x-ray diffractogram of powder shown in Fig. 5 of at least 50% in the described composition.In some embodiments, described x-ray diffractogram of powder comprises the peak of being identified in the x-ray diffractogram of powder shown in Fig. 5 of at least 70%.In some embodiments, described x-ray diffractogram of powder comprises the peak of being identified in the x-ray diffractogram of powder shown in Fig. 5 of at least 90%.In some embodiments, the x-ray diffractogram of powder shown in described x-ray diffractogram of powder and Fig. 5 is basic identical.

In some embodiments, be present in described crystalline polymorph in the described composition and have 143 ℃ the fusing point starting point of being about through determine with dsc method.In some embodiments, described crystalline polymorph is anhydrous basically.In some embodiments, the essentially no solvent of described crystalline polymorph.

In some embodiments, described composition comprises the compound at least about 50%, and described compound exhibits goes out and the essentially identical differential scanning calorimetric of the calorimetric of differential scanning shown in Fig. 6 figure figure.In some embodiments, described crystalline polymorph has 143 ℃ the fusing point starting point of being about through determine with dsc method.In some embodiments, described crystalline polymorph is anhydrous basically.In some embodiments, the essentially no solvent of described crystalline polymorph.

In some embodiments, described composition comprises the compound at least about 75%, and described compound exhibits goes out and the essentially identical differential scanning calorimetric of the calorimetric of differential scanning shown in Fig. 6 figure figure.In some embodiments, described crystalline polymorph has 143 ℃ the fusing point starting point of being about through determine with dsc method.In some embodiments, described crystalline polymorph is anhydrous basically.In some embodiments, the essentially no solvent of described crystalline polymorph.

In some embodiments, described composition comprises the compound at least about 90%, and described compound exhibits goes out and the essentially identical differential scanning calorimetric of the calorimetric of differential scanning shown in Fig. 6 figure figure.In some embodiments, described crystalline polymorph has 143 ℃ the fusing point starting point of being about through determine with dsc method.In some embodiments, described crystalline polymorph is anhydrous basically.In some embodiments, the essentially no solvent of described crystalline polymorph.

In some embodiments, whole basically described compounds all demonstrate and the essentially identical differential scanning calorimetric of the calorimetric of differential scanning shown in Fig. 6 figure figure in the described composition.In some embodiments, described crystalline polymorph has 143 ℃ the fusing point starting point of being about through determine with dsc method.In some embodiments, described crystalline polymorph is anhydrous basically.In some embodiments, the essentially no solvent of described crystalline polymorph.

In some embodiments, N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl-1-(2, the 3-dihydroxypropyl) polymorph of cyclopropane-1-sulfonamide makes unbodied N-(3 by comprising, the method of the step of 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide crystallization prepares.In some embodiments, described crystallisation step comprises crystallization from the mixture of ethyl acetate and heptane, and for example, the ratio of the mixture of ethyl acetate and heptane is that about 1-4 part ethyl acetate is than about 2-10 part heptane, or more specifically, ratio is that about 2 parts of ethyl acetate are than about 5 parts of heptane.

In some embodiments, described compound is become the preparation that directly discharges described compound.In some embodiments, described compound is become to continue to discharge the preparation of described compound.In other embodiments, described compound is become to postpone to discharge the preparation of described compound.

In some embodiments, described composition is a Tabules.In other embodiments, described composition is a capsule formulation.Described composition can be prepared into capsule or Tabules, and can use the optional composition and the preparation method of broad range, 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) ModernPharmaceuticals the 4th edition, 2002.Can use a series of preparation methods, it comprises dry mixed method, wet granulation process, rolled-on method, extrusion, spheronization, coating method and spray drying process.Soft gelatin formulation and preparation method also are fit to.

In some embodiments, described composition comprises filler or thinner.In various embodiments, described filler or thinner are selected from microcrystalline cellulose, silicified microcrystalline cellulose, lactose, mannitol, sompressible sugar, calcium phosphate, calcium sulphate, calcium carbonate, calcium silicates and starch.In other embodiments, described filler or thinner are microcrystalline celluloses.

In some embodiments, described composition comprises disintegrant.In various embodiments, described disintegrant is selected from cross-linked carboxymethyl cellulose sodium, primojel, Crospovidone, methylcellulose, alginic acid, mosanom, starch derivatives, bentonite and aluminium-magnesium silicate.In certain embodiment, described disintegrant is cross-linked carboxymethyl cellulose sodium.

In some embodiments, described composition comprises lubricant.In various embodiments, described lubricant is selected from dolomol, metallic stearate, talcum, sodium stearyl fumarate and stearic acid.In some embodiments, described lubricant is a dolomol.

In some embodiments, described composition comprises wetting agent or surfactant.In various embodiments, described wetting agent or surfactant are selected from lauryl sodium sulfate, glycerine, sorbitan monooleate, Span60, polyoxyethylene anhydrous sorbitol laurate, palmitate, stearate, oleate or six oleates, the pure and mild sorbitan mono-laurate of polyoxyethylene stearyl.In some embodiments, described wetting agent or surfactant are lauryl sodium sulfate.

Can also add other excipient for example glidant, flavor enhancement and colouring agent.At The Handbook ofPharmaceutical Excipients, the 5th edition, 2005 and FDA non-active ingredient database in can find other optional excipient.

The invention still further relates to composition, it comprises:

About 1mg structure is

Compound (such as in any above-mentioned embodiment definition);

About 222.2mg microcrystalline cellulose;

About 12.0mg cross-linked carboxymethyl cellulose sodium;

About 2.4mg lauryl sodium sulfate; With

About 2.4mg dolomol.

The invention still further relates to composition, it comprises:

About 10mg structure is Compound (such as in any above-mentioned embodiment definition);

About 213.2mg microcrystalline cellulose;

About 12.0mg cross-linked carboxymethyl cellulose sodium;

About 2.4mg lauryl sodium sulfate; With

About 2.4mg dolomol.

The invention still further relates to composition, it comprises:

About 20mg structure is

Compound (such as in any above-mentioned embodiment definition);

About 203.2mg microcrystalline cellulose;

About 12.0mg cross-linked carboxymethyl cellulose sodium;

About 2.4mg lauryl sodium sulfate; With

About 2.4mg dolomol.

The invention still further relates to composition, it comprises:

About 40mg structure is

Compound (such as in any above-mentioned embodiment definition);

About 183.2mg microcrystalline cellulose;

About 12.0mg cross-linked carboxymethyl cellulose sodium;

About 2.4mg lauryl sodium sulfate; With

About 2.4mg dolomol.

The invention still further relates to composition, it comprises: the structure of about 0.4 weight % is

Compound (such as in any above-mentioned embodiment definition); Pharmaceutically acceptable carrier or carrier with about 99.6 weight %.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.Further or in other the embodiment, described microcrystalline cellulose accounts for about 92.6 weight % of described composition.Further or in other the embodiment, described composition also comprises: cross-linked carboxymethyl cellulose sodium of about 5 weight %; The lauryl sodium sulfate of about 1 weight %; Dolomol with about 1 weight %.

The invention still further relates to composition, it comprises: the structure of about 4.2 weight % is

Compound (such as in any above-mentioned embodiment definition); Pharmaceutically acceptable carrier or carrier with about 95.8 weight %.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.Further or in other the embodiment, described microcrystalline cellulose accounts for about 88.8 weight % of described composition.Further or in other the embodiment, described composition also comprises: cross-linked carboxymethyl cellulose sodium of about 5 weight %; The lauryl sodium sulfate of about 1 weight %; Dolomol with about 1 weight %.

The invention still further relates to composition, it comprises: the about 2 weight % extremely structure of about 10 weight % are

Compound (such as in any above-mentioned embodiment definition); With pharmaceutically acceptable carrier or the carrier of about 98 weight % to about 90 weight %.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.Further or in other the embodiment, described microcrystalline cellulose accounts for about 85 weight % of described composition to about 95 weight %.Further or in other the embodiment, described composition also comprises: about 1 weight % is to cross-linked carboxymethyl cellulose sodium of about 6 weight %; About 0.1 weight % is to the lauryl sodium sulfate of about 2 weight %; With the dolomol of about 0.25 weight % to about 1.5 weight %.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.Further or in other the embodiment, described microcrystalline cellulose accounts for about 85 weight % of described composition to about 95 weight %.Further or in other the embodiment, described composition also comprises: about 1 weight % is to cross-linked carboxymethyl cellulose sodium of about 6 weight %; With the dolomol of about 0.25 weight % to about 1.5 weight %.

The invention still further relates to composition, it comprises:

About 1mg structure is

Compound;

About 222.2mg microcrystalline cellulose;

About 12.0mg cross-linked carboxymethyl cellulose sodium;

About 2.4mg lauryl sodium sulfate; With

About 2.4mg dolomol.

The invention still further relates to composition, it comprises:

About 10mg structure is

Compound;

About 213.2mg microcrystalline cellulose;

About 12.0mg cross-linked carboxymethyl cellulose sodium;

About 2.4mg lauryl sodium sulfate; With

About 2.4mg dolomol.

The invention still further relates to composition, it comprises:

About 20mg structure is

Compound;

About 203.2mg microcrystalline cellulose;

About 12.0mg cross-linked carboxymethyl cellulose sodium;

About 2.4mg lauryl sodium sulfate; With

About 2.4mg dolomol.

The invention still further relates to composition, it comprises:

About 40mg structure is

Compound;

About 183.2mg microcrystalline cellulose;

About 12.0mg cross-linked carboxymethyl cellulose sodium;

About 2.4mg lauryl sodium sulfate; With

About 2.4mg dolomol.

Compound; Pharmaceutically acceptable carrier or carrier with about 99.6 weight %.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.Further or in other the embodiment, described microcrystalline cellulose accounts for about 92.6 weight % of described composition.Further or in other the embodiment, described composition also comprises: cross-linked carboxymethyl cellulose sodium of about 5 weight %; The lauryl sodium sulfate of about 1 weight %; Dolomol with about 1 weight %.

Compound; Pharmaceutically acceptable carrier or carrier with about 95.8 weight %.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.Further or in other the embodiment, described microcrystalline cellulose accounts for about 88.8 weight % of described composition.Further or in other the embodiment, described composition also comprises: cross-linked carboxymethyl cellulose sodium of about 5 weight %; The lauryl sodium sulfate of about 1 weight %; Dolomol with about 1 weight %.

Compound; With pharmaceutically acceptable carrier or the carrier of about 98 weight % to about 90 weight %.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.Further or in other the embodiment, described microcrystalline cellulose accounts for about 85 weight % of described composition to about 95 weight %.Further or in other the embodiment, described composition also comprises: about 1 weight % is to cross-linked carboxymethyl cellulose sodium of about 6 weight %; About 0.1 weight % is to the lauryl sodium sulfate of about 2 weight %; With the dolomol of about 0.25 weight % to about 1.5 weight %.In some embodiments, described pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.Further or in other the embodiment, described microcrystalline cellulose accounts for about 85 weight % of described composition to about 95 weight %.Further or in other the embodiment, described composition also comprises: about 1 weight % is to cross-linked carboxymethyl cellulose sodium of about 6 weight %; With the dolomol of about 0.25 weight % to about 1.5 weight %.

The invention still further relates to composition, it comprises:

About 1mg structure is

Compound;

About 222.2mg microcrystalline cellulose;

About 12.0mg cross-linked carboxymethyl cellulose sodium;

About 2.4mg lauryl sodium sulfate; With

About 2.4mg dolomol.

The invention still further relates to composition, it comprises:

About 10mg structure is

Compound;

About 213.2mg microcrystalline cellulose;

About 12.0mg cross-linked carboxymethyl cellulose sodium;

About 2.4mg lauryl sodium sulfate; With

About 2.4mg dolomol.

The invention still further relates to composition, it comprises:

About 20mg structure is

Compound;

About 203.2mg microcrystalline cellulose;

About 12.0mg cross-linked carboxymethyl cellulose sodium;

About 2.4mg lauryl sodium sulfate; With

About 2.4mg dolomol.

The invention still further relates to composition, it comprises:

About 40mg structure is

Compound;

About 183.2mg microcrystalline cellulose;

About 12.0mg cross-linked carboxymethyl cellulose sodium;

About 2.4mg lauryl sodium sulfate; With

About 2.4mg dolomol.

The invention still further relates to composition, it comprises: about 0.4 weight % structure is

Also describe pharmaceutical composition herein, it comprises the crystalline polymorph A of N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide of effective dose.In some embodiments, described pharmaceutical composition comprises the N-(S)-(3 of effective dose, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the crystalline polymorph A and at least a pharmaceutically acceptable carrier of 1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide.In some embodiments, described pharmaceutical composition is used for the treatment of illness.In some embodiments, described pharmaceutical composition is used for the treatment of the illness in the mammal.In some embodiments, described pharmaceutical composition is used for the treatment of the illness among the mankind.In some embodiments, described pharmaceutical composition is used for the treatment of or prevents inflammatory disease.In some embodiments, described pharmaceutical composition is used for the treatment of or prevents proliferative diseases.

Comprise the described compound of polymorph and the using method of described composition

In other respects, the present invention relates to obtain among the patient method of effect, it comprises that wherein said effect is selected from the inhibition to various cancers, immunological disease and inflammatory disease to the formula I of patient's effective dosage compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug.In some embodiments, with the composition administration of described compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug as the composition that also comprises pharmaceutically acceptable carrier or carrier.In some embodiments, described effect is to suppress various cancers.Further or in other the embodiment, described effect is to suppress immunological disease.Further or in other the embodiment, described effect is to suppress inflammatory disease.

Described herein and any composition prescription can be used for the method that this part provides.

In some embodiments, administration comprises formula I compound compositions, with other therapy couplings.Further or in other the embodiment, described other therapies are radiotherapy, chemotherapy or operation or their any combination.Further or in other the embodiment, comprise formula I compound compositions and at least a therapeutic agent administering drug combinations.

In some embodiments, oral administration, intraduodenal administration, parenteral (comprising intravenous administration, subcutaneous administration, intramuscular administration, intravascular administration or infusion administration), the described composition of topical or rectally.Further or in other the embodiment, the amount of formula I compound about 0.001 to the scope of about 1000mg/kg body weight/day.Further or in other the embodiment, the amount of formula I compound is in the scope of about 0.5 to about 50mg/kg/ day.Further or in other the embodiment, the amount of formula I compound is about 0.001 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.01 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.02 to about 5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.05 to about 2.5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.1 to about 1g/ day.Further or in other the embodiment, the dosage level that is lower than above-mentioned scope lower limit may enough be had a surplus.Further or in other the embodiment, the dosage level that is higher than above-mentioned range limit may be necessary.

In some embodiments of composition provided herein and method, the MEK kinases inhibitor that also comprises formula I compound is provided, the compound of wherein said formula I exists to the amount of about 200mg with about 0.1m.In other embodiments, described MEK kinases inhibitor comprises the compound of formula I, and it exists to the amount of about 100mg with about 0.2mg.In other embodiments, described MEK kinases inhibitor comprises the compound of formula I, and it exists to the amount of about 90mg with about 0.3mg.In other embodiments, described MEK kinases inhibitor comprises the compound of formula I, and it exists to the amount of about 80mg with about 0.4mg.In other embodiments, described MEK kinases inhibitor comprises the compound of formula I, and it exists to the amount of about 70mg with about 0.5mg.In other embodiments, described MEK kinases inhibitor comprises the compound of formula I, and it exists to the amount of about 80mg with about 0.4mg.In other embodiments, described MEK kinases inhibitor comprises the compound of formula I, and it exists to the amount of about 70mg with about 0.5mg.In other embodiments, described MEK kinases inhibitor comprises the compound of formula I, and it exists to the amount of about 60mg with about 1mg.In other embodiments, described MEK kinases inhibitor comprises the compound of formula I, and it exists to the amount of about 50mg with about 1.5mg.In other embodiments, described MEK kinases inhibitor comprises the compound of formula I, and it exists to the amount of about 45mg with about 2mg.In other embodiments, described MEK kinases inhibitor comprises the compound of formula I, and it exists to the amount of about 40mg with about 2.5mg.In further embodiment, the MEK kinases inhibitor that the formula I compound that exists with the dosage that provides herein also is provided is selected from

In some embodiments of composition provided herein and method, the MEK kinases inhibitor that also comprises formula I compound is provided, the compound of wherein said formula 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 13mg, the amount of about 14mg or about 15mg exists.In further embodiment, the formula I compound that exists with dosage provided herein is selected from

In some embodiments of composition provided herein and method, the MEK kinases inhibitor that also comprises formula I compound is provided, and the compound of wherein said formula 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 180mg, the amount of about 190mg or about 200mg exists.In further embodiment, the formula I that exists with dosage provided herein

Compound is selected from

In some respects, the present invention relates to treat the method for disease in the individuality of suffering from described disease, it comprises the composition that comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug to described individual effective dosage.

Disease and illness that MEK regulates

Also described herein by making MEK contact the method for regulating the MEK activity with a certain amount of formula I compound that is enough to regulate the MEK activity.Adjusting can be to suppress or activation MEK activity.In some embodiments, the invention provides by making the method for MEK and a certain amount of formula I compound contact inhibition MEK activity that is enough to suppress the MEK activity.In some embodiments, the invention provides by making the method for MEK activity in solution and the described solution of a certain amount of formula I compound contact inhibition that is enough to suppress MEK activity in the described solution.In some embodiments, the invention provides by making the method for MEK activity in cell and the described cell of compound contact inhibition a certain amount of as herein described that is enough to suppress MEK activity in the described cell.In some embodiments, the invention provides by making the method for MEK activity in tissue and the described tissue of compound contact inhibition a certain amount of as herein described that is enough to suppress MEK activity in the described tissue.In some embodiments, the invention provides by making the method for MEK activity in biological and the described biology of compound contact inhibition a certain amount of described herein that is enough to suppress MEK activity in the described biology.In some embodiments, the invention provides by making the method for MEK activity in animal and the described animal of compound contact inhibition a certain amount of as herein described that is enough to suppress MEK activity in the described animal.In some embodiments, the invention provides by making the method for MEK activity in mammal and the described mammal of compound contact inhibition a certain amount of as herein described that is enough to suppress MEK activity in the described mammal.In some embodiments, the invention provides by making the method for MEK activity among human and the described mankind of compound contact inhibition a certain amount of as herein described that are enough to suppress MEK activity among the described mankind.

The compound of formula I and comprise formula I compound with and the composition of the acceptable salt of pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug, the activity that can regulate the MEK enzyme; And similarly be used to treat unusual MEK enzymic activity and cause the symptom of the disease or the patient's condition and/or the disease or the patient's condition of symptom.

In some respects, the present invention relates to treat and comprise the illness of being regulated by the MEK cascade in the human mammal or the method for the patient's condition, it comprises a certain amount of formula I compound or the acceptable salt of its pharmacy, ester, prodrug, solvate, hydrate or the derivative of regulating described cascade to described mammal administration effectively.Those skilled in the art can determine suitable dosage for particular patient according to known method.

In other respects, the present invention relates to suppress the method for MEK enzyme.In some embodiments, described method comprises makes described MEK enzyme contact with a certain amount of composition that is enough to suppress described enzyme, described composition comprises compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or the prodrug of formula I, and wherein said enzyme is suppressed.Further or in other the embodiment, described enzyme is suppressed at least about 1%.Further or in other the embodiment, described enzyme is suppressed at least about 2%.Further or in other the embodiment, described enzyme is suppressed at least about 3%.Further or in other the embodiment, described enzyme is suppressed at least about 4%.Further or in other the embodiment, described enzyme is suppressed at least about 5%.Further or in other the embodiment, described enzyme is suppressed at least about 10%.Further or in other the embodiment, described enzyme is suppressed at least about 20%.Further or in other the embodiment, described enzyme is suppressed at least about 25%.Further or in other the embodiment, described enzyme is suppressed at least about 30%.Further or in other the embodiment, described enzyme is suppressed at least about 40%.Further or in other the embodiment, described enzyme is suppressed at least about 50%.Further or in other the embodiment, described enzyme is suppressed at least about 60%.Further or in other the embodiment, described enzyme is suppressed at least about 70%.Further or in other the embodiment, described enzyme is suppressed at least about 75%.Further or in other the embodiment, described enzyme is suppressed at least about 80%.Further or in other the embodiment, described enzyme is suppressed at least about 90%.Further or in other the embodiment, described enzyme is suppressed basically fully.Further or in other the embodiment, described MEK enzyme is the MEK kinases.Further or in other the embodiment, described MEK enzyme is MEK1.Further or in other the embodiment, described MEK enzyme is MEK2.Further or in other the embodiment, described contact occurs in the cell.Further or in other the embodiment, described cell is mammiferous cell.Further or in other the embodiment, described mammiferous cell is the human cell.Further or in other the embodiment, the composition of the pharmaceutically acceptable salt of the involved formula I compound of described MEK enzyme suppresses.

Further or other aspect, the present invention relates to treat the method for illness described in the individuality of the illness of suffering from MEK mediation, it comprises the composition to described individual effective dosage, and described composition comprises compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or the prodrug of formula I.In some embodiments, oral administration, intraduodenal administration, parenteral (comprising intravenous administration, subcutaneous administration, intramuscular administration, intravascular administration or infusion administration), topical or rectally comprise formula I compound compositions.In some embodiments, described pharmaceutical composition is the form that is suitable for oral administration.Further or in other the embodiment, described pharmaceutical composition is the form of tablet, capsule, pill, powder, sustained release preparation, solution, supensoid agent, for parenteral injection is aseptic solution, supensoid agent or emulsion, for topical is ointment or emulsifiable paste, is suppository for rectally perhaps.Further or in other the embodiment, described pharmaceutical composition is the unit dosage forms that is suitable for accurate dosage single-dose.Further or in other the embodiment, described pharmaceutical composition also comprises pharmaceutical carriers, excipient and/or assistant agent.

In some embodiments, administration comprises formula I compound compositions, with other therapy couplings.Further or in other the embodiment, described other therapies are radiotherapy, chemotherapy, operation or their any combination.Further or in other the embodiment, comprise the described composition and at least a therapeutic agent administering drug combinations of formula I compound.Further or in other the embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic.Further or in other the embodiment, described antineoplastic is selected from alkylating agent, antimetabolite, epidophylltoxin, antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibitor, hormone/antihormones therapeutic agent and hemopoieticgrowth factor.Further or in other the embodiment, described therapeutic agent is selected from taxol, bortezomib or the two.

In some embodiments, the illness of described MEK mediation is selected from inflammatory disease, infection, autoimmune disease, apoplexy, ischemic, cardiac conditions, neurological disorders, fibrillatable illness, proliferative disorders, excess proliferative illness, non-cancer excess proliferative illness, tumour, leukemia, knurl, cancer, cancer, metabolic disease, malignant diseases, reangiostenosis, psoriasis, atherosclerotic, rheumatoid arthritis, osteoarthritis, heart failure, chronic ache, neuropathic pain, dry eyes, angle-closure glaucoma and open-angle glaucoma.Further or in other the embodiment, the illness of described MEK mediation is an inflammatory disease.Further or in other the embodiment, the illness of described MEK mediation is an excess proliferative disease.Further or in other the embodiment, the illness of described MEK mediation is selected from tumour, leukemia, knurl, cancer, cancer and malignant diseases.Further or in other the embodiment, described illness is cancer of the stomach, the cancer of the brain, breast cancer, lung cancer, oophoroma, cancer of pancreas, prostate cancer, kidney, colorectal cancer or leukemia.Further or in other the embodiment, described fibrillatable illness is chorionitis, polymyositis, systemic lupus, rheumatoid arthritis, cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis.Further or in other the embodiment, the composition of the pharmaceutically acceptable salt that comprises formula I compound of effective dosage.

The invention still further relates to by making MEK and being enough to regulate a certain amount of N-(S)-(3 of MEK activity, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the crystalline polymorph A contact of 1-(2, the 3-dihydroxypropyl) ring third-1-sulfonamide regulates the method for MEK activity.Adjusting can be to suppress or activation MEK activity.In some embodiments, the invention provides by making MEK and a certain amount of N-(S)-(3 that is enough to suppress the MEK activity, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-method of the crystalline polymorph A contact inhibition MEK activity of 1-(2, the 3-dihydroxypropyl) ring third-1-sulfonamide.In some embodiments, the invention provides by making solution and a certain amount of N-(S)-(3 that is enough to suppress MEK activity in the described solution, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the described solution of crystalline polymorph A contact inhibition of 1-(2, the 3-dihydroxypropyl) ring third-1-sulfonamide in the method for MEK activity.In some embodiments, the invention provides by making cell and a certain amount of N-(S)-(3 that is enough to suppress MEK activity in the described cell, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the described cell of 1-(2, the 3-dihydroxypropyl) ring third-1-sulfonamide crystalline polymorph A contact inhibition in the method for MEK activity.In some embodiments, the invention provides by making tissue and a certain amount of N-(S)-(3 that is enough to suppress MEK activity in the described tissue, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the described tissue of crystalline polymorph A contact inhibition of 1-(2, the 3-dihydroxypropyl) ring third-1-sulfonamide in the method for MEK activity.In some embodiments, the invention provides by making biology and a certain amount of N-(S)-(3 that is enough to suppress MEK activity in the described biology, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the described biology of crystalline polymorph A contact inhibition of 1-(2, the 3-dihydroxypropyl) ring third-1-sulfonamide in the method for MEK activity.In some embodiments, the invention provides by making animal and a certain amount of N-(S)-(3 that is enough to suppress MEK activity in the described animal, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-method of MEK activity in the described animal of crystalline polymorph A contact inhibition of 1-(2, the 3-dihydroxypropyl) ring third-1-sulfonamide.In some embodiments, the invention provides by making mammal and a certain amount of N-(S)-(3 that is enough to suppress MEK activity in the described mammal, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the described mammal of crystalline polymorph A contact inhibition of 1-(2, the 3-dihydroxypropyl) ring third-1-sulfonamide in the method for MEK activity.In some embodiments, the invention provides by making the mankind and a certain amount of N-(S)-(3 that is enough to suppress MEK activity among the described mankind, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the described mankind of crystalline polymorph A contact inhibition of 1-(2, the 3-dihydroxypropyl) ring third-1-sulfonamide in the method for MEK activity.

Cancer

In other respects, the present invention relates to method for cancer in treatment or prevention (prevention or prophylaxis) individuality, it comprises to the formula I of described individual effective dosage compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug.In some embodiments, with the composition administration of described compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug as the composition that also comprises pharmaceutically acceptable carrier or carrier.Further or in other the embodiment, described cancer is the cancer of the brain, breast cancer, lung cancer, oophoroma, cancer of pancreas, prostate cancer, kidney, colorectal cancer, cancer of the stomach or leukemia.Further or in other the embodiment, described fibrillatable illness is chorionitis, polymyositis, systemic lupus, rheumatoid arthritis, cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis.Further or in other the embodiment, described cancer is the cancer of the brain, breast cancer, lung cancer, oophoroma, cancer of pancreas, prostate cancer, kidney, colorectal cancer, leukemia, melanoma, thyroid cancer, or basal-cell carcinoma.Further or in other the embodiment, described cancer is the cancer of the brain or adrenocortical carcinoma.Further or in other the embodiment, described cancer is a breast cancer.Further or in other the embodiment, described cancer is an oophoroma.Further or in other the embodiment, described cancer is a cancer of pancreas.Further or in other the embodiment, described cancer is a prostate cancer.Further or in other the embodiment, described cancer is a kidney.Further or in other the embodiment, described cancer is a colorectal cancer.Further or in other the embodiment, described cancer is a myeloid leukemia.Further or in other the embodiment, described cancer is a glioblastoma.Further or in other the embodiment, described cancer is a folliculus type lymphoma.Further or in other the embodiment, described cancer is preceding B acute leukemia.Further or in other the embodiment, described cancer is a chronic lymphocytic B leukemia.Further or in other the embodiment, described cancer is a celiothelioma.Further or in other the embodiment, described cancer is a small-cell carcinoma of the lung.In some embodiments, described cancer is a cancer of the stomach.

In some embodiments, oral administration, intraduodenal administration, parenteral (comprising intravenous administration, subcutaneous administration, intramuscular administration, intravascular administration or infusion administration), topical or the described composition of rectally.Further or in other the embodiment, with the single dose compound of Medicine-feeding type I once a day.Further or in other the embodiment, with compound multiple dose every day more than single administration formula I.Further or in other the embodiment, every day twice Medicine-feeding type I compound.Further or in other the embodiment, every day three Medicine-feeding type I compound.Further or in other the embodiment, the compound of four times a day Medicine-feeding type I.Further or in other the embodiment, every day is more than the compound of four Medicine-feeding type I.In some embodiments, the individuality of suffering from cancer is a mammal.Further or in other the embodiment, described individuality is human.Further or in other the embodiment, the composition of the pharmaceutically acceptable salt that comprises formula I compound of effective dosage.

Unusual cell growth

Compound, pharmaceutical composition and the method for the cell growth that is used to suppress unusual have also been described herein.In some embodiments, described unusual cell growth occurs in the mammal.The method that suppresses the growth of unusual cell comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or the derivative of effective dosage, and wherein unusual cell growth is suppressed.The method of unusual cell growth comprises to a certain amount of formula I compound of described mammal administration or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative in the inhibition mammal, and the compound of wherein said amount or salt suppress cell growth unusual in the mammal effectively.

In some embodiments, described method comprises the formula I compound of effective dose or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative, with a certain amount of chemotherapeutant administering drug combinations, the amount of wherein said compound or its salt, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative and described chemotherapeutant suppresses unusual cell growth jointly effectively.Many chemotherapeutants are known in the art at present, and can with compound coupling 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, topoisomerase enzyme inhibitor, biological response modifier, antihormones, angiogenesis inhibitor and antiandrogen.

The method of the cell growth that suppresses unusual in the mammal has also been described, it comprises to a certain amount of formula I compound of described mammal administration or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative, with the radiotherapy coupling, wherein said compound or its salt, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, the amount of hydrate or derivative and radiotherapy coupling suppress cell growth unusual in the mammal effectively or treat excess proliferative disease in the mammal.It is known in the art using radiotherapeutic technology, and these technology can with therapy coupling as herein described.The administration that can determine at this conjoint therapy Chinese style I compound as described herein.

The invention still further relates to the method and the pharmaceutical composition of the cell growth that suppresses unusual in the mammal, described pharmaceutical composition comprises a certain amount of formula I compound, or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative, or its isotope-labeled derivative and a certain amount of one or more materials that are selected from antiangiogenic agent, signal transduction inhibitor and antiproliferative.

Antiangiogenic agent, for example MMP-2 (matrix metalloproteinase 2) inhibitor, MMP-9 (matrix metalloproteinase 9) inhibitor and COX-11 (cyclo-oxygenase 11) inhibitor, can with compound of the present invention and pharmaceutical composition coupling as herein described.The example of useful COX-II inhibitor comprises: CELEBREX ^TM(Sai-Mi-Xi-Bu (alecoxib)), valdecoxib and rofecoxib.The case description of useful NMPI is in WO 96/33172 (being published on October 24th, 1996), WO 96/27583 (being published on March 7th, 1996), No. 97304971.1, european patent application (being filed on July 8th, 1997), No. 99308617.2, european patent application (being filed on October 29th, 1999), WO 98/07697 (being published on February 26th, 1998), 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 (being published 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 31 nineteen ninety), WO 99/52910 (being published on October 21st, 1999), WO 99/52889 (being published on October 21st, 1999), WO 99/29667 (being published on June 17th, 1999), PCT International Application PCT/IB98/01113 number (being filed on July 21st, 1998), No. 99302232.1, european patent application (being filed on March 25th, 1999), No. 9912961.1, UK Patent Application (being filed on June 3rd, 1999), U.S. Provisional Application 60/148, No. 464 (being filed on August 12nd, 1999), United States Patent (USP) 5,863,949 (being issued on January 26th, 1999), United States Patent (USP) 5,861, No. 510 (being issued on January 19th, 1999), and European patent publication 780, in 386 (being published on June 25th, 1997), it is all intactly quoted and adds as herein.Some MMP-2 and MMP-9 inhibitor almost do not have MMP-1 and suppress active or do not have the MMP-1 inhibition active, and with respect to other matrix metalloproteinases (being MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12 and MMP-13), some MMP-2 and MMP-9 inhibitor optionally suppress MMP-2 and/or AMP-9.Some instantiations that are used for the present invention's MMP inhibitor are AG-3340, RO32-3555 and RS 13-0830.

In other respects, the present invention relates to make the method for cancer cell degeneration, anticancer growth or kill cancer cell, it comprises that the composition that makes described cell and make described cell degradation effectively, suppress described cell growth or kill the amount of described cell contacts, and described composition comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug.In some embodiments, described cancer cell comprises 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 the embodiment, described composition and at least a therapeutic agent administering drug combinations.Further or in other the embodiment, described therapeutic agent is taxol, bortezomib or the two.Further or in other the embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic.Further or in other the embodiment, described antineoplastic is selected from alkylating agent, antimetabolite, epidophylltoxin; Antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibitor, hormone/antihormones therapeutic agent and hemopoieticgrowth factor.

In some embodiments, described cancer cell is degenerated.Further or in other the embodiment, 1% described cancer cell is degenerated.Further or in other the embodiment, 2% described cancer cell is degenerated.Further or in other the embodiment, 3% described cancer cell is degenerated.Further or in other the embodiment, 4% described cancer cell is degenerated.Further or in other the embodiment, 5% described cancer cell is degenerated.Further or in other the embodiment, 10% described cancer cell is degenerated.Further or in other the embodiment, 20% described cancer cell is degenerated.Further or in other the embodiment, 25% described cancer cell is degenerated.Further or in other the embodiment, 30% described cancer cell is degenerated.Further or in other the embodiment, 40% described cancer cell is degenerated.Further or in other the embodiment, 50% described cancer cell is degenerated.Further or in other the embodiment, 60% described cancer cell is degenerated.Further or in other the embodiment, 70% described cancer cell is degenerated.Further or in other the embodiment, 75% described cancer cell is degenerated.Further or in other the embodiment, 80% described cancer cell is degenerated.Further or in other the embodiment, 90% described cancer cell is degenerated.Further or in other the embodiment, 100% described cancer cell is degenerated.Further or in other the embodiment, whole described cancer cells are degenerated.

In some embodiments, described cancer cell is killed.Further or in other the embodiment, 1% described cancer cell is killed.Further or in other the embodiment, 2% described cancer cell is killed.Further or in other the embodiment, 3% described cancer cell is killed.Further or in other the embodiment, 4% described cancer cell is killed.Further or in other the embodiment, 5% described cancer cell is killed.Further or in other the embodiment, 10% described cancer cell is killed.Further or in other the embodiment, 20% described cancer cell is killed.Further or in other the embodiment, 25% described cancer cell is killed.Further or in other the embodiment, 30% described cancer cell is killed.Further or in other the embodiment, 40% described cancer cell is killed.Further or in other the embodiment, 50% described cancer cell is killed.Further or in other the embodiment, 60% described cancer cell is killed.Further or in other the embodiment, 70% described cancer cell is killed.Further or in other the embodiment, 75% described cancer cell is killed.Further or in other the embodiment, 80% described cancer cell is killed.Further or in other the embodiment, 90% described cancer cell is killed.Further or in other the embodiment, 100% described cancer cell is killed.Further or in other the embodiment, whole basically described cancer cells all are killed.

Further or in other the embodiment, the growth of described cancer cell is suppressed.Further or in other the embodiment, the growth of described cancer cell is suppressed about 1%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 2%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 3%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 4%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 5%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 10%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 20%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 25%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 30%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 40%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 50%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 60%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 70%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 75%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 80%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 90%.Further or in other the embodiment, the growth of described cancer cell is suppressed about 100%.Further or in other the embodiment, use the composition of the pharmaceutically acceptable salt that comprises formula I compound.

The method that suppresses abnormal cell growth is also described herein.In some embodiments, described abnormal cell growth occurs in the mammal.The method that suppresses abnormal cell growth comprises the N-(S)-(3 of effective dosage, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) the crystalline polymorph A of cyclopropane-1-sulfonamide, wherein abnormal cell growth is suppressed.The method that suppresses abnormal cell growth in the mammal comprises to a certain amount of N-of described mammal administration (S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) the crystalline polymorph A of cyclopropane-1-sulfonamide, N-(S)-(3 wherein, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-amount of the crystalline polymorph A of 1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide suppresses the abnormal cell growth in the mammal effectively.

In some embodiments, described method comprises the N-(S)-(3 of administering drug combinations effective dose, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) the crystalline polymorph A of cyclopropane-1-sulfonamide and a certain amount of chemotherapeutant, N-(S)-(3 wherein, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) the crystalline polymorph A of cyclopropane-1-sulfonamide and the amount of described chemotherapeutant suppress abnormal cell growth jointly effectively.

At present, many chemotherapeutants are known in the art, and can with compound of the present invention and composition coupling.In some embodiments, described chemotherapeutant is selected from mitotic inhibitor, alkylating agent, antimetabolite, embedding antibiotic, growth factor receptor inhibitors, cell cycle inhibitor, enzyme, topoisomerase enzyme inhibitor, biological response modifier, antihormones, angiogenesis inhibitor and antiandrogen.

In some embodiments, the method that suppresses abnormal cell growth in the mammal comprises to a certain amount of N-of described mammal administration (S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) the crystalline polymorph A of cyclopropane-1-sulfonamide, with the radiotherapy coupling, N-(S)-(3 wherein, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-amount and the described radiotherapy coupling of the crystalline polymorph A of 1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide suppress abnormal cell growth effectively.It is known in the art using radiotherapeutic technology, and these technology can be used for conjoint therapy as herein described.

Treatment excess proliferative illness

In other respects, the present invention relates to treat the method that mammal comprises excess proliferative illness among the mankind, it comprises to the formula I compound of described mammal drug treatment effective dose or the acceptable salt of its pharmacy, solvate, polymorph, ester, dynamic isomer or prodrug.

In other respects, the present invention relates to treat or prevent the method for proliferative diseases in the individuality, it comprises to the formula I of described individual effective dosage compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug.In some embodiments, described compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug are as the composition administration of composition, and described composition also comprises pharmaceutically acceptable carrier or carrier.In some embodiments, described proliferative diseases is cancer, psoriasis, ISR, autoimmune disease or atherosclerotic.Further or in other the embodiment, described proliferative diseases is an excess proliferative disease.Further or in other the embodiment, described proliferative diseases is selected from tumour, leukemia, knurl, cancer, cancer and malignant diseases.Further or in other the embodiment, described cancer is the cancer of the brain, breast cancer, lung cancer, oophoroma, cancer of pancreas, prostate cancer, kidney, cancer of the stomach, colorectal cancer or leukemia.Further or in other the embodiment, described fibrillatable illness is chorionitis, polymyositis, systemic lupus, rheumatoid arthritis, cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis.Further or in other the embodiment, described cancer is the cancer of the brain, breast cancer, lung cancer, oophoroma, cancer of the stomach, cancer of pancreas, prostate cancer, kidney, colorectal cancer or leukemia.Further or in other the embodiment, described cancer is the cancer of the brain or adrenocortical carcinoma.Further or in other the embodiment, described cancer is a breast cancer.Further or in other the embodiment, described cancer is an oophoroma.Further or in other the embodiment, described cancer is a cancer of pancreas.Further or in other the embodiment, described cancer is a prostate cancer.Further or in other the embodiment, described cancer is a kidney.Further or in other the embodiment, described cancer is a colorectal cancer.Further or in other the embodiment, described cancer is a myeloid leukemia.Further or in other the embodiment, described cancer is a glioblastoma.Further or in other the embodiment, described cancer is a folliculus type lymphoma.Further or in other the embodiment, described cancer is preceding B acute leukemia.Further or in other the embodiment, described cancer is a chronic lymphocytic B leukemia.Further or in other the embodiment, described cancer is a celiothelioma.Further or in other the embodiment, described cancer is a small-cell carcinoma of the lung.In some embodiments, described cancer is a cancer of the stomach.

In some embodiments, administration comprises formula I compound compositions, with other therapy couplings.Further or in other the embodiment, described other therapies are radiotherapy, chemotherapy, operation or their combination.Further or in other the embodiment, comprise the described composition and at least a therapeutic agent administering drug combinations of formula I compound.Further or in other the embodiment, described therapeutic agent is selected from cytotoxic agent, antiangiogenic agent and antineoplastic.Further or in other the embodiment, described antineoplastic is selected from alkylating agent, antimetabolite, epidophylltoxin, antitumor enzyme, topoisomerase enzyme inhibitor, procarbazine, mitoxantrone, platinum coordination complex, biological response modifier and growth inhibitor, hormone/antihormones therapeutic agent and hemopoieticgrowth factor.Further or in other the embodiment, described therapeutic agent is selected from taxol, bortezomib or the two.

The tumour size

In other respects, the present invention relates to reduce the tumour size in individuality, suppress the method that the tumour size increases, reduces tumor proliferation or prevention tumor proliferation, it comprises to the formula I of described individual effective dosage compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug.In some embodiments, described compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug are as the composition administration of composition, and described composition also comprises pharmaceutically acceptable carrier or carrier.In some embodiments, the size of tumour is reduced.Further or in other the embodiment, the size of tumour is reduced at least 1%.Further or in other the embodiment, the size of tumour is reduced at least 2%.Further or in other the embodiment, the size of tumour is reduced at least 3%.Further or in other the embodiment, the size of tumour is reduced at least 4%.Further or in other the embodiment, the size of tumour is reduced at least 5%.Further or in other the embodiment, the size of tumour is reduced at least 10%.Further or in other the embodiment, the size of tumour is reduced at least 20%.Further or in other the embodiment, the size of tumour is reduced at least 25%.Further or in other the embodiment, the size of tumour is reduced at least 30%.Further or in other the embodiment, the size of tumour is reduced at least 40%.Further or in other the embodiment, the size of tumour is reduced at least 50%.Further or in other the embodiment, the size of tumour is reduced at least 60%.Further or in other the embodiment, the size of tumour is reduced at least 70%.Further or in other the embodiment, the size of tumour is reduced at least 75%.Further or in other the embodiment, the size of tumour is reduced at least 80%.Further or in other the embodiment, the size of tumour is reduced at least 85%.Further or in other the embodiment, the size of tumour is reduced at least 90%.Further or in other the embodiment, the size of tumour is reduced at least 95%.Further or in other the embodiment, described tumour is uprooted.In some embodiments, the size of tumour does not increase.

In some embodiments, tumor proliferation is slowed down 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 at least 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 reduced at least 70%.In some embodiments, tumor proliferation is reduced at least 75%.In some embodiments, tumor proliferation is reduced at least 75%.In some embodiments, tumor proliferation is reduced at least 80%.In some embodiments, tumor proliferation is reduced at least 90%.In some embodiments, tumor proliferation is reduced at least 95%.In some embodiments, tumor proliferation is prevented from.

Inflammatory disease

In other respects, the present invention relates to treat or prevent the method for inflammatory disease in the individuality, it comprises to the formula I of described individual effective dosage compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug.In some embodiments, described compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer or prodrug are as the composition administration of composition, and described composition also comprises pharmaceutically acceptable carrier or carrier.Further or in other the embodiment, described inflammatory disease is to be selected from chronic inflammatory disease, rheumatoid arthritis, rheumatoid arthritis, spondyloarthropathy, ankylosing spondylitis, gout, myotenositis, bursal synovitis, sciatica, urarthritis, osteoarthritis, juvenile arthritis,juvenile chronic arthritis,juvenile rheumatoid arthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, pyogenic arthritis, atherosclerotic, systemic loupus erythematosus, inflammatory bowel disease, IBS, ulcerative colitis, reflux esophagitis, Crohn's disease, gastritis, asthma, anaphylaxis, Respiratory Distress Syndrome(RDS), pancreatitis, COPD, pulmonary fibrosis, psoriasis, eczema or chorionitis.

In some embodiments, administration comprises the compound compositions of formula, with other therapy couplings.Further or in other the embodiment, comprise the described composition and at least a therapeutic agent administering drug combinations of formula I compound.In some embodiments, oral administration, intraduodenal administration, parenteral (comprising intravenous administration, subcutaneous administration, intramuscular administration, intravascular administration or infusion administration), topical or the described composition of rectally.Further or in other the embodiment, the amount of formula I compound about 0.001 to the scope of about 1000mg/kg body weight/day.Further or in other the embodiment, the amount of formula I compound is in the scope of about 0.5 to about 50mg/kg/ day.Further or in other the embodiment, the amount of formula I compound is about 0.001 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.01 to about 7g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.02 to about 5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.05 to about 2.5g/ day.Further or in other the embodiment, the amount of formula I compound is about 0.1 to about 1g/ day.Further or in other the embodiment, the dosage level that is lower than above-mentioned scope lower limit may enough be had a surplus.Further or in other the embodiment, the dosage level that is higher than above-mentioned range limit may be necessary.

Mode of administration

This paper describes formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative.The pharmaceutical composition that comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative has also been described.Compound as herein described and composition can be individually dosed, perhaps according to standard pharmaceutical practice, in pharmaceutical composition with pharmaceutically acceptable carrier, excipient or thinner combination medicine-feeding.

This paper also describes pharmaceutical composition, and it comprises the crystalline polymorph (A type) of N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide.Compound as herein described and composition can be individually dosed, perhaps according to standard pharmaceutical practice, in pharmaceutical composition with pharmaceutically acceptable carrier, excipient or thinner combination medicine-feeding.Can realize administration by any method that described compound can be delivered to action site.These methods comprise, but be not limited to, (comprise oral by approach in the intestines, stomach or duodenum feeding tube, rectal suppository and rectal enema), parenteral route (injection or infusion, comprise intra-arterial, intracardiac, in the corium, in the duodenum, in the marrow, intramuscular, in the bone, in the peritonaeum, in the sheath, in the blood vessel, intravenous, in the vitreum, epidural and subcutaneous), suck, transdermal, saturating mucous membrane, the hypogloeeis, contain clothes and the part (comprise epicuticle (epicutaneous), corium, enema, eye drops, auristilla, in the nose, vagina) administration is sent, but the optimum approach may depend on for example recipient's the patient's condition and illness.Those skilled in the art can know the medicine-feeding technology that can be used for The compounds of this invention and method.Only as example, can be by local infusion, local application such as cream or ointment, injection, conduit or implant during the operation for example, to the regional administration compound as herein described of needs treatment, described implant is made by material (comprising film or fiber such as the sialastic film) for example porous, non-porous or glue partly.Also can carry out administration by directly injecting at the position of illing tissue or organ.

Can realize the administration of compound described herein and composition by any method that described compound can be released into action site.These methods comprise oral route, intraduodenal route, parenteral injection (comprise in intravenous, subcutaneous, the peritonaeum, in the intramuscular, blood vessel or infusion), topical and rectally.For example, can be to the regional topical compound as herein described of needs treatment.This can be by for example cream, ointment, injection, conduit or implant realize that described implant is made by material (comprising film or fiber such as the sialastic film) for example porous, non-porous or glue such as but not limited to local infusion, local application during the operation.Also can directly inject and carry out administration by the position (or former position) of before tumour or tumor tissue or knurl, organizing.Those skilled in the art know the preparation and the medicine-feeding technology that can be used for The compounds of this invention and method, for example at Goodman and Gilman, and The PharmacologicalBasis of Therapeutics, current edition; Pergamon; And Remington ' s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton is discussed among the Pa.

Described preparation comprises and is applicable to administration in oral administration, parenteral (comprising administration in administration in subcutaneous administration, the corium, intramuscular administration, intravenous administration, intra-articular administration and the marrow), the peritonaeum, transmucosal administration, cutaneous penetration, rectally and topical (comprise the corium administration, contain clothes administration, sublingual administration and eye drops), but the optimum approach may depend on for example recipient's the patient's condition and illness.Described preparation can be a unit dosage forms easily, and can be by known any method preparation in the pharmaceutical field.All methods comprise makes compound of the present invention or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative (" active component ") and the carrier-bound step that constitutes one or more auxiliary agents.Generally speaking, evenly and closely combine, then, if necessary, make product be configured as required preparation and prepare described preparation by making active component and liquid-carrier or the solid carrier that grinds or the two.

The preparation that is applicable to oral administration can be the unit that separates for example capsule, cachet or tablet, and it respectively comprises the active component of scheduled volume; Powder or granule; Solution in waterborne liquid or the non-aqueous liquid or supensoid agent; Perhaps oil-in-water liquid emulsion or Water-In-Oil liquid emulsion.Described active component can also be for injecting agent, electuary or paste.

The pharmaceutical preparation that is used for oral administration comprises tablet, agrees with capsule by pushing of making of gelatin, and the sealing soft capsule of being made by gelatin and plasticizer such as glycerine or sorbierite.Can be by randomly compressing or molding prepares tablet with one or more auxiliary agents.Can prepare compressed tablets by the active component that is in free-flowing form (as powder or particle) that compression in suitable machine randomly mixes with adhesive, inert diluent or lubricant, surfactant or surface dispersant.Can be by in suitable machine, preparing molded tablet through the mixture molding of the moistening powdered compounds of inert liquid diluent.Can be randomly with described tablet coating or indentation, and can prepare described tablet to provide active component therefrom slowly or sustained release.All preparations that are used for oral administration should be the dosage that is suitable for administration like this.Described pushing agreed with capsule or tablet can comprise active component; Be mixed with filler for example microcrystalline cellulose, silicified microcrystalline cellulose, pregelatinized starch, lactose, calcium monohydrogen phosphate or sompressible sugar; Adhesive such as Hydroxypropyl methylcellulose, polyvidone or gelatinized corn starch; Disintegrant such as cross-linked carboxymethyl cellulose sodium, Crospovidone or primojel; Surfactant such as lauryl sodium sulfate and/or lubricant and processing aid such as talcum, dolomol, stearic acid or cataloid, and optional stabilizing agent.In soft capsule, described reactive compound can be dissolved in or be suspended in suitable liquid for example in fat oil, atoleine or the liquid macrogol.In addition, can add stabilizing agent.The dressing dragee sheet heart suitably.For this reason, use concentrated sugar solution, it can randomly comprise gum Arabic, talcum, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture.In order to distinguish or the various combination of characterization active compound doses, dyestuff or pigment can be added described tablet or dragee dressing.

Pharmaceutical preparation can be prepared into the preparation that is used for carrying out as bolus infusion or continuous infusion by injection parenteral.The preparation that is used to inject can be unit dosage forms, as in ampoule or in multi-dose container, and is added with preservative.Described composition can adopt supensoid agent, solution or the emulsion form in oiliness for example or the aqueous carrier, and can comprise formula agent (formulatory agents) for example suspending agent, stabilizing agent and/or dispersant.Described preparation can be unit-dose container or multi-dose container, for example Mi Feng ampoule and bottle, and can preserve with powder type or freeze-drying (freeze drying) state, before use, only need to add at once aseptic liquid-carrier, for example salt solution or aseptic apyrogenic water.From aseptic powder, granule and the tablet of the above-mentioned type, can prepare instant injection solution and supensoid agent.

The preparation that is used for parenteral comprises water-based and non-aqueous (oiliness) aseptic parenteral solution of reactive compound, and it can comprise antioxidant, buffer, bacteriostatic agent, and makes described preparation and have a mind to the solute that recipient's blood etc. oozes; And water-based can comprise suspending agent and thickener with nonaqueous aseptic supensoid agent.The lipophilic solvent or the carrier that are fit to comprise fat oil for example sesame oil or Acrawax such as ethyl oleate or glyceryl ester, or liposome.The water-based injection suspension can comprise the material that improves described supensoid agent viscosity, for example sodium carboxymethylcellulose, sorbierite or glucan.Randomly, for solution that can compounding high concentration, described supensoid agent can also comprise suitable stabilizing agent or improve the reagent of described compound dissolution degree.

Pharmaceutical preparation can also be prepared into depot formulation.By implantation (for example subcutaneous implantation or intramuscular are implanted) or by intramuscular injection, can the such long-acting type preparation of administration.Therefore, for example, described compound can be prepared with suitable polymer or hydrophobic material (for example as the emulsion in acceptable oil) or ion exchange resin, or as sl. sol. derivative, for example sl. sol. salt is prepared.

For containing clothes administration or sublingual administration, described composition can adopt tablet, lozenge, pastille or the gel of preparation in a usual manner.Such composition can be contained in active component flavoured base for example in sucrose and gum Arabic or the bassora gum.

Pharmaceutical preparation can also be prepared into rectal compositions for example suppository or enema,retention, for example comprises conventional suppository base for example cocoa butter, polyethylene glycol or other glyceride.

Can the topical pharmaceutical preparation, promptly by non-general administration.This comprises compound of the present invention externally is applied to epidermis or oral cavity, and with such compound instil pleasant, eye and nose, so that described compound does not enter in the blood flow in large quantities.By contrast, the general administration means administration and intramuscular administration in oral administration, intravenous administration, the peritonaeum.

The pharmaceutical preparation that is suitable for topical comprises and is suitable for liquid or the semi-liquid preparations that transdermal enters inflammation part, for example gel, liniment, lotion, cream, ointment or paste, and be suitable for drops to eye, ear or nasal administration.For topical, active component can account for described preparation 0.001% to 10%w/w, 1 weight % to 2 weight % for example.But active component can account for the nearly 10%w/w of described preparation, perhaps can account for the 5%w/w that is lower than of described preparation, or 0.1% to 1%w/w.

Pharmaceutical preparation by inhalation can be easily from other facilitated method dispensers of insufflator, sprayer pressurized package or administration aerosol spray.Pressurized package can comprise suitable propellant for example dicholorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane, carbonic acid gas or other suitable gas.Under the situation of the aerosol that pressurizes, described dosage unit can be by providing valve quantitative administration.Perhaps, for by sucking or being blown into administration, pharmaceutical preparation can adopt the form of dry powder composite, for example described compound and suitable powder matrix such as the mixture of powders of lactose or starch.Described powder composition can be unit dosage form, for example is capsule, cartridge case (cartridge), gelatin or blisterpack, relies on inhalator or the insufflator can be from the described powder of administration wherein.

Should be understood that except the composition of above specially mentioning compound as herein described and composition can comprise about other conventional in the field of the preparation type of being discussed reagent, the composition that for example is suitable for oral administration can comprise flavor enhancement.

Preparation

It should be noted that any composition as herein described and compound can be used with any preparation that discuss this part, its intention is not restriction and should be understood that restrictive.

Compound as herein described or composition can with for example liposome administration of vesicle (referring to for example, Langer, Science1990,249,1527-1533; Treat etc., Liposomes in the Therapy of Infectious Disease andCancer, Lopez-Bemstein and Fidler, Ed., Liss, N.Y., pp.353-365,1989).Compound as herein described and pharmaceutical composition can also be with the controlled release system administrations.In one embodiment, can use pump (referring to, 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).In addition, controlled release system can be placed near the treatment target spot (referring to, Goodson, Medical Applications of Controlled Release, 1984, Vol.2, pp.115-138).Pharmaceutical composition as herein described can also be included in active component in the form that is suitable for orally using, for example, adopt tablet, dragee, lozenge, water-based or oiliness supensoid agent, dispersible powder or granule, emulsion, hard shell capsules or soft capsule, or syrup or elixir.Any method according to pharmaceutical compositions known in the art, can prepare intention and be used for oral composition, and for pharmaceutically attractive in appearance and good to eat preparation is provided, such composition can comprise one or more reagent that is selected from sweetener, flavor enhancement, colouring agent and preservative.Tablet comprises described active component and mixes the acceptable excipient of avirulent pharmacy that is applicable to the preparation tablet.These excipient for example can be, inert diluent such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulation agent and disintegrant; Filler is microcrystalline cellulose, silicified microcrystalline cellulose, pregelatinized starch, lactose, calcium monohydrogen phosphate or sompressible sugar for example; Adhesive is Hydroxypropyl methylcellulose, polyvidone or gelatinized corn starch for example; Disintegrant is cross-linked carboxymethyl cellulose sodium, Crospovidone or primojel for example; Surfactant is lauryl sodium sulfate for example, and/or lubricant, and processing aid for example talcum, cross-linked carboxymethyl cellulose sodium, corn starch or alginic acid; Bond (binding agents) is starch, gelatin, polyvinylpyrrolidone or gum Arabic for example, and lubricant for example dolomol, stearic acid or cataloid, and optional talcum.For the taste of masking agents or postpone in intestines and stomach disintegration and absorb and more long-term continuous action is provided thus,, can carry out not dressing or dressing to described tablet by known method.For example, can suitably use water-soluble taste masked material for example HYDROXY PROPYL METHYLCELLULOSE or hydroxy propyl cellulose, or delay time material for example ethyl cellulose or acetylbutyrylcellulose.The preparation that orally uses can also be hard gelatin capsule, for example calcium carbonate, calcium phosphate or kaolin mix wherein said active component with inert solid diluent, perhaps be Perle, wherein said active component and water-solubility carrier be polyethylene glycol or oil medium such as peanut oil, atoleine or mixed with olive oil for example.Comprise dry mixed and wet granulation technique by various process technologies, can prepare described capsule and Tabules.In the dry mixed preparation method, by with the excipient dry mixed, be encapsulated in the capsule shells then or be pressed into tablet form, described pharmaceutical pack can be contained in the formulation.The operation of described dry mixed can be carried out step by step, and is included in the step of sieving between the blend step so that form uniform mixture.In the wet granulation method, described medicine can be added in the dry excipient, mix, add binder solution then, perhaps can be with described medicine dissolution, and add as the solution of the part of granulating.In wet granulation technique, if use surfactant, then it can be added in the dry excipient, perhaps it is added in the binder solution, and be contained in wherein with the solution form.By described medicine is dissolved in can be packed into the hard gelatin capsule shell and with subsequently can colligation and the compatible material of the hard gelatin capsule shell of sealing in, also can prepare capsule formulation.In the material that described medicine is dissolved in the fusion form of the polyethylene glycol of HMW for example, be cooled to solid forms, grind, and this material is comprised to the process of conventional capsule and tablet, also can prepare capsule and Tabules.

Aqueous suspension comprises described active component, and mixed the excipient that is applicable to the preparation aqueous suspension is arranged.Such excipient is a suspending agent, for example sodium carboxymethylcellulose, methylcellulose, HYDROXY PROPYL METHYLCELLULOSE, mosanom, polyvinylpyrrolidone, gum tragacanth and gum Arabic; Dispersant or wetting agent can be naturally occurring phosphatide, lecithin for example, the perhaps condensation product of alkylene oxide and fatty acid, Myrj 45 for example, the perhaps condensation product of oxirane and long-chain fatty alcohol, for example 17 vinyl-oxygen hexadecanol (heptadecaethylene-oxycetanol), or oxirane and derived from the condensation product of the partial ester (as octadecanoic acid ester of polyethylene glycol) of fatty acid and hexitol, perhaps oxirane and condensation product derived from the partial ester (for example polyethylene sorbitan monooleate) of fatty acid and hexitol dehydrate.Described aqueous suspension can also comprise one or more preservatives (for example ethyl-para-hydroxybenzoate or P-hydroxybenzoic acid n-propyl), one or more colouring agents, one or more flavor enhancements and one or more sweeteners (for example sucrose, asccharin or aspartame).

By active component being suspended in vegetable oil (for example peanut oil, olive oil, sesame oil or cocoa butter), perhaps in the mineral oil (as atoleine), can prepare the oiliness supensoid agent.Described oiliness supensoid agent can comprise thickener, for example beeswax, hard paraffin or hexadecanol.Can add all sweeteners as indicated above and flavor enhancement good to eat oral formulations is provided.By adding antioxidant, for example Butylated Hydroxyanisole or alpha-tocopherol can be preserved these compositions.

Generate the mixed active component that dispersant or wetting agent, suspending agent and one or more preservatives are arranged by water being added in the dispersible powder that is suitable for preparing aqueous suspension and the particle.Suitable dispersant or wetting agent and suspending agent are by illustrating of above having mentioned.Other excipient, for example sweetener, flavor enhancement and colouring agent also can exist.By adding antioxidant such as ascorbic acid, can preserve these compositions.

Pharmaceutical composition can also be the form of oil in water emulsion.Oil phase can be vegetable oil (for example olive oil or peanut oil), perhaps mineral oil (for example atoleine), perhaps these mixture.Suitable emulsifier can be naturally occurring phosphatide (a for example soybean lecithin), with derived from the ester of fatty acid and hexitol dehydrate or the condensation product (for example polyoxyethylene 20 sorbitan monooleate) of partial ester (for example sorbitan monooleate) and described partial ester and oxireme.Described emulsion can also comprise sweetener, flavor enhancement, preservative and antioxidant.

For example glycerine, propane diols, sorbierite or sucrose can prepare syrup and elixir with sweetener.Such preparation can also comprise moderator, preservative, flavor enhancement and colouring agent and antioxidant.

Pharmaceutical composition can be the form of the aqueous solution agent of sterile injectable.Water, ringer's solution and isotonic sodium chlorrde solution are arranged in operable acceptable carrier and solvent.Described sterile injectable preparation can also be aseptic injectable oil-in-water microemulsion, wherein described active component is dissolved in the oil phase.For example, at first described active component can be dissolved in the mixture of soybean oil or soybean lecithin.Then this oily solution is imported in the mixture of water and glycerine, through being processed to form microemulsion.By local bolus infusion, described injectable solutions or microemulsion can be imported in patient's the blood flow.Perhaps, administration solution or microemulsion may be favourable with the constant circulation concentration that keeps instant compound by this way.In order to keep such constant density, can use continuation intravenous administration device.The example of such device is Deltec CADD-PLUS ^TMType 5400 intravenous pumps.Described pharmaceutical composition can be the sterile injectable water-based that is used for intramuscular and subcutaneous administration or the form of oiliness supensoid agent.According to known technique, use those the suitable dispersants above mentioned or wetting agent and suspending agent can prepare this supensoid agent.Described sterile injectable preparation can also be sterile injectable solution agent or the supensoid agent in avirulence parenteral acceptable diluent or solvent, for example 1, and the solution in the 3-butanediol.In addition, aseptic fixed oil is routinely as solvent or suspension medium.For this reason, can use any non-irritating fixed oil that comprises synthetic monoglyceride or double glyceride.In addition, fatty acid for example oleic acid be used to prepare the injectable agent.

Pharmaceutical composition can also be to be used for the suppository form administration of the described medicine of rectally.Can prepare these compositions by described inhibitor is mixed with suitable non-irritating excipient, described excipient is solid at normal temperatures but is liquid under rectal temperature, and therefore can melt in rectum with the release medicine.Such material comprises the mixture of cocoa butter, glycerin gelatine, hydrogenated vegetable oil, various molecular weight polyethylene glycol and the fatty acid ester of polyethylene glycol.

Use for the part, cream, ointment, jelly, solution or the supensoid agent etc. that comprise compound of the present invention or composition are used for topical.Local application used herein can comprise collutory and gargle.

Use carrier and doser in the suitable nose by the part, perhaps by through the skin approach, use well known to those skilled in the art those through skin patch form, can be with form administration pharmaceutical composition in the nose.

Described preparation can be a unit dosage form easily, and can prepare by the method that pharmaceutical field is known.All methods comprise compound or the acceptable salt of its pharmacy, ester, prodrug or the solvate (" active component ") and the carrier-bound step that constitutes one or more auxiliary agents that makes the invention of this main body.Generally speaking, the two evenly and closely combines by making active component and liquid-carrier or the solid carrier that grinds or this, then, if desired, product is shaped as required preparation prepares described preparation.To those skilled in the art, the method for preparing various pharmaceutical compositions with the reactive compound of specified quantitative is known, and is perhaps conspicuous.For with the percutaneous dosing form administration, formulation can be continuity but not intermittent certainly in whole dosage regimen.

Dosage

The dosage of pharmaceutical composition at first depends on the mammal of receiving treatment.In the situation of human experimenter's administration medicine composition, daily dose is determined by the evolution doctor usually, dosage is generally along with seriousness, administration time, method of administration, the disposal of described composition, drainage rate, the drug combination of the seriousness of each patient's age, sex, diet, body weight, general health and reaction, patient's symptom, the idicatio accurately of receiving treatment or the patient's condition, the idicatio of receiving treatment or the patient's condition, and evolution doctor's judgment.And method of administration can depend on the patient's condition and seriousness thereof and change.Described pharmaceutical composition can be unit dosage form.With such form, preparation is subdivided into the unit dose that comprises an amount of active component, the effective dose that for example accomplishes the end in view.Determine that in light of the circumstances suitable dosage is in the technology category of this area.Generally speaking, use the smaller dose begin treatment of the dose,optimum that is lower than described compound.After this, with a small amount of increase dosage until the suitableeest effect that reaches under described situation.For convenience, if desired, by day can be with total daily dose portioning and by a part administration.Consider factor mentioned above, adjust the dosage and the administration frequency of compound as herein described according to the judgement that cures mainly clinician (doctor), and if suitable, adjust the amount of application and the frequency of other treatment agent and/or therapy.Therefore, the dosage of pharmaceutical composition may differ greatly.Dosage can for about 0.001mg/kg body weight to about 100mg/kg body weight every day (with single dose or broken dose administration), perhaps at least about 0.1mg/kg body weight every day.Concrete therapeutic dose can comprise that for example, about 0.01mg is to the compound of about 7000mg, and perhaps for example about 0.05mg is to about 2500mg.According to concrete purposes, can be at about 0.1mg to 1000mg, about 1mg to 300mg, perhaps in the 10mg to 200mg, change or unit of adjustment's dosage formulation in the content of reactive compound.In some cases, the dosage level that is lower than above-mentioned scope lower limit may enough be had a surplus, and in other cases, can use even bigger dosage and do not cause any harmful side effect, for example by so heavy dose is divided into the administration in all day of some low doses.Dosage can depend on the specific IC of the compound of use ₅₀Value changes.At described compound is not in the associating dispenser of unique therapy, and the compound of the low amount of possible administration also still has treatment or prevention effect.

Other dosage is provided in whole specification and claim.

Formulation

Described pharmaceutical composition can be the form of the tablet that for example is suitable for oral administration, capsule, pill, powder, sustained release preparation, solution, supensoid agent, the form that is suitable for sterile solution agent, supensoid agent or the emulsion of parenteral injection, the form that is suitable for the ointment or the cream of topical perhaps is suitable for the form of the suppository of rectally.Described pharmaceutical composition can be for being suitable for the unit dosage form of the accurate dosage of single-dose.Described pharmaceutical composition can comprise conventional pharmaceutical carriers or excipient and as the compound of the present invention of active component.In addition, it can comprise other medicinal or pharmaceutical agents, carrier, assistant agent etc.

Exemplary parenteral form comprises solution or the supensoid agent of reactive compound in aseptic aqueous solution (for example, moisture propane diols or glucose solution).If desired, can suitably carry out buffered to such formulation.

The pharmaceutical carriers that is fit to comprises inert diluent or filler, water and various organic solvent.If desired, described pharmaceutical composition can comprise other compositions, for example flavor enhancement, adhesive, excipient etc.Therefore, for oral administration, tablet comprises various excipient, and for example citric acid can use with various disintegrants (for example starch, alginic acid and silicate that some is complicated) and adhesive (for example sucrose, gelatin and gum Arabic).In addition, lubricant such as dolomol, lauryl sodium sulfate and talcum are through being usually used in the film-making purpose.The solid composite of similar type also can be used for soft-filled gelatin capsule and hard-filled gelatin capsule, and it comprises the polyethylene glycol of lactose and HMW.When needs aqueous suspension or elixir are used for oral administration, reactive compound wherein can with various sweeteners or flavor enhancement, colouring agent or dyestuff, and, if need, emulsifier or suspending agent, thinner (as water, ethanol, propane diols, glycerine or their combination) mixing in addition.

To those skilled in the art, the compound method of various pharmaceutical compositions that contains the reactive compound of specified quantitative is known, perhaps can be conspicuous.For example referring to Remington ' s Pharmaceutical Sciences, MackPublishing Company, ester, Pa., the 18th edition (1990).

Conjoint therapy

Compound as herein described or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative can be used as monotherapy and use.All right administration compound as herein described or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative are with other one or more therapy couplings.

This paper also describes N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide (A type), and it can be used as monotherapy and uses.The crystalline polymorph type A of all right administration N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide is with other one or more therapy couplings.

Only as example, if when accepting one of compound as herein described, one of side reaction that the patient stands is a hypertension, then suitably administering drug combinations antihypertensive and described compound.Perhaps, only as example, can improve the treatment benefit (be that adjuvant itself may only have minimum treatment benefit, but the another kind of therapeutic agent of coupling, total treatment benefit of patient is increased) of one of compound as herein described by the administration adjuvant.Perhaps, only as example, the therapeutic agent (it also comprises therapeutic scheme) by one of administering drug combinations compound as herein described and another kind also have the treatment benefit can improve the benefit that the patient is subjected to.Only, in the treating diabetes that relates to one of administration compound as herein described, can also improve the treatment benefit in fact by another kind of Remedies for diabetes is provided to the patient as example.Under any circumstance, do not consider disease, illness or the patient's condition of receiving treatment, total benefit that the patient stands may be the simple adduction of two kinds of therapeutic agents, perhaps patient's benefit that may stand to work in coordination with.

Other therapies include but not limited to, use other treatment agent, radiotherapy or the two.Under the situation of compound as herein described and other treatment agent administering drug combinations, compound as herein described do not need with the other treatment agent in identical administered in pharmaceutical compositions, and since different physics and chemical feature, can pass through different administrations.For example, described compound can be taken orally with generation and keeps its good blood levels, and another kind of therapeutic agent can intravenous administration.Under possible situation, determine mode of administration and administration adaptability in the identical pharmaceutical composition, be that specialized clinician is known.Can carry out the initial stage administration according to the scheme that this area is set up, then, effect according to the observation, specialized clinician can be adjusted dosage, mode of administration and administration time.Attending doctor's diagnosis and they judgement to patient's patient's condition and suitable therapeutic scheme is depended in the concrete selection of compound (and suitably time, other treatment agent and/or radiation).The other treatment agent can comprise the chemotherapeutant such as antitumorigenic substance, for example is selected from mitotic inhibitor (for example vincaleukoblastinum); Alkylating agent (for example cis-platinum, carboplatin and cyclophosphamide); Antimetabolite (for example 5 FU 5 fluorouracil, cytarabine and hydroxycarbamide, perhaps for example be disclosed in antimetabolite N-(5-[N-(3,4-dihydro-2-methyl-4-oxo quinazoline-6-ylmethyl))-N-methylamino for example in No. 239362, the european patent application]-the 2-Thenoyl)-L-glutamic acid); Growth factor receptor inhibitors; Cell cycle inhibitor; Embed antibiotic (for example adriamycin and bleomycin); Enzyme (for example interferon); And antihormones (antiestrogenic Nolvadex for example for example ^TM(Tamoxifen) or for example antiandrogen such as Casodex ^TM(4 '-cyano group-3-(4-fluorophenyl sulfonyl)-2-hydroxy-2-methyl-3 '-(trifluoromethyl) propionanilide)).By side by side, in turn or respectively component is respectively treated in administration, can realize such therapeutic alliance.

Compound as herein described and composition (with suitable chemotherapeutant and/or radiotherapy) can be used (for example side by side, basically side by side or in same therapeutic scheme) jointly, perhaps in turn use, this depends on the character of described disease of patient or illness, and with the chemotherapeutant and/or the radiotherapeutic actual selection of described compound coupling (promptly in single therapeutic scheme).

In co-administered and use, described compound and chemotherapeutant and/or radiotherapy do not need side by side or basically side by side to use, and described compound and chemotherapeutant and/or the radiotherapeutic initial order of using may be inessential.Therefore, at first administration compound of the present invention is used chemotherapeutant and/or radiotherapy then; Perhaps can at first use chemotherapeutant and/or radiotherapy, then administration compound of the present invention.During single therapeutic scheme, can repeat this optional application process.After the disease of receiving treatment and the patient's condition of evaluate patient, determine the order of administration during therapeutic scheme and the number of times of each therapy of repetitive administration, in the ken of specialist.For example, can at first use chemotherapeutant and/or radiotherapy, if particularly it is a cytotoxic agent, continue treatment by the compound of the present invention of administration subsequently then, in determining favourable situation, then use chemotherapeutant and/or radiation etc., finish until therapeutic scheme.Therefore, rule of thumb and knowledge, along with treatment is carried out, each dosage regimen of the compound that the medical practitioner can be used for the treatment of according to the needs adjustment of individual patient.In the treatment under judging dosage whether effectively, cure mainly the general health that the clinician will consider the patient, and clearer and more definite sign, for example the actual contraction of the inhibition of the alleviation of disease related symptom, tumor growth, tumour or shift and suppress.By standard method such as for example CAT or MRI scanning of radiologic investigation, can measure the size of tumour, and follow-up measured value can be used to judge whether growth of tumor has been suppressed or even reverse.The disease related symptom for example improvement of the alleviation of pain and the overall patient's condition also can be used to help to judge the validity of treatment.

The concrete limiting examples of possible conjoint therapy comprises the medicament in coupling compound of the present invention and the following pharmacotherapy classification as described below.These tabulations should not be construed as sealing, and should be used as the common illustrative example in present associated treatment field.And the coupling scheme can comprise various methods of administration, and should comprise oral, intravenous, intraocular, subcutaneous, local skin and local inhalation.

In order to treat tumor disease, proliferative disorders and cancer, compound of the present invention can be selected from down the group the medicament administering drug combinations, described medicament group comprises: aromatase inhibitor, antiestrogenic, antiandrogen, corticosteroid, the Gonadorelin activator,

topoisomerase

1 and 2 inhibitor, the microtubule activator, alkylating agent, nitroso ureas, antitumor antimetabolite, contain platinum compounds, fat or the agent of protein kinase target, IMiDs, albumen or the agent of lipophosphatidic acid enzyme target, antiangiogenic agent, the Akt inhibitor, the IGF-I inhibitor, the FGF3 conditioning agent, the mTOR inhibitor, the Smac analogies, hdac inhibitor, the medicament of inducing cell differentiation, bradykinin 1 receptor antagonist, the Angiotensin II antagonist, cyclooxygenase-2 inhibitor, heparitinase (heparanse) inhibitor, the lymphokine inhibitor, cell factor inhibitors, the IKK inhibitor, the P38MAPK inhibitor, ARRY-797, the HSP90 inhibitor, many inhibitors of kinases, diphosphonate (bisphosphanate), rapamycin derivative, anti-apoptosis pathway inhibitor, the apoptosis pathway activator, the PPAR activator, the RAR activator, Ras isoform inhibitor, telomerase inhibitor, protease inhibitors, metal protease inhibitors, amastatin, SHIP activator-AQX-MN100, Humax-CD20 (ofatumumab), the CD20 antagonist, IL2-diphtheria toxin fusions.

In order to treat tumor disease, proliferative disorders and cancer, compound of the present invention can with the medicament administering drug combinations that is selected from down group, described group comprises: Dacarbazine (DTIC), act-C ₂, act-C ₃, actinomycin D and actinomycin F ₁, cyclophosphamide, melphalan, Estramustine, maytansinol, rifamycin, dalacin, Doxorubicin, daunorubicin, epirubicin, idarubicin, Detorubicin, carminomycin, idarubicin, epirubicin, esorubicin, mitoxantrone, bleomycin A, bleomycin A ₂With bleomycin B, camptothecine, Irinotecan .RTM., Hycamtin .RTM., 9-aminocamptothecin, 10,11-methylene-dioxy camptothecine, the 9-nitrocamptothecin, bortezomib, Temozolomide, TAS103, NPI0052, Combretastatin, Combretastatin A-4-2, Combretastatin A-4-4, calicheamycin, neoearcinostain, Epothilones A, epothilone B, Epothilone C and semisynthetic variant, Trastuzumab .RTM., Mabthera .RTM., CD40 antibody, L-Asparaginasum, interleukins, interferon, leuproside and Pegaspargase, 5 FU 5 fluorouracil, fluorodeoxyuridine, ptorafur, 5 '-doxifluridine, UFT, MITC, the S-1 capecitabine, diethylstilbestrol, Tamoxifen, Toremifene, Tomudex (tolmudex), thymitaq, Flutamide, Fluoxymesterone, Bicalutamide, Finasteride, estradiol, Trioxifene, dexamethasone, leuprorelin acetate, Estramustine, Droloxifene, Medroxyprogesterone, megestrol acetate, aminoglutethimide, testolactone, testosterone, diethylstilbestrol, hydroxyprogesterone, Mitomycin A, Mitomycin B and mitomycin C, porfiromycin, cis-platinum, carboplatin, oxaliplatin, four platinum, platinum-DACH, Ormaplatin, Thalidomide, lenalidomide, CI-973, the telomere chalone, CHIR258, Rad 001, SAHA, Tubacin, 17-AAG, Sorafenib, JM-216, podophyllotoxin, epipodophyllotoxin, Etoposide, Teniposide, it fills in watt .RTM., Iressa .RTM., Imatinib .RTM., Miltefosine .RTM., piperazine founds the new .RTM. of good fortune, aminopterin, methotrexate (MTX), methopterin, dichioromethotrexate, the 6-mercaptopurine, thioguanine, azattuoprine, allopurinol, the upright shore of carat, fludarabine, Pentostatin, 2-chlorine adenosine, deoxycytidine, cytarabine, cytarabine, azacitidine, 5-azepine cytimidine, gemcitabine, 5-azepine cytimidine-Arabinoside, vincristine, vincaleukoblastinum, vinorelbine, leurosine, leurosidine and eldisine, taxol, taxotere and docetaxel.

In order to treat inflammatory disease or pain, the acceptable salt of the pharmacy of compound of the present invention and described compound can with the medicament administering drug combinations that is selected from down group, described medicament group comprises: corticosteroid, on-steroidal AID, muscle relaxant and with the combination of other medicaments, anaesthetic and with the combination of other medicaments, expectorant and with combination, antidepressants, anticonvulsive drug and the combination thereof of other medicaments; Antihypertensive, opiates, local Cannabinoids, capsaicine, BDP (synergy with non-beneficiated), betamethasone valerate, clobetasol propionate, metacortandracin, methylprednisolone, the oxalic acid diflorasone, halobetasol propionate, Amcinonide, dexamethasone, Desoximetasone (dexosimethasone), fluocinolone acetonide, Fluocinonide, Halcinonide (halocinonide), the neopentanoic acid clocortolone, Desoximetasone (dexosimetasone), flurandrenolide, salicylate (salt), brufen, Ketoprofen, Etodolac, Diclofenac, meclofenamate sodium, naproxen, piroxicam, celecoxib, cyclobenzaprine, Baclofen, cyclobenzaprine/lidocaine, Baclofen/cyclobenzaprine, cyclobenzaprine/lidocaine/Ketoprofen, lidocaine, lidocaine/DDG, prilocaine, EMLA cream (the eutectic mixture of local anesthetic (lidocaine 2.5% and prilocaine 2.5%), gualfenesin, gualfenesin/Ketoprofen/cyclobenzaprine, amitriptyline (amitryptiline), doxepin, desipramine, imipramine, amoxapine, clomipramine, nortriptyline, protriptyline, Duloxetine, Mirtazapine (mirtazepine), Nisoxetine, maprotiline, Reboxetine, Prozac, Fluvoxamine, carbamazepine, Felbamate, Lamotrigine, Topiramate, Tiagabine, Oxcarbazepine, carbamazepine (carbamezipine), Zonisamide, mexiletine, Gabapentin/clonidine, Gabapentin/carbamazepine, carbamazepine/cyclobenzaprine, antihypertensive comprises: clonidine, codeine, Loperamide, tramadol, morphine, fentanyl, Oxycodone, hydrocodone, levorphanol, butorphanol, menthol, wintergreen, camphor, eucalyptus oil, turpentine oil; The CB1/CB2 part, paracetamol, English monoclonal antibody of sharp former times, nitric oxide synthase inhibitors, the inhibitor of derivable nitricoxide synthase particularly, PDE4 inhibitor-mechanism is similar in appearance to Ibudilast (AV-411), CDC-801, jnk inhibitor-CC-401, TNF/PDE4 composite restrainer-CDC-998, IL1 antagonist such as anakinra-Kineret, AMG 108, (mAb) of target IL-1, SHIP activator-AQX-MN100, the C5 antagonist, the C5a inhibitor, training gram pearl monoclonal antibody, pyrimidine synthesis inhibitors, the lymphokine inhibitor, cell factor inhibitors, the IKK inhibitor, the P38MAPK inhibitor, ARRY-797, the HSP90 inhibitor, many inhibitors of kinases, bisphosphonates (salt), the PPAR activator, Cox1 and cox2 inhibitor, anti--the CD4 therapy, the B-cytostatics, the COX/LOX double inhibitor, immunosuppressive drug, the iNOS inhibitor, NSAID, the sPLA2 inhibitor, colchicine, allopurinol, oxipurinol, gold, Ruide-Anranofin, Febustat, Puricase, PEG-uricase preparation, Benzbromarone, long-acting type β-2 activator (LABA), salmeterol (Serevent Diskus) and Formoterol (Foradil), leukotrienes regulator comprises montelukast (Singulair) and zafirlukast (Accolate), induction type look sweet acid (Intal) or nedocromil (Tilade), theophylline.Fugitive type β-2 activator, ipratropium (Atrovent), immunotherapeutic agent-(allergia desensitization injection), anti--IgE monoclone antibody-Xolair, common DMARD comprises: hydroxychloroquine (Plaquenil), gold compound Anranofin (Ruide), Sulfasalazine (Azulfidine), minocycline (Dynacin, Minocin) and methotrexate (MTX) (Rheumatrex), leflunomide (Arava), imuran (according to lily magnolia), cyclosporin (Neoral, Sandimmune) and cyclophosphamide (Cytoxan), antibiotic, the CD80 antagonist, the costimulator antagonist, Humax-CD20 (ofatumumab); CD20 antagonist, mek inhibitor, NF κ-B inhibitor, anti-B-cell antibody, Shu Dankang, the mAb of the receptor activators of target nuclear factor κ B part (RANKL) specifically.IL17 deactivation antibody, IL-17 receptor antagonist/inhibitor, the CTLA inhibitor, the CD20 inhibitor, soluble VEGFR-1 acceptor, anti-VEGFR-1 receptor antibody, anti-VEGF antibodies, integrain receptor antagaonists, select protein inhibitor, P-selects protein inhibitor and E-to select protein inhibitor, PLA 2 inhibitors, lipoxidase inhibitor, RANKL and RANK antagonist/antibody, protect the ossein antagonist, the lymphotoxin inhibitor, B-lymphocyte stimulatory factors, the MCP-1 inhibitor, the MIF inhibitor, the CD2 inhibitor, the CD3 inhibitor, the CD4 inhibitor, the CD25 inhibitor, CD40 inhibitor and CD40 part CD152 (CTLA4) inhibitor, the macrolide immunosuppressive drug, the selective depressant of nucleotide metabolism, the inhibitor of chemotaxis, CXC acceptor and CXC ligand inhibitor, chemokine antagonists, the leukocyte chemotaxis inhibitor, the adhesion molecule retarding agent, select albumen lymphocyte function antigen-1 (LFA-1, CD11a) antagonist, Vla-4-4 (VLA-4) antagonist, NMPI, elastatinal, cathepsin inhibitors.

In order to treat eye disorders and eye illness, the acceptable salt of the pharmacy of compound of the present invention and described compound can be selected from down the group the medicament administration, described group comprises: beta-Blocking agent, carbonic anhydrase inhibitor, alpha-adrenergic antagonist and beta-adrenergic antagonist comprise alpha 1 adrenergic antagonist, α 2 activators, myotic, prostaglandin analogue, corticosteroid and immunosuppressive drug.

In order to treat eye disorders and eye illness, the acceptable salt of the pharmacy of compound of the present invention and described compound can be selected from down the group the medicament administering drug combinations, described group comprises: timolol, betaxolol, Levobetaxolol, carteolol, levobunolol, Propranolol, brinzolamide, Dorzolamide, nipradilol, p-aminoclonidine, Brimonidine, pilocarpine, adrenaline, Latanoprost, travoprost, bimatoprost, Unoprostone, dexamethasone, metacortandracin, methylprednisolone, imuran, cyclosporin and immunoglobulin.

In order to treat autoimmune disease, the acceptable salt of the pharmacy of compound of the present invention or described compound can with the medicament administering drug combinations that is selected from down group, described group comprises: corticosteroid, immunosuppressive drug, prostaglandin analogue and antimetabolite.

In order to treat autoimmune disease, compound of the present invention can be selected from down the group the medicament administering drug combinations, described group comprises: dexamethasone, metacortandracin, methylprednisolone, imuran, cyclosporin, immunoglobulin, Latanoprost, travoprost, bimatoprost, Unoprostone, English monoclonal antibody of sharp former times, Rituximab, methotrexate (MTX), the on-steroidal AID, muscle relaxant and with the combination of other medicaments, anaesthetic and with the combination of other medicaments, expectorant and with the combination of other medicaments, antidepressants, anticonvulsive drug and combination thereof; Antihypertensive, opiates, local Cannabinoids, and other medicaments, capsaicine for example, BDP (synergy with non-beneficiated), betamethasone valerate, clobetasol propionate, metacortandracin, methylprednisolone, the oxalic acid diflorasone, halobetasol propionate, Amcinonide, dexamethasone, Desoximetasone, fluocinolone acetonide, Fluocinonide, Halcinonide, the neopentanoic acid clocortolone, Desoximetasone, flurandrenolide, salicylate (salt), brufen, Ketoprofen, Etodolac, Diclofenac, meclofenamate sodium, naproxen, piroxicam, celecoxib, cyclobenzaprine, Baclofen, cyclobenzaprine/lidocaine, Baclofen/cyclobenzaprine, cyclobenzaprine/lidocaine/Ketoprofen, lidocaine, lidocaine/DDG, prilocaine, EMLA cream (the eutectic mixture of local anesthetic (lidocaine 2.5% and prilocaine 2.5%), gualfenesin, gualfenesin/Ketoprofen/cyclobenzaprine, amitriptyline, doxepin, desipramine, imipramine, amoxapine, clomipramine, nortriptyline, protriptyline, Duloxetine, Mirtazapine, Nisoxetine, maprotiline, Reboxetine, Prozac, Fluvoxamine, carbamazepine, Felbamate, Lamotrigine, Topiramate, Tiagabine, Oxcarbazepine, carbamazepine, Zonisamide, mexiletine, Gabapentin/clonidine, Gabapentin/carbamazepine, carbamazepine/cyclobenzaprine, antihypertensive comprises: clonidine, codeine, Loperamide, tramadol, morphine, fentanyl, Oxycodone, hydrocodone, levorphanol, butorphanol, menthol, wintergreen, camphor, eucalyptus oil, turpentine oil; CB1/CB2 part, paracetamol, English monoclonal antibody of sharp former times; The inhibitor of nitric oxide synthase inhibitors, particularly derivable nitricoxide synthase; And other medicaments, for example capsaicine.PDE4 inhibitor-mechanism is similar in appearance to Ibudilast (AV-411), CDC-801, jnk inhibitor-CC-401, TNF/PDE4 composite restrainer-CDC-998, IL1 antagonist such as anakinra-Kineret, AMG 108, (mAb) of target IL-1, SHIP activator-AQX-MN100, the C5 antagonist, the C5a inhibitor, training gram pearl monoclonal antibody, pyrimidine synthesis inhibitors, the lymphokine inhibitor, cell factor inhibitors, the IKK inhibitor, the P38MAPK inhibitor, ARRY-797, the HSP90 inhibitor, many inhibitors of kinases, bisphosphonates (salt), the PPAR activator, Cox1 and cox2 inhibitor, anti--the CD4 therapy, the B-cytostatics, the COX/LOX double inhibitor, immunosuppressive drug, the iNOS inhibitor, NSAID, the sPLA2 inhibitor, colchicine, allopurinol, oxipurinol, gold, Ruide-Anranofin, Febustat, Puricase, PEG-uricase preparation, Benzbromarone, long-acting type β-2 activator (LABA), salmeterol (Serevent Diskus) and Formoterol (Foradil), leukotrienes regulator comprises montelukast (Singulair) and zafirlukast (Accolate).Induction type look sweet acid (Intal) or nedocromil (Tilade), theophylline.Fugitive type β-2 activator, ipratropium (Atrovent), immunotherapeutic agent-(allergia desensitization injection), anti--IgE monoclone antibody-Xolair, common DMARD comprises hydroxychloroquine (Plaquenil), gold compound Anranofin (Ruide), Sulfasalazine (Azulfidine), minocycline (Dynacin, Minocin) and methotrexate (MTX) (Rheumatrex), leflunomide (Arava), imuran (according to lily magnolia), cyclosporin (Neoral, Sandimmune) and cyclophosphamide (Cytoxan), antibiotic, the CD80 antagonist, the costimulator antagonist, Humax-CD20 (ofatumumab); CD20 antagonist, mek inhibitor, NF kB inhibitor, anti-B cell antibody, Shu Dankang, the mAb of the receptor activators of target nuclear factor κ B part (RANKL) specifically.IL17 deactivation antibody, IL-17 receptor antagonist/inhibitor, the CTLA inhibitor, the CD20 inhibitor, soluble VEGFR-1 acceptor, anti-VEGFR-1 receptor antibody, anti-VEGF antibodies, integrain receptor antagaonists, select protein inhibitor, P-selects protein inhibitor and E-to select protein inhibitor, PLA 2 inhibitors, lipoxidase inhibitor, RANKL and RANK antagonist/antibody, protect the ossein antagonist, the lymphotoxin inhibitor, B-lymphocyte stimulatory factors, the MCP-1 inhibitor, the MIF inhibitor, the CD2 inhibitor, the CD3 inhibitor, the CD4 inhibitor, the CD25 inhibitor, CD40 inhibitor and CD40 part CD152 (CTLA4) inhibitor, the macrolide immunosuppressive drug, the selective depressant of nucleotide metabolism, the inhibitor of chemotaxis, CXC acceptor and CXC ligand inhibitor, chemokine antagonists, the leukocyte chemotaxis inhibitor, the adhesion molecule retarding agent, select albumen lymphocyte function antigen-1 (LFA-1, CD11a) antagonist, Vla-4-4 (VLA-4) antagonist, NMPI, elastatinal, cathepsin inhibitors.

In order to treat metabolic disorder; the acceptable salt of the pharmacy of compound of the present invention and described compound can be selected from down the group the medicament administering drug combinations; described group comprises: insulin; insulin derivates and analogies; the insulin secretagogue element; the insulin sensitiser thing; biguanides reagent; alpha-glucosidase restrainer; pancreotropic hormone sulfonylureas receptors ligand; Protein-tyrosine-phosphatase-1B (PTP-1B) inhibitor; GSK3 (glycogen synthase kinase-3) inhibitor; GLP-1 (glucagon-like-peptide-1); the GLP-1 analog; DPPIV (DPP IV) inhibitor; RXR part sodium dependent glucose cotransporter inhibitor; glycogen phosphorylase A inhibitor; the AGE disrupting agent; the PPAR conditioning agent; LXR and FXR conditioning agent; Fei Gelie ketone type PPARS activator; selectivity glucocorticoid antagonist; melbine; Glipizide; glibenclamide; Ya Moli; meglitinide; nateglinide; Repaglinide; 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; Sha Gelieting; GSK23A; Pioglitazone; Rosiglitazone; (R)-1-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-ylmethoxy of in patent application WO 03/043985, describing]-benzenesulfonyl } 2; 3-dihydro-1H-indole-2-carboxylic acid; as the compound 19 of embodiment 4, and GI-262570.

Disease

This paper describes the method that treatment suffers from disease described in the individuality of disease, and it comprises to the formula I of described individual effective dosage compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative.

This paper also describes the method that treatment suffers from disease described in the individuality of disease or illness or illness, it comprises the N-(S)-(3 to described individual effective dosage, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide (A type).The present invention relates to N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide (A type) and be used for the treatment of purposes in the medicine of disease or illness in preparation.

In some embodiments, the present invention relates to prevent or treat any disease or the illness that the MEK kinases plays a role, it comprises without limitation: tumor disease, hematologic disease, inflammatory disease, eye disease, neuropathy, immunological disease, cardiovascular disease, and skin disease, and, comprise and for example in human or other mammals, exceedingly or not regulate and control ground generation TNF, IL-1, IL-6 and IL-8 because of exceedingly or not producing the caused disease of proinflammatory cytokine to regulation and control.The present invention relates to such purposes of described compound, and described compound is used for the treatment of purposes in the medicine of so cytokine mediated disease or illness in preparation.In addition, the present invention relates to treat any such disease or illness to the mek inhibitor of human effective dosage.

The MEK kinases directly or through proinflammatory cytokine (comprises cytokine TNF, IL-1, IL-6 and IL-8) disease or the illness that play a role comprise without limitation: dry eyes, glaucoma, autoimmune disease, inflammatory disease, destructive osteopathy, proliferative diseases, neurodegenerative disorders, viral disease, anaphylaxis, infectious disease, heart attack, blood vessel generation illness, perfusion/ischemic again during apoplexy, blood vessel hyperplasia, the organ anoxic, cardiomegaly, the platelet aggregation that fibrin ferment causes, and with the relevant patient's condition of prostaglandin endoperoxidase synthase-2 (COX-2).

Of the present invention aspect some, described disease is the excess proliferative patient's condition of the mankind or animal body, and it includes but not limited to the propagation that causes behind cancer, hyperplasia, ISR, inflammation, immunological diseases, cardiomegaly, atherosclerotic, pain, antimigraine, the blood vessel generation correlation patient's condition or illness, the medical conditions (including but not limited to operation, angioplasty or other situations).

In further embodiment, the described excess proliferative patient's condition is selected from hematologic disease cancer and non-hematologic disease cancer.In other other embodiments, described hematologic disease cancer is selected from Huppert's disease, leukemia and lymphoma.In embodiment further, described leukemia is to be selected from acute leukemia and chronic leukemia.In embodiment further, described acute leukemia is selected from acute lymphoblastic leukemia (ALL) and acute non lymphocytic leukemia (ANLL).In embodiment further, described chronic leukemia is selected from chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML).In further embodiment, described lymphoma is selected from Hodgkin lymphoma and non-Hodgkin lymphoma.In further embodiment, described hematologic disease cancer is a Huppert's disease.In other embodiments, described hematologic disease cancer is low cancer, moderate cancer or height cancer.In other embodiments, described non-hematologic disease cancer is selected from the cancer of cancer, cancer of pancreas and urinary system of cancer, the digestive system of the cancer of the brain, head and neck cancer, lung cancer, breast cancer, genital 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 carcinoma of urinary bladder or clear-cell carcinoma.In further embodiment, the cancer of described genital system is a prostate cancer.

Use the cancer of the treatable other types of Compounds and methods for as herein described to comprise: the cancer of cancer, neural cancer, lymphoid cancer and the endocrine system of cancer, eye and the eye socket of the cancer in the cancer of oral cavity and pharynx, the cancer of respiratory system, bone and joint, the cancer of soft tissue, cutaneum carcinoma, genital system.In certain embodiments, these cancers can be selected from the cancer by tongue, mouth, pharynx or other oral cavities; The cancer of the esophagus, cancer of the stomach, or carcinoma of small intestine; The colon cancer or the carcinoma of the rectum, cancer of anus or anal orifice and rectal intestine cancer; Liver cancer, stones in intrahepatic bile duct cancer, carcinoma of gallbladder, cancer of pancreas, or other gall-bladders or Alimentary cancer; The cancer of laryngocarcinoma, bronchiolar carcinoma and other respiratory apparatus; Heart cancer, melanoma, basal-cell carcinoma, squamous cell carcinoma, other non-epithelium cancers; The cancer of the uterus or cervical carcinoma; Carcinoma of uterine body; Oophoroma, carcinoma of vulva, carcinoma of vagina, or the cancer of other female genital organs; The cancer of prostate cancer, carcinoma of testis, penis or other male genitals; The uropoiesis carcinoma of urinary bladder; The cancer of kidney; Kidney, pelvic cancer or urethra cancer, or other cancers of Genito-urinary organ; The cancer of thyroid cancer or other endocrine gland; Chronic lymphocytic leukemia; And granulocyte and single celled CTCL.

Use the cancer of the treatable other other types of Compounds and methods for as herein described to comprise: gland cancer, angiosarcoma, astrocytoma, acoustic neurinoma, glioblastoma multiforme, basal-cell carcinoma, glioblastoma (blastoglioma), chondrosarcoma, choriocarcinoma, chordoma, craniopharyngioma, cutaneous melanoma, cystadenocarcinoma, endotheliosarcoma, embryonal carcinoma, ependymoma, ewing's tumor, epithelioma, fibrosarcoma, cancer of the stomach, the genitourinary tract cancer, glioblastoma multiforme, angioblastoma, hepatocellular carcinoma, liver cancer, Kaposi sarcoma, large cell carcinoma, leiomyosarcoma, embryonal-cell lipoma, lymphangioendothelial sarcoma, lymphangioendothelial sarcoma, medullary carcinoma of thyroid gland, medulloblastoma, meningioma, celiothelioma, myeloma, myxosarcoma, neuroblastoma, neurofibrosarcoma, oligodendroglioma, osteogenic sarcoma, the epithelium oophoroma, papillary carcinoma, papillary adenocarcinoma, parathyroid adenoma, pheochromocytoma, pinealoma, plasmacytoma, retinoblastoma, rhabdomyosarcoma, carcinoma of sebaceous glands, seminoma, cutaneum carcinoma, melanoma, small-cell carcinoma of the lung, squamous cell carcinoma, syringocarcinoma, synovialoma, thyroid cancer, uvea melanoma and wilms' tumor.

The method of excess proliferative disease in the treatment mammal is also described, it comprises formula I compound or the acceptable salt of its pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivative to described mammal administering drug combinations treatment effective dose, and antineoplastic.In some embodiments, described antineoplastic is selected from mitotic inhibitor, alkylating agent, antimetabolite, embedding antibiotic, growth factor receptor inhibitors, cell cycle inhibitor, enzyme inhibitor, topoisomerase enzyme inhibitor, biological response modifier, antihormone, angiogenesis inhibitor, antiandrogen, SHIP activator-AQX-MN100, Humax-CD20 (ofatumumab), CD20 antagonist, IL2-diphtheria toxin fusions.

Using the disease of compound as herein described, composition and method treatment can be blood disorder.In certain embodiments, described blood disorder is selected from sickle cell anemia, myeloproliferative disorder disease (MDS) and bone marrow proliferative diseases.In further embodiment, described bone marrow proliferative diseases is selected from polycythemia vera, myelofibrosis and primary thrombocytosis.

Compound as herein described, composition and method can and have significantly lower additional benefits of harmful side effect as antiinflammatory agent.Compound as herein described, composition and method are used for the treatment of arthritis, include but not limited to rheumatoid arthritis, spondyloarthropathy, ankylosing spondylitis, gout, urarthritis, osteoarthritis, systemic loupus erythematosus, juvenile arthritis,juvenile chronic arthritis,juvenile rheumatoid arthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, and pyogenic arthritis.Compound as herein described, composition and method also are used for the treatment of osteoporosis and other relevant bone disorders.These compounds as herein described, composition and method also are used for the treatment of the stomach and intestine patient's condition, for example reflux esophagitis, diarrhoea, inflammatory bowel disease, Crohn's disease, gastritis, IBS and ulcerative colitis.Compound as herein described, composition and method can also be used for the treatment of such as the lung inflammation relevant with virus infections and cystic fibrosis.In addition, compound as herein described, composition and method are also united individually or with the immunomodulator of routine and are used for the organ transplant patient.Further, compound as herein described, composition and method are used for the treatment of itch and leucoderma.Particularly, compound as herein described, composition and method are used for the treatment of specific inflammatory disease rheumatoid arthritis.

Other inflammatory diseases that can prevent or treat comprise without limitation: asthma, anaphylaxis, Respiratory Distress Syndrome(RDS), perhaps acute or chronic pancreatitis.In addition, the respiratory disease that can prevent or treat includes but not limited to chronic obstructive pulmonary disease and pulmonary fibrosis.In addition, MEK inhibitors of kinases as herein described is also relevant with the generation of prostaglandin endoperoxidase synthase-2 (COX-2).Derived from the pro-inflammatory mediator of arachidonic cyclo-oxygenase approach, for example prostaglandin is produced by derivable COX-2 enzyme.The adjusting of COX-2 can be regulated and control these pro-inflammatory mediators, and it has influence on various kinds of cell, and is the important and crucial inflammatory mediator of the various disease states and the patient's condition.Particularly, these inflammatory mediators have related to pain (for example sensitization of pain receptor) and oedema.Therefore, the kinase mediated illness of other MEK that can prevent or treat comprises oedema, analgia, fever and pain (for example neuromuscular pain, headache, toothache, arthritis ache and by the pain due to the cancer).

In addition, the disease through compound as herein described, composition and method treatment can be an eye disease.Ophthalmology disease and blood vessel occur in the other diseases that plays a role in the pathogenesis, can be treated or be prevented, and include but not limited to: dry eyes (comprising Sjogren syndrome), macular degeneration, angle-closure glaucoma and open-angle glaucoma, ganglia retinae sex change, eye ischemic, the retinitis, PVR, uveitis, eye photophobia, and with relevant inflammation and the pain of ocular tissue's acute injury.Compound as herein described, composition and method are used for the treatment of glaucoma PVR and/or BDR. and compound as herein described, composition and method also are used for the treatment of the inflammation or the pain of postoperative, as the ophthalmic surgery inflammation or the pain that cause of cataract operation and refractive surgery for example.In further embodiment, described eye disease is to be selected from dry eyes, angle-closure glaucoma and open-angle glaucoma.

In addition, the disease through compound as herein described, composition and method treatment can be an autoimmune disease.The autoimmune disease that can be prevented or treat includes but not limited to: rheumatoid arthritis, inflammatory bowel disease, inflammatory pain, ulcerative colitis, Crohn's disease, periodontosis, temporomandibular arthrosis, multiple sclerosis, diabetes, glomerulonephritis, systemic loupus erythematosus, chorionitis, chronic thyroiditis, Graves disease, hemolytic anemia, autoimmunity gastritis, autoimmune neutropenia, thrombopenia, CAH, myasthenia gravis, atopic dermatitis, graft versus host disease and psoriasis.The inflammatory disease that can prevent or treat includes but not limited to: asthma, anaphylaxis, Respiratory Distress Syndrome(RDS) or acute pancreatitis or chronic pancreatitis.Particularly, compound as herein described, composition and method are used for the treatment of specific autoimmune disease rheumatoid arthritis and multiple sclerosis.

In addition, the disease through compound as herein described, composition and method treatment can be a skin disorder.In certain embodiments, described skin disorder is selected from down group, described group comprises melanoma, basal-cell carcinoma, squamous cell carcinoma without limitation, with other non-epithelium cutaneum carcinomas, and psoriasis and continuation itch, also have the other diseases relevant, can treat or prevent described skin disorder with MEK inhibitors of kinases of the present invention with skin and skin texture.

The metabolic disease that can treat or prevent comprises metabolic syndrome, insulin resistance without limitation, and I type and type ii diabetes.In addition, composition described herein can be used for the treatment of insulin resistance and typically with excessive inflammatory signal correction such as atherosclerotic other metabolic disorder.

Compound as herein described, composition and method also are used for the treatment of such as angiosis, antimigraine, kussmaul's disease, thyroiditis, alpastic anemia, Hodgkin's disease, chorionitis (sclerodoma), rheumatic fever, type i diabetes, neuromuscular junction disease (comprising myasthenia gravis), white matter disease (comprising multiple sclerosis), sarcoidosis, ephritis, nephrotic syndrome, behcet's syndrome, polymyositis, oulitis, periodontitis (periodontis), hypersensitivity, damage back swelling, ischemic (comprises myocardial ischemia, cardiovascular ischemic and heart stopping collecting Secondary cases ischemic) etc. disease in tissue damage in.Compound as herein described, composition and method can also be used for the treatment of allergic rhinitis, Respiratory Distress Syndrome(RDS), endotoxin shock syndrome and atherosclerotic.

In addition, the disease through compound as herein described, composition and method treatment can be the cardiovascular patient's condition.In certain embodiments, the described cardiovascular patient's condition is selected from atherosclerotic, cardiomegaly, idiopathic cardiomyopathy, heart failure, the relevant patient's condition or the illness of blood vessel generation, and the propagation that causes behind the medical conditions, described medical conditions includes but not limited to because of the ISR due to operation and the angioplasty.

In addition, the disease through compound as herein described, composition and method treatment can be a neurological disorders.In certain embodiments, described neurological disorders is selected from Parkinson's, Alzheimer disease, Alzheimer and because of the central lesion due to apoplexy, ischemic and the wound.In other embodiments, described neurological disorders is selected from epilepsy, neuropathic pain, depression and bipolar disorder.

In addition, through compound as herein described, the disease of composition and method treatment can be cancer, for example acute myeloid leukemia, thymic carcinoma, the cancer of the brain, lung cancer, squamous cell carcinoma, cutaneum carcinoma, cancer eye, retinoblastoma, the intraocular melanoma, oral cavity and oropharynx cancer, carcinoma of urinary bladder, stomach (gastric) cancer, stomach (stomach) cancer, pancreas, carcinoma of urinary bladder, breast cancer, cervical carcinoma, the head cancer, neck cancer, kidney, kidney, liver cancer, oophoroma, prostate cancer, colorectal cancer, the cancer of the esophagus, carcinoma of testis, gynecological cancer, thyroid cancer, the CNS cancer, the PNS cancer, the cancer that cancer (as lymphoma and Kaposi sarcoma) that AIDS is relevant or virus cause.In some embodiments, described compound and composition are used for the treatment of non-cancer excess proliferative illness, as the hyperplasia of prostate of skin (as psoriasis), ISR or prostate (as benign prostatauxe (BPH)).

In addition, through compound as herein described, the disease of composition and method treatment can be the pancreatitis in the mammal, kidney trouble (comprising the ephrosis that proliferative glomerulonephritis and diabetes cause), pain, relevant disease takes place with angiogenesis or blood vessel, tumor vessel takes place, chronic inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, atherosclerotic, skin disease is (as psoriasis, eczema and chorionitis), diabetes, BDR, retinopathy of prematurity, the macular degeneration that age is relevant, angioma, myotenositis, bursal synovitis, sciatica, glioma, melanoma, Kaposi sarcoma and oophoroma, breast cancer, lung cancer, cancer of pancreas, prostate cancer, colon cancer and epidermoid carcinoma.

In addition, the disease through compound as herein described, composition and method treatment can be to stop the blastocyte in the mammal to be implanted.

According to method of the present invention, can comprise with the patient of compound as herein described or the acceptable salt of their pharmacy, solvate, polymorph, ester, acid amides, dynamic isomer, prodrug, hydrate or derivatives for treatment, for example, diagnosed the patient who suffers from following disease, described disease comprises: psoriasis; ISR; Atherosclerotic; BPH; Breast cancer, for example duct carcinoma in the tracheal tissue in the mammary gland, cephaloma, mucinous carcinoma, tubule cancer and IBC; Oophoroma (comprise the gland cancer in epithelium ovarian neoplasm such as the ovary and be transferred to gland cancer the abdominal cavity) from ovary; The cancer of the uterus; Cervix cancer is as the gland cancer in the epithelium of cervix uteri (comprising squamous cell carcinoma and gland cancer); Prostate cancer, as be selected from following prostate cancer: the gland cancer that has been transferred to bone; Cancer of pancreas is as last dermoid cancer in the pancreatic duct tissue and the gland cancer in the pancreatic duct; Carcinoma of urinary bladder is as tumour, squamous cell carcinoma, gland cancer and the cellule cancer in the urothelium cell in the transitional cell carcinoma in the uropoiesis bladder, urothelium cancer (transitional cell carcinoma), the bladder lining; Leukemia is acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell, myelodysplasia and bone marrow proliferative illness for example; Osteocarcinoma; Lung cancer is non-small cell lung cancer (NSCLC) for example, is divided into squamous cell carcinoma, gland cancer and maxicell undifferentiated carcinoma, and small-cell carcinoma of the lung; Cutaneum carcinoma is basal-cell carcinoma, melanoma, squamous cell carcinoma and actinic keratoma (it is the skin disease that develops into squamous cell carcinoma sometimes) for example; The eyes retina blastoma; Cutaneous melanoma or intraocular (eye) melanoma; Primary carcinoma of liver (originating in the cancer of liver); Kidney; Thyroid cancer such as papillary thyroid carcinoma, folliculus thyroid cancer, medullary thyroid carcinoma and polymorphy thyroid cancer; AIDS correlation lymphoma such as diffuse large B cell lymphoma, B immunoblast's cell lymphoma and small non-cleaved cell lymphoma; Kaposi sarcoma; The cancer that virus causes (comprising hepatitis b virus (HBV), hepatitis C virus (HCV) and hepatocellular carcinoma); People's lymphotropic virus 1 type (HTLV-1) and Adult T-cell leukemia/lymphoma; And human papilloma virus (HPV) and cervical carcinoma; Central nervous system cancer (CNS) is as primary brain tumor, and it comprises glioma (astrocytoma, glioblastoma multiforme or glioblastoma multiforme), oligodendroglioma, ependymoma, meningioma, lymphoma, neurinoma and medulloblastoma; Peripheral neverous system (PNS) cancer such as acoustic neurinoma and pernicious peripheral nerve sheath knurl (MPNST) comprise neurofibroma and neurinoma, malignant fibrous sexual cell knurl, malignant fibrous histiocytoma, malignant meningioma, malignant mesothelioma and pernicious Combination muller's steatoma; Carcinoma of mouth and oropharynx cancer are for example swallowed cancer, laryngocarcinoma, nasopharyngeal carcinoma and oropharynx cancer; Cancer of the stomach such as lymphoma, stomach stromal tumor and carcinoid tumor; Carcinoma of testis such as gonioma (GCTs), it comprises seminoma and nonseminoma and sexual gland stromal tumor, it comprises leydig cell tumor and Sai Ertuoli cytoma; Thymic carcinoma such as thymoma, thymic carcinoma, Hodgkin's disease, non-Hodgkin lymphoma carcinoid or carcinoid tumor; The carcinoma of the rectum; And colon cancer.

Medicine box

Compound as herein described, composition and method are provided for treating the medicine box such as those illnesss as herein described.These medicine boxs comprise one or more compounds as herein described or composition in container, and randomly comprise the specification that uses described medicine box according to the whole bag of tricks as herein described and step instruction.Such medicine box can also comprise such information, for example science list of references, package insert material, clinical test results and/or these summary etc., its explanation or prove the activity and/or the advantage of described composition, and/or it describes dosage, medication, side effect, drug interaction, or other information useful to the health care supplier.Such information can be based on the result of various researchs, and for example, the research of service test animal comprises the body inner model and based on human clinical trial's research.Can comprise that doctor, nurse, pharmacists, prescription official etc. provide, sell and/or promote medicine box as herein described to medical supplier.In some embodiments, can also directly sell medicine box to the consumer.

Compound as herein described can be used for diagnostics and be used as research reagent.For example, compound as herein described makes up individually or with other compounds, can be as the instrument in difference and/or the combinatory analysis to illustrate the expression of gene pattern of expression in cell and the tissue.As a limiting examples, contrast is with the interior expression pattern of the cell or tissue of one or more compound treatment with without the control cells or the in-house expression pattern of compound treatment, the pattern of analyzing gained is measured the level of difference of gene expression, because they relate to, for example, disease association, signal path, celluar localization, detection expression of gene level, size, structure or function.Through stimulate or without stimulated cells on, and, can carry out these analyses in other compounds existence that influences expression pattern or not.

Except being used for the human treatment, compound of the present invention and preparation also are used for the veterinary treatment of pet (as dog, cat), rare animal and domestic animal (as horse), and it comprises mammal, rodent etc.

Embodiment that below provides and preparation method further illustrate and illustrate compound of the present invention and prepare the method for such compound.Should understand the scope that scope of the present invention never is subject to following examples and preparation method.

Embodiment

The further generalized exemplary step of synthetic sulfonamide

Steps A: in the solution (3mL/mmole) of amine (1eq) in anhydrous methylene chloride, add anhydrous triethylamine (5eq).In this solution, add sulfonic acid chloride (1eq), and at room temperature stir this solution 16h.Evaporating solvent, and by flash column chromatography through the silica gel purification residue.

Step B: in the solution (5ml/mmole) through stir of amine (1eq) in anhydrous pyridine, add sulfonic acid chloride (1-5eq).Stirred this reactant mixture 48 hours at 40 ℃.Water and EtOAc distribute this reactant mixture.Use the salt water washing, dry (MGSO ₄), and under reduced pressure concentrate.By flash column chromatography through the silica gel purification residue.

Step C: replace the iodine atom:

In microwave reactor, will be contained in 1eq. aryl iodide, 1.5eq. boric acid or borate, 0.25eq.PdCl in the deoxidation mixture of diox and water (3: 1) ₂(dppf) x DCM and 10eq. anhydrous K ₂CO ₃The suspension of powder is at 115 ℃ of heating 60min.Use aq.NH ₄The Cl/THF extraction, and use Na ₂SO ₄Dry organic moiety.Use flash column chromatography (Si, EtOAc/ hexane, perhaps CHCl ₃/ MeOH) purifying crude reaction product.Yield: 20-40%.

Step D: synthetic N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-2-(alkyl amino) ethyl sulfonamide:

(0.1ml 1mmol) adds 5,6-two fluoro-N with 2-chloro-ethyl sulfonic chloride ¹-(2-fluoro-4-iodophenyl) benzene-1, the 2-diamines (0.364g, 1mmol) and triethylamine (0.28ml is 2mmol) at CH ₂Cl ₂In the solution (5ml), and at room temperature stir this reactant mixture 16h.Use in the solution then or the excessive amine (10eq) of neat liquid is handled this reactant mixture.At room temperature stir this reactant mixture 6h again.Use CH ₂Cl ₂(10ml) and water (10ml) dilute this reactant mixture.Organic layer is used rare HCl successively, and (2x20ml is 2N) with saturated NaHCO ₃(2x10ml) solution washing.Dry then (MgSO ₄) CH ₂Cl ₂Layer, and evaporation obtains crude product.The product of purification of impure obtains the pure products of 50-60% yield under preparation HPLC condition.

Embodiment 1

N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) Methanesulfomide:

Steps A: 2,3-two fluoro-N-(2-fluoro-4-iodophenyl)-6-nitroaniline:

At 0 ℃, (11.40g 47mmol) drips the 1M solution (47ml) of LHMDS in THF (47mmol) in the solution in the anhydrous THF of 100ml to 2-fluoro-4-Iodoaniline.The color of solution becomes mulberry.Solution is transferred to dropping funel through sleeve pipe, and at 0 ℃ this solution (comprising the amine free alkali) sub-fraction sub-fraction ground is added 2,3, (8.321g is 47.0mmol) in the solution in anhydrous THF (50ml) for the 4-trifluoronitrobenzene.After adding finishes, at room temperature, under argon gas, stirred this mixture 15 hours.Reduce the volume of solvent, then with ethyl acetate and salt solution extraction.Through the dried over sodium sulfate organic layer, remove and desolvate, and by flash chromatography (EtOAc/ hexane 1: 5, R _f=0.58) purifying gained dark oil obtains crude product, and it becomes brown solid (yield: 6.23g, 33.6%): m/z=393[M-1 through vacuum drying] ^-

Step B: 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamines:

To nitro-diaryl amine (6.23g, 15.8mmol) add in the solution in 300ml ethanol iron powder (13.74g, 246mmol) and ammonium chloride (13.59g 254mmol), and follows this mixture of agitating heating 14 hours under 100 ℃ of oil bath temperatures.Filter, and with twice of washing with alcohol filter residue.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 salt water washing that merges, and through dried over sodium sulfate.Remove and desolvate, and from CHCl ₃/ hexane (1: 50) recrystallization crude product.Obtain brown needle-like product (2.094g, 66%), R _f=0.44 (EtOAc/Hex 1: 3). ¹H-NMR(500MHz，CDCl ₃)，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，NH ₂，br)，LRMS(ESI)：m/z＝365[M+H] ^-。

Step C: N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) Methanesulfomide:

According to general step A, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1, the product that 2-diamines and mesyl chloride reaction obtain expecting. ¹HNMR：(500MHz，CDCl ₃)：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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) cyclopropane sulfonamide:

According to general step A, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1, the product that 2-diamines and the reaction of cyclopropane sulfonic acid chloride obtain expecting. ¹HNMR：(500MHz，CDCl ₃)：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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) propane-2-sulfonamide:

According to general step A, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1, the product that 2-diamines and the reaction of isopropyl sulfonic acid chloride obtain expecting.Yield: 39%. ¹H-NMR(500MHz，CDCl ₃)：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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) butane-1-sulfonamide:

According to general step A, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1, the product that 2-diamines and the reaction of normal-butyl sulfonic acid chloride obtain expecting.Yield: 55%. ¹H-NMR(500MHz，CDCl ₃)：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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-2,2,2-trifluoroethyl sulfonamide:

According to general step A, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamines and 1,1, the product that the reaction of 1-trifluoroethyl sulfonic acid chloride obtains expecting.Yield: 28%.m/z＝509[M-1] ^-。

Embodiment 6

N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) butane-2-sulfonanilide:

According to general step A, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1, the product that 2-diamines and the reaction of sec-butyl sulfonic acid chloride obtain expecting.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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-N-methyl cyclopropane sulfonamide:

At-78 ℃, to N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) cyclopropane-sulfonamide (referring to implementing 2) (283.9mg, 0.61mmol) the 1M solution (0.6ml of adding LHMDS in the solution in the anhydrous THF of 3ml, 0.6mol), and under this temperature, stir this solution 10min.Then, (0.8ml, 1.824g 12.9mmol), and make this mixture be warmed to room temperature and stir 7h to add iodomethane.Remove and to desolvate and with EtOAc and salt solution extraction leftover.Use Na ₂SO ₄Dry organic moiety is also removed and is desolvated.With flash column chromatography (Si, EtOAc/ hexane 1: 2, R _f=0.45) purifying gained crude product.Yield: (205mg, 70%). ¹H-NMR(500MHz，CDCl ₃)；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

1-chloro-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) Methanesulfomide:

According to general step A, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1, the product that 2-diamines and the reaction of chloromethane sulfonic acid chloride obtain expecting, m/z=475[M-1] ^-

Embodiment 9

N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-2-methylpropane-2-sulfonamide:

According to general step B, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1, the product that 2-diamines and 2-methylpropane-2-sulfonic acid chloride (synthetic according to the document step) reaction obtains expecting. ¹H NMR (300MHz, CDCl ₃): δ 7.50 (m, 1H), 7.43 (dd, J=1.8﹠amp; 10.5Hz, 1H), 7.28 (br s, 1H), 7.10 (dd, J=9.0﹠amp; 17.7Hz, 1H), 6.48 (br s, D ₂O is commutative, 1H), and 6.19 (t, J=7.8﹠amp; 9.6Hz, 1H), 5.58 (br s, D ₂O is commutative, 1H), 1.39 (s, 9H); M/z=383[M-1] ^-

Embodiment 10

N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) pentamethylene sulfonamide:

According to general step B, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1, the product that 2-diamines and the reaction of pentamethylene sulfonic acid chloride obtain expecting. ¹H NMR (300MHz, CDCl ₃): δ 7.42 (dd, J=2.1﹠amp; 10.5Hz, 1H), 7.36 (ddd, J=2.4,4.8 ， ﹠amp; 9.3Hz, 1H), 7.25 (m, 2H), 7.10 (dd, J=9.6﹠amp; 17.7Hz, 1H), 6.67 (br s, D ₂O is commutative, 1H), and 6.20 (dt, J=1.5,8.4﹠amp; 17.4Hz, 1H), 3.53 (p, 1H), 1.80 (m, 8H); M/z=495[M-1] ^-

Embodiment 11

N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) cyclohexane sulfonamide:

According to general step B, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1, the product that 2-diamines and the reaction of cyclohexane sulfonic acid chloride obtain expecting. ¹H NMR (300MHz, CDCl ₃): δ 7.43 (dd, J=1.5﹠amp; 10.2Hz, 1H), 7.37 (ddd, J=2.4,4.8﹠amp; 9.6Hz, 1H), 7.27 (m, 1H), 7.11 (dd, J=9.3﹠amp; 18.0Hz, 1H), 6.64 (br s, 1H), 6.18 (dt, J=1.5,9.0﹠amp; 17.4Hz, 1H), 5.63 (br s, 1H), 2.95 (three groups of triplets, and 2.10-1.16 (m, 10H); M/z=509[M-1] ^-

Embodiment 12

N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-1-methyl cyclopropane-1-sulfonamide:

Steps A: The positive butyl ester of 3-chloro-1-propane sulfonic acid:

Will be at CH ₂Cl ₂(28ml, (36.6g, 200mmol) (18.4g is 240mmol) at CH with the 1-butanols 200mmol) to add 3-chloro-1-propane sulfonic acid chloride lentamente for triethylamine (50ml) ₂Cl ₂In the ice-cold solution (250ml), and continue to stir 16h.Use CH ₂Cl ₂(200ml) dilute this mixture, washing (the HCl aqueous solution), dry (MgSO ₄), and evaporating solvent obtains the little butyrous title product 1 (40.85g, 95%) of rough form, promptly is used for the next step without being further purified. ¹H NMR (CDCl ₃₎) 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 ℃, under blanket of nitrogen, (1.6M THF) adds among the THF (150ml) simultaneously for 14.7ml, 23.53mmol with 3-chloro-1-propane sulfonic acid 1-butyl acetate solution (4.6g, 21.39mmol is in 25ml THF) and butyl lithium solution.Make this solution be warmed to 0 ℃, use (2ml) cessation reaction then.The vapourisation under reduced pressure volatile materials, and use CH ₂Cl ₂(150ml) extraction leftover.Wash extract with water, dry (MgSO ₄), and evaporate the almost product of the rough expectation of the pale yellow oily of pure form (3.23g, 78.22%) of generation, soon it is used for next step without being further purified. ¹H NMR (300MHz, CDCl ₃) δ 0.94 (t, J=7.5Hz, 3H), 1.07 (m, 2H), 1.25 (m, 2H), 1.45 (sextet, 2H), 1.74 (quintet, 2H), 2.45 (heptet, 1H), 4.23 (t, J=6.6Hz, 2H).

Step C: 1-methyl-cyclopropane sulfonic acid butyl ester:

At-78 ℃, under blanket of nitrogen, to cyclopropane sulfonic acid 1-butyl ester (1g, 5.58mmol) add lentamente in the solution in THF (15ml) butyl lithium solution (3.84ml, 6,14mmol, 1.6M, THF).After 15 minutes, (0.72ml 11.16mmol), makes solution be warmed to 0 ℃, and water (1ml) cessation reaction to add MeI.The vapourisation under reduced pressure volatile materials, and use CH ₂Cl ₂(100ml) extraction leftover.Wash extract with water, dry (MgSO ₄), and evaporation.Residue is through silica gel chromatography (eluant, eluent: hexane/CH ₂Cl ₂) purifying obtains the title product (0.59g, 55.0%) of colorless oil. ¹H?NMR(300MHz，CDCl ₃₎)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 rhodanide (0.194g, 2mmol) the mixture backflow 16h in DME (5ml) and water (5ml).Evaporation of volatile substances obtains rough sulfonate (0.348g, quantitatively), at 50 ℃ with its dry 16h under vacuum.This crude product is used for the next step without being further purified soon. ¹HNMR(300MHz，D ₂O)δ0.56(t，J＝6.3Hz，2H)，0.96(t，J＝6.3Hz，2H)，1.26(s，3H)。

Step e: 1-methyl-cyclopropane sulfonic acid chloride:

At 60 ℃, make 1-methyl-cyclopropane potassium sulfonate (0.348g, 2mmol), the solution backflow 16h of thionyl chloride (5ml) and DMF (5).The vapourisation under reduced pressure volatile materials, and use CH ₂Cl ₂(50ml) extracted residues.Wash extract with water, dry (MgSO ₄), and evaporation obtains yellow colloid oily crude product, is about to it and is used for the next step without being further purified.

Step F: N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl oxygen base) phenyl)-1-methyl cyclopropane-1-sulfonamide:

According to general step B, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1, the product that 2-diamines and 1-methyl-reaction of cyclopropane sulfonic acid chloride obtains expecting. ¹H?NMR(300MHz，CDCl ₃)：δ7.42(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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide:

Steps A: Cyclopropane sulfonic acid butyl ester:

With the cyclopropane sulfonic acid chloride (5g, 35mmol 1eq) are dissolved among the excessive BuOH (20ml) ,-10 ℃ the cooling these reactant mixtures, and drip lentamente pyridine (5.8mL, 70mmol, 2eq).Making this mixture be warmed to room temperature lentamente and stir spends the night.Under reduced pressure remove and desolvate, and the gained white solid is dissolved in CHCl ₃In.Water, salt water washing organic facies, dry (MgSO4) concentrates then and generates oil (4.8g, 24.9mmol, 71%). ¹H?NMR(300MHz，CDCl ₃)：δ4.25(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 ℃, under blanket of nitrogen, to cyclopropane sulfonic acid 1-butyl ester (4.8g, 24.9mmol) add simultaneously in the solution in THF butyl lithium solution (15.6ml, 24.9mmol, 1.6M, THF) and allyl iodide (24.9mmol).Stirred this reactant mixture 2 hours at-78 ℃, and at room temperature stirred 3 hours.The vapourisation under reduced pressure volatile materials, and use CH ₂Cl ₂(100ml) extraction leftover.Wash extract with water, dry (MgSO ₄), evaporation then.Residue is through silica gel chromatography (eluant, eluent: hexane/CH ₂Cl ₂) purifying obtains the title product (3.75g, 69.0%) of colorless oil. ¹H?NMR(300MHz，CDCl ₃)：δ5.6(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: 1-pi-allyl cyclopropane-1-potassium sulfonate:

Make 1-methyl-cyclopropane sulfonic acid 1-butyl ester (3.75g, 17.2mmol) and potassium rhodanide (1.7g, 17.2mmol) the mixture backflow 16h in DME (20ml) and water (20ml).Evaporation of volatile substances obtains rough sulfonate (3.44g, quantitatively), at 50 ℃ with its dry 16h under vacuum.This crude product is used for the next step without being further purified soon. ¹H?NMR(CDCl ₃)：δ5.6(m，1H)，4.91-4.85(dd，2H)，2.471-2.397(d，2H)，0.756(m，2H)，0.322(m，2H)。

Step D: 1-pi-allyl cyclopropane-1-sulfonic acid chloride:

At 60 ℃, make 1-pi-allyl cyclopropane-1-potassium sulfonate (3.44g, 17.2mmol), the solution backflow 16h of thionyl chloride (10ml) and DMF (5).The vapourisation under reduced pressure volatile materials, and use CH ₂Cl ₂(50ml) extraction leftover.Wash extract with water, dry (MgSO ₄), and the evaporation obtain yellow colloid oily crude product, it promptly is used to (2.7g, 15mmol, 87%) in the next step through hexane wash without being further purified. ¹H?NMR(300MHz，CDCl ₃)：δ5.728(m，1H)，5.191(t，2H)，2.9(d，2H)，0.756(m，2H)，0.322(m，2H)。

Step e: 1-pi-allyl-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) cyclopropane-1-sulfonamide:

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

Step F: N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulphonyl Amine:

With 1-pi-allyl-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) cyclopropane-1-sulfonamide (0,77g, 1.52mmol) (0,18g 1.52mmol) is dissolved among the THF (50mL) with 4-methyl morpholine N-oxide.(4% at H for 0.152mmol, 0.965mL at room temperature to add osmium tetroxide ₂Among the O), and at room temperature stirred this reactant mixture 16 hours.Add EtOAc, wash organic facies with water, dry (MgSO ₄), and decompression concentrates down.(eluant, eluent: EtOAc/MeOH) purifying obtains title product (0.65g, 79%) to residue through silica gel chromatography. ¹H?NMR(300MHz，CDCl ₃+D ₂O)：δ7.38(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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide:

Obtain pure S isomer by chirality HPLC separation of racemic mixture (embodiment 13). ¹H?NMR(300MHz，CDCl ₃+D ₂O)：δ7.38(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 15

(R)-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide:

Obtain pure R isomer by chirality HPLC separation of racemic mixture (embodiment 13). ¹H?NMR(300MHz，CDCl ₃+D ₂O)：δ7.38(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 16

N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl-1-(2-hydroxyethyl) cyclopropane-1-sulfonamide:

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

0 ℃ to pure diethyl zinc (3.3ml, 3.977g, 30mmol) drip very lentamente in the solution in the anhydrous DCM of 100ml trifluoroacetic acid (2.31ml, 3.4188g, 30mmol).(points for attention: violent gas discharges, heat release! ).TFA add finish after, under uniform temp, stir this suspension 20min, add then diiodomethane (2.45ml, 8.134g, 30.4mmol).Stir 20min again at 0 ℃, under uniform temp, add 3-bromine fourth-3-alkene-1-alcohol (1ml, 1.523g, 10.1mmol) solution in 10ml DCM then.Add finish after, make this mixture be warmed to room temperature and stirred 4 hours.Stop the reaction of this mixture with 100ml MeOH and 40ml salt solution, then it is stirred 30min again.Reduce solvent, and use CHCl ₃/ aq.NH ₄The Cl extraction leftover.Collected organic layer is used salt solution and water washing, and removes 2-(1-bromine the cyclopropyl)-ethanol (1.6564g, 100%) of the enough purity of generation of desolvating. ¹H-NMR(500MHz，CDCl ₃)：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 1-bromine cyclopropyl) ethanol of TBS protection:

To cyclopropyl alcohol (steps A) (1.303g, 7.95mmol) add in the solution in the anhydrous DCM of 30ml anhydrous pyridine (1.2ml, 1,1736g, 14.8mmol) and TBSOTf (2.7ml, 3.1077g 11.76mol), and at room temperature stir this solution 16h.Use CHCl ₃The extraction of/salt solution, and use MgSO ₄Dry organic moiety.Reduce solvent, and with flash column chromatography (Si, CHCl ₃/ hexane 1: 10, R _f=0.4) purifying crude product.Yield: 0.796g, 36%. ¹H-NMR(500MHz，CDCl ₃)：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 ℃, the Cyclopropyl Bromide that in step B, prepares (1.1227g, 4.04mmol) add in the solution in the 15ml anhydrous diethyl ether 1.7M solution of t-BuLi in pentane (4.8ml, 8.16mmol).Stir this solution 30min under this temperature, (0.65ml, 1.029g is 8.1mmol) in the solution in the 8ml diethyl ether to be transferred to the sulfonic acid chloride of new distillation at-78 ℃ by transfer sleeve pipe (transfer canola) then.Make yellow suspension be warmed to room temperature.Remove and to desolvate, and in a vacuum dried residue to remove excessive sulfonic acid chloride.Then, with hexane extraction residue twice, after the filtration, evaporating solvent generates the colorless oil sulfonic acid chloride of enough purity in a vacuum.Yield: 870mg (72%). ¹H-NMR(300MHz，CDCl ₃)：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-(3.4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-1-(2-hydroxyethyl) cyclopropane of TBS protection -1-sulfonamide:

According to general step B, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1, the product that the cyclopropyl sulfonic acid chloride for preparing among 2-diamines and step C reaction obtains expecting. ¹H-NMR(300MHz，CDCl ₃)：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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-1-(2-hydroxyethyl) cyclopropane-1-sulfonamide:

At 0 ℃, (21mg 0.033mmol) adds 0.1ml aq.1.2N HCl solution, and stirs this solution 2h the sulfonamide of the TBS protection for preparing in step D in the solution in 1ml THF.Reduce solvent, and use NaHCO ₃The aqueous solution and EtOAc extraction leftover.Use MgSO ₄Dry organic moiety, and remove volatile materials.With flash column chromatography (Si, CHCl ₃/ MeOH 10: 1, R _f=0.45) the purifying crude product generates pure product.Yield: 16.9mg (100%). ¹H-NMR(300MHz，CDCl ₃)：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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-3-hydroxy propane-1-sulfonamide:

To 3-chloro-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-propane-1-sulfonamide (69.4mg, 0.138mmol) at 8ml, 1,4-diox and 2ml H ₂(0.674g 12.0mmol), and heats this mixture to reflux temperature and continues 3 days to add the KOH powder in the solution in the mixture of O.With the extraction of EtOAc/ salt solution, use Na ₂SO ₄Dry organic moiety, and remove volatile materials.With flash column chromatography (Si, DCM/MeOH 5: 1, R _f=0.3) purifying residue.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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-2-methyl-5-(trifluoromethyl) furans-3-sulfonamide:

According to general step B, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamines (0.182mmol) forms N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-2-methyl-5-(trifluoromethyl) furans-3-sulfonamide with 2-methyl-5-(trifluoromethyl) furans-3-sulfonic acid chloride (0.5mmol) reaction. ¹H?NMR(CDCl ₃)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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) sulfamoyl)-methylthiazol-2-yl) acetamide:

According to general step B; 5; 6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1; 2-diamines (0.182mmol) obtains N-(5-(N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) sulfamoyl)-4-methylthiazol-2-yl) acetamide with 2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-sulfonic acid chloride (0.5mmol) reaction. ¹H?NMR(CDCl ₃₎)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-yl)-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) thiophene-2-sulfonamide:

According to general step B, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamines (0.182mmol) and 5-(5-chloro-1,2,4-thiadiazoles-3-yl) thiophene-2-sulfonic acid chloride (0.5mmol) reaction obtains 5-(5-chloro-1,2,4-thiadiazoles-3-yl)-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) thiophene-2-sulfonamide. ¹H?NMR(300MHz，CDCl ₃₎)δ5.8(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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-3,5 dimethyl isoxazoles-4-sulfonamide:

According to general step B, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamines (0.182mmol) and 3,5-dimethyl isoxazole-4-sulfonic acid chloride (0.5mmol) reaction obtains N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-3,5-dimethyl isoxazole-4-sulfonamide. ¹H?NMR(300MHz，CDCl ₃))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

5-chloro-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-1,3-dimethyl-lH-pyrazoles-4-sulfonamide:

According to general step B, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamines (0.182mmol) and 5-chloro-1,3-dimethyl-1H-pyrazoles-4-sulfonic acid chloride (0.5mmol) reaction obtains 5-chloro-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-1,3-dimethyl-1H-pyrazoles-4-sulfonamide. ¹H?NMR(300MHz，CDCl ₃₎)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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-2,5-dimethyl furan-3-sulfonamide:

According to general step B, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamines (0.182mmol) and 2,5-dimethyl furan-3-sulfonic acid chloride (0.5mmol) reaction obtains N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-2,5-dimethyl furan-3-sulfonamide. ¹H?NMR(300MHz，CDCl ₃))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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazoles-4-sulfonamide:

According to general step B, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamines (0.182mmol) obtains N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazoles-4-sulfonamide with 1-methyl-3-(trifluoromethyl)-1H-pyrazoles-4-sulfonic acid chloride (0.5mmol) reaction. ¹H?NMR(300MHz，CDCl ₃₎)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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-2,4-dimethylthiazole-5-sulfonamide:

According to general step B, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamines (0.182mmol) and 2,4-dimethylthiazole-5-sulfonic acid chloride (0.5mmol) reaction obtains N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-2,4-dimethylthiazole-5-sulfonamide. ¹H?NMR(300MHz，CDCl ₃))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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-1,2-dimethyl-1H-imidazoles-4-sulfonamide:

According to general step B, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamines and 1,2-dimethyl-1H-imidazoles-4-sulfonic acid chloride reaction obtains title compound. ¹H?NMR(300MHz，CDCl ₃)：δ7.95(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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) thiophene-3-sulfonamide:

According to general step B, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamines and thiophene-3-sulfonic acid chloride reaction obtains title compound. ¹HNMR (300MHz, CDCl ₃): δ 8.00 (dd, J=1.2﹠amp; 3.3Hz, 1H), 7.45 (dd, J=0.9﹠amp; 5.1Hz, 1H), 7.35 (m, 2H), 7.27 (m, 2H), 6.91 (dd, J=9.3﹠amp; 17.1Hz, 1H), 6.64 (ddd, J=2.1,4.8﹠amp; 8.7Hz, 1H), 6.34 (dt, J=5.4,8.7﹠amp; 14.1Hz, 1H), 5.98 (br d, J=2.1Hz, D ₂O is commutative, 1H).

Embodiment 28

N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) furans-2-sulfonamide:

According to general step B, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamines and furans-2-sulfonic acid chloride reaction obtains title compound. ¹HNMR (300MHz, CDCl ₃): δ 7.53 (br s, D ₂O is commutative, 1H), and 7.38 (dd, J=1.8﹠amp; 10.5Hz, 1H), 7.30 (d, J=8.4Hz, 1H), 7.21 (d, J=3.0Hz, 1H), 6.96 (dd, J=8.7﹠amp; 16.5Hz, 1H), 6.87 (ddd, J=1.8,5.1﹠amp; 9.0Hz, 1H), 6.53 (dd, J=1.8﹠amp; 3.6Hz, 1H), 6.44 (dt, J=5.1,8.7﹠amp; 13.8Hz, 1H), 6.22 (br s, D ₂O is commutative, 1H).

Embodiment 29

N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-5-methylthiophene-2-sulfonamide:

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

Embodiment 30

5-chloro-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) thiophene-2-sulfonamide:

According to general step B, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamines and 5-chlorothiophene-2-sulfonic acid chloride reaction obtains title compound. ¹H NMR (300MHz, CDCl ₃): δ 7.38 (dd, J=1.5﹠amp; 10.2Hz, 1H), 7.32 (ddd, J=2.1,5.1﹠amp; 9.3Hz, 1H), 7.25 (d, J=3.9Hz, 1H), 7.10 (dd, J=9.0﹠amp; 18.6Hz, 3H), 6.84 (d, J=4.2Hz, 1H), 5.86 (dt, J=1.8,8.7﹠amp; 17.4Hz, 1H), 5.49 (br s, D ₂O is commutative, 1H).

Embodiment 31

5-bromo-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) thiophene-2-sulfonamide:

According to general step B, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamines and 5-bromothiophene-2-sulfonic acid chloride reaction obtains title compound. ¹H?NMR(300MHz，CDCl ₃)：δ7.39-7.29(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

4-bromo-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) thiophene-3-sulfonamide:

According to general step B, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamines and 4-bromothiophene-3-sulfonic acid chloride reaction obtains title compound. ¹H?NMR(300MHz，CDCl ₃)：δ7.48(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

4-bromo-5-chloro-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) thiophene-2-sulfonamide:

According to general step B, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamines and 4-bromo-5-chlorothiophene-2-sulfonic acid chloride reaction obtains title compound. ¹H?NMR(300MHz，CDCl ₃)：δ7.42-7.34(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

3-bromo-5-chloro-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) thiophene-2-sulfonamide:

According to general step B, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamines and 3-bromo-5-chlorothiophene-2-sulfonic acid chloride reaction obtains title compound. ¹H?NMR(300MHz，CDCl ₃)：δ7.41(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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-2,5-thioxene-3-sulfonamide:

According to general step B, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamines and 2,5-thioxene-3-sulfonic acid chloride reaction obtains title compound. ¹H?NMR(300MHz，CDCl ₃)：δ7.39(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

2,5-two chloro-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) thiophene-3-sulfonamide:

According to general step B, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamines and 2,5-dichloro-thiophene-3-sulfonic acid chloride reaction obtains title compound. ¹H?NMR(300MHz，CDCl ₃)：δ7.41(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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) sulfamoyl) thiophene-2-carboxylic acid methyl esters:

According to general step B, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1, the reaction of 2-diamines and 3-(chlorosulfonyl) thiophene-2-carboxylic acid methyl esters obtains title compound. ¹H?NMR(300MHz，CDCl ₃)：δ8.58(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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) sulfamoyl)-1-methyl isophthalic acid H-pyrroles-2-carboxylate methyl ester:

According to general step B, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamines and 5-(chlorosulfonyl)-1-methyl isophthalic acid H-pyrroles-2-carboxylate methyl ester reaction obtains title compound. ¹HNMR(300MHz，CDCl ₃)：δ7.37(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(brs，1H)，3.65(s，3H)，3.75(s，3H)。

Embodiment 39

N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-5-methyl-isoxazole-4-sulfonamide:

According to general step A, 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1, the 2-diamines obtains title compound with corresponding sulfonic acid chloride reaction.Yield: 22%.m/z＝508[M-1] ^-。

Embodiment 40

3-chloro-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) propane-1-sulfonamide:

According to general step A, 5,6-two fluoro-N-1-(2-fluoro-4-iodophenyl) benzene-1, the product that 2-diamines and 3-chloropropane-reaction of 1-sulfonic acid chloride obtains expecting. ¹H?NMR(500MHz，CDCl ₃)：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-fluorophenyl amino)-3,4-difluorophenyl) cyclopropane sulfonamide:

Referring to embodiment 1. ¹H?NMR(300MHz，CDCl ₃)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-(3,4-two fluoro-2-(4-iodo-2-aminomethyl phenyl amino) phenyl) cyclopropane sulfonamide:

Referring to embodiment 1. ¹H?NMR(CDCl ₃)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-chlorphenyl amino)-3,4-difluorophenyl) cyclopropane sulfonamide:

Referring to embodiment 1. ¹H?NMR(300MHz，CDCl ₃)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-1] ^-。

Embodiment 44

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

Referring to embodiment 1. ¹H?NMR(300MHz，CDCl ₃)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

3-chloro-N-(3,4-two fluoro-2-(2-fluoro-4-trifluoromethyl) phenyl amino) phenyl) propane-1-sulfonamide:

Referring to embodiment 1. ¹H NMR (300MHz, CDCl ₃): δ 7.39-7.26 (m, 2H), 7.25 (m, 1H), 7.18 (dd, J=9.0﹠amp; 17.7Hz, 1H), 6.78 (br s, D ₂O is commutative, 1H), 6.50 (t, J=8.1Hz, 1H), 6.00 (br d, D ₂O is commutative, J=1.5Hz, 1H), 3.63 (t, J=6.0﹠amp; 6.3Hz, 2H), 3.29 (t, J=7.2﹠amp; 7.8Hz, 2H), 2.26 (quintet, 2H); M/z=445[M-1] ^-

Embodiment 46

N-(3,4-two fluoro-2-(2-chloro-4-trifluoromethyl) phenyl amino) Methanesulfomide:

Referring to embodiment 1. ¹H NMR (300MHz, CDCl ₃): δ 7.65 (d, J=7.8Hz, 1H), 7.33 (m, 2H), 7.19 (dd, J=9.3﹠amp; 17.4Hz, 1H), 6.90 (br s, D ₂O is commutative, 1H), and 6.45 (dd, J=1.5﹠amp; 8.4Hz, 1H), 6.39 (br s, D ₂O is commutative, 1H), 3.02 (s, 3H); M/z=399[M-1] ^-

Embodiment 47

3-chloro-N-(3,4-two fluoro-2-(2-chloro-4-trifluoromethyl) phenyl amino) phenyl) propane-1-sulfonamide:

Referring to embodiment 1. ¹H NMR (300MHz, CDCl ₃): δ 7.66 (d, J=1.5Hz, 1H), 7.36 (m, 2H), 7.19 (dd, J=9.0﹠amp; 17.4Hz, 1H), 6.91 (br s, D ₂O is commutative, 1H), and 6.50 (dd, J=8.4﹠amp; 1.5Hz, 1H), 6.37 (s, D ₂O is commutative, 1H), 3.62 (t, J=6.0Hz, 2H), 3.29 (t, J=7.5﹠amp; 7.8Hz, 2H), 2.27 (quintet, 2H); M/z=462[M-1] ^-

Embodiment 48

3-chloro-N-(3,4-two fluoro-2-(2-bromo-4-trifluoromethyl) phenyl amino) phenyl) propane-1-sulfonamide:

Referring to embodiment 1. ¹H NMR (300MHz, CDCl ₃): δ 7.82 (s, 1H), 7.38 (m, 2H), 7.20 (dd, J=9.0﹠amp; 17.7Hz, 1H), 6.62 (br s, D ₂O is commutative, 1H), 6.43 (d, J=8.4Hz, 1H), 6.23 (s, D ₂O 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 (3,4,6-three fluoro-2-(2-fluoro-4-iodo-phenyl amino)-phenyl)-acid amides:

Steps A: (2-fluoro-4-iodo-phenyl)-(2,3,5-three fluoro-6-nitro-phenyl)-amine:

Under nitrogen, (3.64gm, 15.37mmol) solution of the stirring in anhydrous THF (100ml) is cooled to-78 ℃, and adds 1.0M hexamethyl two silica-based lithium amide (LiN (SiMe lentamente with 2-fluoro-4-Iodoaniline ₃) ₂) " LHMDS " solution (15.37ml, 15.37mmol).Continue again to stir this reactant mixture one hour at-78 ℃, add 2,3,4 then, 6-tetrafluoro nitrobenzene.Make this reactant mixture be warmed to room temperature, and continue again to stir 16 hours.(200ml) adds in this reactant mixture with ethyl acetate, and washes with water.Organic layer is through dried over sodium sulfate, and is further purified by column chromatography and generates yellow solid (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: 3,4,6-three fluoro-N ² -(2-fluoro-4-iodo-phenyl)-benzene-1, the 2-diamines:

To (2-fluoro-4-iodo-phenyl)-(2,3,5-three fluoro-6-nitro-phenyl)-amine 3 (5.2gm, 12.62mmol) add in the solution of the stirring in EtOH (200ml) ammonium chloride (10.12gm, 189.3mmol) and iron powder (10.57gm, 189.3mmol).Continue this reactant mixture of stirring and refluxing 16 hours.Make the reactant mixture cooling, (celite) filters and is concentrated into dried through diatomite.The gained residue is placed EtOAc, and wash with water.The EtOAc layer is through dried over sodium sulfate, and generates pale solid (3.2gm, yield: 66.39%) by further being purified from the EtOH crystallization.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: 4,6,7-three fluoro-1-(' 2-fluoro-4-iodo-phenyl)-1,3 ,-dihydrobenzo imidazoles-2-ketone:

To 3,4,6-three fluoro-N2-(2-fluoro-4-iodo-phenyl)-benzene-1, (0.285gm is 0.74mmol) at CH for 2-diamines 3 ₂Cl ₂Add 1,1 in the solution of the stirring (2ml) '-carbonyl dimidazoles (0.125gm, 0.75mmol).At room temperature continue to stir this reactant mixture 16 hours, during the product precipitation separate out.Filter white solid, it promptly is used further (0.2gm, yield: 65.85%) without any purifying.m/z＝407[M-1] ^-。

Step D/E: Cyclopropane sulphur enzyme (3,4,6-three fluoro-2-(2-fluoro-4-iodo-phenyl amino)-phenyl)-acid amides:

Under nitrogen, with 4,6,7-three fluoro-1-(2-fluoro-4-iodo-phenyl)-1,3 ,-dihydrobenzo imidazoles-2-ketone (0.2gm, 0.41mmol) solution of stirring in anhydrous THF (4ml) is cooled to-78 ℃, and add lentamente 1.0M LiHMDS solution (0.41ml, 0.41mmol).(2ml) add subsequently the cyclopropane sulfonic acid chloride (0.050ml, 0.49mmol).At room temperature continue to stir this reactant mixture 16 hours, and be concentrated into driedly, and place EtOAc.EtOAc partly washes with water, through dried over sodium sulfate, and is concentrated into dried.With gained residue 1-cyclopropane sulfonyl-4,5,7-three fluoro-3-(2-fluoro-4-iodo-phenyl)-1,3-dihydro-benzimidazolyl-2 radicals-ketone 5 places diox (2ml), and to wherein adding 1.0N NaOH (0.5ml), and continues to stir 16 hours at 50 ℃.TLC shows not complete reaction, generates pale solid (4.4mg) by the HPLC purified product.M+H ⁺：484.7，M-H ⁺：486.7。 ¹HNMR(CDCl ₃，300MHZ)：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-(3,4-two fluoro-2-(4-fluoro-2-iodophenyl amino)-6-ethoxyl phenenyl) cyclopropane sulfonamide:

Steps A: (2,3-two fluoro-5-methoxyl group-6-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine:

Under nitrogen, with (2-fluoro-4-iodo-phenyl)-(2,3,5-three fluoro-6-nitro-phenyl)-amine (1.23gm, 3mmol) solution of the stirring in anhydrous THF (25ml) is cooled to-78 ℃, and add lentamente 25%NaOMe solution (0.68ml, 0.3mmol).Make reactant mixture be warmed to room temperature, and continue again to stir 16 hours.TLC shows not complete reaction.(100ml) adds in this reactant mixture with ethyl acetate, and washes with water.Organic layer is through dried over sodium sulfate, and is further purified by column chromatography and generates yellow solid (0.6gm, yield: 47.6%).m/z＝424[M＝H] ⁺。

Step B: 5,6-two fluoro-N1-(4-fluoro-2-iodophenyl)-3-methoxybenzene-1, the 2-diamines:

To (2,3-two fluoro-5-methoxyl group-6-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine (0.57gm, 1.34mmol) add in the solution of the stirring in EtOH (20ml) ammonium chloride (1.18gm, 20.16mmol) and iron powder (1.15gm, 21.44mmol).Continue this reactant mixture of stirring and refluxing 16 hours.Make the reactant mixture cooling,, and be concentrated into dried through diatomite filtration.The gained residue is placed EtOAc, and wash with water.The EtOAc layer is through dried over sodium sulfate, and generates pale solid (0.47gm, yield: 90.3%) by further being purified from the EtOH crystallization.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: 6,7-two fluoro-1-(4-fluoro-2-iodophenyl)-4-methoxyl group-1H-benzo [d] imidazoles-2 (3H)-ketone:

To 5,6-two fluoro-N1-(4-fluoro-2-iodophenyl)-3-methoxybenzene-1, (0.17gm is 0.43mmol) at CH for the 2-diamines ₂Cl ₂Add 1,1 in the solution of the stirring (2ml) '-carbonyl dimidazoles (0.085gm, 0.53mmol).At room temperature continue to stir this reactant mixture 16 hours, during the product precipitation separate out.Filter white solid, it promptly is used further (0.089gm) without any purifying; M/z=419[M-1] ^-

Step D/F: N-(3,4-two fluoro-2-(4-fluoro-2-iodophenyl amino)-6-methoxyphenyl) cyclopropane sulfonamide:

Under nitrogen; with 1-(cyclopropyl sulfonyl)-4; 5-two fluoro-3-(2-fluoro-4-iodophenyl)-7-methoxyl group-1H-benzo [d] imidazoles-2 (3H)-ketone (0.89gm; 0.17mmol) solution of stirring in anhydrous THF (4ml) is cooled to-78 ℃; and add lentamente 1.0M LiHMDS solution (0.17ml, 0.17mmol).(2ml) add subsequently the cyclopropane sulfonic acid chloride (0.021ml, 0.21mmol).At room temperature continue to stir this reactant mixture 16 hours, and be concentrated into driedly, and place EtOAc.The EtOAc part through dried over sodium sulfate, and is concentrated into dried through water washing.With gained 1-(cyclopropyl sulfonyl)-4,5-two fluoro-3-(2-fluoro-4-iodophenyl)-7-methoxyl group-1H-benzo [d] imidazoles-2 (3H)-ketone places diox (2ml), and to wherein adding 1.0N NaOH (0.5ml), and continues to stir 16 hours at 50 ℃.TLC shows not complete reaction, generates pale solid (2.5mg) by the HPLC purified product.M+H ⁺：484.7，M-H ⁺：497.3。 ¹H?NMR(CDCl ₃，300MHz)：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 (3,4-two fluoro-2-(2-fluoro-4-iodo-phenyl amino)-6-methoxyl group-phenyl)-acid amides:

To 5,6-two fluoro-N1-(4-fluoro-2-iodophenyl)-3-methoxybenzene-1, (0.150gm is 0.38mmol) at anhydrous CH for the 2-diamines ₂Cl ₂Add lentamente in the solution (4ml) through stirring TEA (264ml, 1.9mmol) and mesyl chloride.At room temperature continue to stir this reactant mixture 16 hours, TLC shows not complete reaction, observes raw material and two kinds of products.Wash reactant mixture with water, organic layer is through dried over sodium sulfate, and be concentrated into dried, by the column chromatography purified product.Find that secondary product is expected compound (6.4mg).M-H ⁺：471.5。 ¹H?NMR(CDCl ₃，300MHz)：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

1-(2,3-dihydroxy-propyl group)-cyclopropane sulfonic acid [3,4,6-three fluoro-2-(4-fluoro-2-iodo-phenyl amino)-phenyl]-acid amides:

Steps A: 1-pi-allyl-cyclopropane sulfonic acid [3,4.6-three fluoro-2-(2-fluoro-4-iodo-phenyl amino) phenyl]-acid amides:

According to general step B, 1-pi-allyl-cyclopropane sulfonic acid chloride and 3,5,6-three fluoro-N ¹-(2-fluoro-4-iodophenyl) benzene-1, the 2-diamine reactant obtains title product. ¹H?NMR(CDCl ₃，300MHz)：δ7.41(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: 1-(2, the 3-dihydroxypropyl)-N-(3,4,6-three fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) cyclopropane-1-sulphonyl Amine:

[3,4,6-three fluoro-2-(2-fluoro-4-iodo-phenyl amino)-phenyl]-(110mg, 0.21mmol) (24.6mg 0.21mmol) is dissolved among the THF (8mL) acid amides with 4-methyl morpholine N-oxide with 1-pi-allyl-cyclopropane sulfonic acid.(4% at H for 0.021mmol, 0.153mL at room temperature to add osmium tetroxide ₂Among the O), and at room temperature stirred this reactant mixture 16 hours.Add EtOAc, organic facies is through water washing, dry (MgSO ₄), and concentrating under reduced pressure.(eluant, eluent: EtOAc/MeOH) purifying obtains title product (0.89g, 75%) to residue through silica gel chromatography. ¹H?NMR(CDCl ₃，300MHz)：δ7.39(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，1H)，1.46(m，1H)，1.28(m，1H)，1.20(m，2H)，0.92(m，2H)；m/z＝559[M-1] ^-。

Embodiment 53

(S)-1-(2, the 3-dihydroxypropyl)-N-(3,4,6-three fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) cyclopropane-1-sulfonamide:

Obtain pure S isomer by chirality HPLC separation of racemic mixture (embodiment 52). ¹HNMR(CDCl ₃，300MHz)：δ7.39(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，1H)，1.46(m，1H)，1.28(m，1H)，1.20(m，2H)，0.92(m，2H)；m/z＝559[M-1] ^-。

Embodiment 54

(R)-1-(2, the 3-dihydroxypropyl)-N-(3,4,6-three fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) cyclopropane-1-sulfonamide:

Obtain pure R isomer by chirality HPLC separation of racemic mixture (embodiment 52). ¹H?NMR(CDCl ₃，300MHz)：δ7.39(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，1H)，1.46(m，1H)，1.28(m，1H)，1.20(m，2H)，0.92(m，2H)；m/z＝559[M-1] ^-。

Embodiment 55

N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide:

Steps A: 1-pi-allyl-N-3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl) cyclopropane-1-sulphonyl Amine:

According to general step B, 1-pi-allyl-cyclopropane sulfonic acid chloride and 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl)-3-methoxybenzene-1, the 2-diamine reactant obtains title product. ¹H?NMR(CDCl ₃，300MHz)：δ7.417(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，1H)，5.668(m，1H)，5.11(t，1H)，3.9(s，3H)，2.75(d，2H)，1.21(m，2H)，0.767(m，2H)。

Step B: N-(3.4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulphonyl Amine:

(97mg, 0.18mmol) (21mg 0.18mmol) is dissolved among the THF (8mL) cyclopropane-1-sulfonamide with 4-methyl morpholine N-oxide with 1-pi-allyl-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl).(4% at H for 0.018mmol, 0.13mL at room temperature to add osmium tetroxide ₂Among the O), and at room temperature stirred this reactant mixture 16 hours.Add EtOAc, organic facies is through water washing, dry (MgSO ₄), and decompression concentrates down.(eluant, eluent: EtOAc/MeOH) the purifying residue obtains title product (0.80g, 78%) through silica gel chromatography. ¹H?NMR(CDCl ₃，300MHz)：δ7.38(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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide:

Obtain pure S isomer by chirality HPLC separation of racemic mixture (embodiment 55). ¹H?NMR(CDCl ₃，300MHz)：δ7.38(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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide:

Obtain pure R isomer by chirality HPLC separation of racemic mixture (embodiment 55). ¹H?NMR(CDCl ₃，300MHz)：δ7.38(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-(3,4,6-three fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) cyclopropane-1-sulfonamide:

Steps A: 1-(2-hydroxyethyl)-N-(3.4,6-three fluoro-2-(2-fluoro-4-iodophenyl oxygen base) phenyl) ring third of TBS protection Alkane-1-sulfonamide:

According to general step B, the sulfonic acid chloride for preparing among the step C of embodiment 16 and 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl)-3-fluorobenzene-1, the 2-diamine reactant obtains title product.Yield: 13%. ¹H-NMR(300MHz，CDCl ₃)：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-1] ^-。

Step B: 1-(2-hydroxyethyl)-N-(3,4,6-three fluoro-2-(2-fluoro-4-iodophenyl amino)-phenyl) cyclopropane-1-sulphonyl Amine:

With the step in the step e of embodiment 16.Yield: 100%. ¹H-NMR(300MHz，CDCl ₃)：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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2-hydroxyethyl) cyclopropane-1-sulfonamide:

Steps A: N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(the 2-hydroxyl second of TBS protection Base) cyclopropane-1-sulfonamide:

According to general step B, the sulfonic acid chloride for preparing among the step C of embodiment 16 and 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl)-3-methoxyl group-benzene-1, the 2-diamine reactant obtains title product.Yield: 37%. ¹H-NMR(300MHz，CDCl ₃)：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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2-hydroxyethyl) cyclopropane-1- Sulfonamide:

With the step in the step e of embodiment 16.Yield: 100%. ¹H-NMR(300MHz，CDCl ₃)：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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(3-hydroxyl-2-(hydroxymethyl) propyl group) cyclopropane-1-sulfonamide:

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

At 0 ℃, under argon gas, (5.0g 125mmol) adds dimethyl malenate (11.7ml, 100mmol) solution in HMPA (5ml) in the suspension the HMPA (50ml is from the calcium hydride distillation) to sodium hydride.Mixture is heated to 50 ℃ and stirred 1 hour.After this, again this solution is cooled to 0 ℃, and with 2, (12.2ml, 100mmol) solution in HMPA (5ml) adds in this reactant mixture the 3-propylene bromide.Then, make this solution be warmed to 40 ℃ and stirred 1 hour.This reactant mixture with the HCl aqueous solution (10%, 88ml) cessation reaction, and extract with ether (3x45ml).Collect organic moiety, through MgSO ₄Drying, and remove in a vacuum and desolvate.(eluant, eluent: chloroform/hexane) purification of crude oil obtains colorless oil title product (16.3g, 65%) by silica gel chromatography. ¹H-NMR(300MHz，CDCl ₃)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) the third-1, the 3-glycol:

(1.9g 7.65mmol) forms slurry, and be cooled to-78 ℃ in dry ice/acetone batch in anhydrous diethyl ether (50ml) to make lithium aluminium hydride reduction.Drip product (0.639g, 16.84mmol) solution in absolute ether (26ml) that derives from steps A then.After adding this malonate, make solution be warmed to room temperature and continue and stirred 3 hours.With salt solution (50ml) cessation reaction, with ethyl acetate (3x25ml) extraction, and through MgSO ₄Dry.Removing in a vacuum desolvates generates the product (1.3g, 86%) of expectation, and soon it is used for next step without being further purified. ¹H-NMR(300MHz，CDCl ₃)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: The 2-(2-bromine pi-allyl) the third-1 of di-t-butyl dimetylsilyl protection, the 3-glycol:

(2.8g 14.20mmol) is dissolved among the anhydrous THF (140ml) with the product that derives from step B.(2.5ml 31.24mmol), and is dissolved in this and is cooled to 0 ℃ to add anhydrous pyridine.(7.2ml 31.24mmol), when adding finishes, is heated to 35 ℃ with this reaction solution to drip the t-butyldimethylsilyl triflate.Stir after 6 days, with 100ml salt solution cessation reaction, with ethyl acetate (3x50ml) extraction, and through MgSO ₄Dry.The organic facies that evaporation merges obtains yellow oily crude product (5.5g, 91%), and soon it is used for next step without being further purified. ¹H-NMR(300MHz，CDCl ₃)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: The 2-((1-bromine cyclopropyl) methyl) the third-1 of di-t-butyl dimetylsilyl protection, the 3-glycol:

At 0 ℃, in reaction flask, add anhydrous CH ₂Cl ₂(10ml) and diethyl zinc (1.0M in hexane, 4.65ml, 4.65mmol).(0.358ml 4.65mmol), and stirred this solution 20 minutes to drip trifluoroacetic acid.(0.375ml 4.65mmol), and stirred this solution 20 minutes again to add diiodomethane then.At last, (0.492g 1.16mmol), and makes this solution be warmed to environmental temperature, stirs 16 hours to add the product that derives from step C.With saturated NH ₄The Cl aqueous solution stops this reaction.Distribute each layer, and with chloroform (3x 5ml) aqueous phase extracted.With the organic facies of salt solution (10ml) washing merging, through MgSO ₄Drying, and remove volatile materials in a vacuum.(eluant, eluent: chloroform/hexane) purifying gained crude product generates the oily product (0.280g, 64%) of clarification by silica gel chromatography. ¹H-NMR(300MHz，CDCl ₃)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-1-sulphur of di-t-butyl dimetylsilyl protection Acyl chlorides:

(0.507g 1.16mmol) is dissolved in the absolute ether (6ml), and this reaction solution is cooled to-78 ℃ with the product that derives from step D.After this, in 5 minutes, drip tert-butyl lithium (1.7M in pentane, 1.50ml, 2.55mmol).Stir after 0.5 hour, (0.206ml is 2.55mmol) in the solution through stirring in absolute ether (6ml) by sleeve pipe the product of lithiumation to be transferred to sulfonic acid chloride at-78 ℃.Finish in case shift, just to make solution be warmed to room temperature, evaporating solvent, and the gained white solid formed slurry in anhydrous hexane.Pass through this slurry of diatomite filtration immediately, and remove whole volatile materials in a vacuum.Separating obtained yellow oily crude product (0.376g, 71%), and be about to it and be used for next step without being further purified. ¹H-NMR(300MHz，CDCl ₃)δ3.60(m，4H)，2.16(m，1H)，2.03(d，2H)，0.88(s，18H)，0.04(s，9H)。

Step F: The N-of di-t-butyl dimetylsilyl protection (3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxy The base phenyl)-1-(3-hydroxyl-2-(hydroxymethyl) propyl group) cyclopropane-1-sulfonamide:

Under argon atmospher, with 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl)-3-methoxybenzene-1, (8.8mg 0.022mmol) is dissolved in the anhydrous pyridine (0.5ml) the 2-diamines.(20.5mg 0.045mmol) adds in the reaction flask, and adds these mixtures 21 hours at 80 ℃ will to be dissolved in the product that derives from step e in the anhydrous pyridine (0.5ml).Remove in a vacuum and desolvate, and (eluant, eluent: ethyl acetate/hexane) purifying gained crude product generates title compound (2.75mg, 15%) by silica gel chromatography.m/z?813.5(M-1)。

Step G: N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(3-hydroxyl-2-(hydroxymethyl) Propyl group) cyclopropane-1-sulfonamide:

(27.9mg 0.0342mmol) is dissolved among the THF (1ml), and (1.2N 0.2ml) handles with the HCl aqueous solution at 0 ℃ with the product that derives from step F.Stirred gained solution 4 hours.After this, use saturated NaHCO ₃The aqueous solution stops this reaction, uses ethyl acetate extraction, through MgSO ₄Drying, and remove volatile materials in a vacuum.(eluant, eluent: methyl alcohol/chloroform) then by the LC-MS purifying, purifying gained crude product generates title compound (11.8mg, 59%) by silica gel chromatography. ¹H-NMR(300MHz，CD ₃OD)δ7.32(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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl) cyclobutane sulfonamide:

Steps A: The cyclobutane sulfonic acid chloride:

(0.790g, 32.5mmol) sub-fraction sub-fraction ground adds cyclobutyl bromine (1.8ml, 2.5722g, the 19.1mmol) solution in the 20ml diethyl ether, vigorous stirring simultaneously in the suspension in the 20ml anhydrous diethyl ether to the Mg bits.After initial exothermic reaction has stopped, heat this mixture again to reflux temperature 30min.This suspension is cooled to room temperature, and supernatant sub-fraction sub-fraction ground is added sulfonic acid chloride, and (4.6ml, 7.728g is 57.2mmol) in the ice-cold solution in the anhydrous DCM of 30ml.After adding finishes, this suspension is warmed to room temperature, and removes volatile materials in a vacuum.Dried residue 15min in the vacuum oil pump uses hexane (150ml) extraction then.Filter this hexane suspension, and remove hexane generation mulberry oily crude product in a vacuum, soon it is used for next step without being further purified.Still there are some unreacted Cyclopropyl Bromides to exist.Crude product yield: 1.1g (38%).

Step B: N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl) cyclobutane sulfonamide:

According to general step B, the cyclobutyl sulfonic acid chloride and 5 for preparing in the above step, 6-two fluoro-N1-(2-fluoro-4-iodophenyl)-3-methoxybenzene-1, the 2-diamine reactant obtains title product.Yield: 75%. ¹H-NMR(300MHz，CDCl ₃)：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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-aminomethyl phenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide:

Steps A: (3,4, the 5-trifluorophenyl) methyl alcohol:

To the cooling (5 ℃) 3,4, the 5-trifluro benzaldehyde (7.0g, 43.75mmol) in the solution in the mixture (50ml, 9: 1) of THF and water, in 30min, slowly add in batches NaBH4 (1.662g, 43.75mmol).In the time of 2h, make this reactant mixture reach room temperature, and be poured into carefully ice-cold rare HCl (200ml, 1N) in.Oil reservoir is extracted into CH ₂Cl ₂(250ml), organic layer washs through water (200ml), dry (MgSO ₄), and evaporation.(7.08g quantitatively) continues to use without being further purified the gained crude product.

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

To (3,4, the 5-trifluorophenyl) methyl alcohol (40mmol) at CH ₂Cl ₂(6.16ml is 80mmol) at CH to add thionyl bromide in the solution (150ml) lentamente ₂Cl ₂Solution (50ml).At room temperature, stir this reactant mixture 16h, and be poured in the frozen water (200ml).Organic layer is separated, with saturated NaHCO ₃(2x200ml), water (200ml) washs dry (MgSO ₄), and evaporation obtains corresponding light yellow oily bromo compound with quantitative yield.This crude product continues on for the next step without being further purified soon.

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

Above bromine compounds (40mmol) mixes with triethyl-silicane (48mmol), and uses solid PdCl ₂(4mmol) this reactant mixture is handled on sub-fraction sub-fraction ground.After a few minutes, violent exothermic reaction taking place then, notes by installing back the content of flow condenser backflow flask.At room temperature, stir this reactant mixture 6h again, and make this content leave standstill 16h.Topple over crude liquid product then carefully, soon it continues on for the next step without being further purified.Suppose that this reaction carries out with quantitative yield.

Step D: 1,2,3-three fluoro-5-methyl-4-nitrobenzene:

0-5 ℃ with 1,2,3-three fluoro-5-methylbenzene (40mmol) add dense H ₂SO ₄(50ml).Use dense HNO then ₃(3.39ml, 48.44mmol, 90%) handles this reactant mixture lentamente, keeps internal temperature to be lower than 20 ℃ simultaneously.At room temperature stir this reactant mixture 16h, it is poured onto on ice (300g), and use CH ₂Cl ₂(2x125ml) extraction oil reservoir.Organic layer water (2x200ml), salt solution (200ml) washing, dry (MgSO ₄), and the evaporation obtain crude product, this crude product obtains title product (6.5g, 85%) through fast silica gel chromatogram method purifying. ¹H-NMR (300MHz, CDCl ₃): δ 6.96 (heptet, 1H), 2.39 (s, 3H). ¹⁹FNMR(CDCl ₃)：δ-128.18，-141.50，-159.05。

Step e: 2,3-two fluoro-N-(2-fluoro-4-iodophenyl)-5-methyl-6-nitroaniline:

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

Step F: 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl)-3-methylbenzene-1,2-diamines:

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

Step G: 1-pi-allyl-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-aminomethyl phenyl) cyclopropane-1-sulfonamide:

According to general step B, and 1-pi-allyl-cyclopropane sulfonic acid chloride (142mg, 142mg) with 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl)-3-methylbenzene-1, the 2-diamines (150mg, 0.4mmol) reaction obtains title product (100mg, 47%); M/z=521[M-1] ^-

Step H: N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-aminomethyl phenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane -1-sulfonamide:

(150mg, 0.29mmol) (33mg 0.29mmol) is dissolved among the THF (5mL) cyclopropane-1-sulfonamide with 4-methyl morpholine N-oxide with 1-pi-allyl-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-aminomethyl phenyl).(4% at H for 0.029mmol, 0.18mL at room temperature to add osmium tetroxide ₂Among the O), and at room temperature stirred this reactant mixture 16 hours.Add EtOAc, organic facies is through water washing, dry (MgSO ₄), and under reduced pressure concentrate.(eluant, eluent: EtOAc/MeOH) the purifying residue obtains title product (0.110g, 68%) through silica gel chromatography. ¹H-NMR(300MHz，CDCl ₃)：δ7.07(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, the 3-dihydroxypropyl)-N-(6-ethyl-3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) cyclopropane-1-sulfonamide:

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

(17.41ml, 52.24mmol 3M) add 3,4 lentamente, and (6.96g is 43.53mmol) in the solution in THF (125ml) for the 5-trifluro benzaldehyde at-78 ℃ of diethyl ether solutions with MeMgBr.At room temperature stir this reactant mixture 16h, cooling (0 ℃), and use excessive acetic acid ethyl ester (10ml) and water (5ml) cessation reaction successively.Add excessive anhydrous MgSO ₄(5g), and at room temperature stirred 30 minutes.Through diatomite filtration suspension, and with ethyl acetate (2x25ml) washing solid.The filtrate that evaporation merges obtains product (7.65g) with quantitative yield.

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

(7.65g is 43.5mmol) at CH to 1-(3,4, the 5-trifluorophenyl) ethanol ₂Cl ₂(18.1g is 87mmol) at CH to add thionyl bromide in the solution (250ml) lentamente ₂Cl ₂Solution (50ml).At room temperature stir this reactant mixture 16h, and be poured in the frozen water (200ml).Organic layer is separated, and with saturated NaHCO ₃(2x200ml), water (200ml) washs dry (MgSO ₄), and evaporation obtains the corresponding bromine compounds (10.4g) of lark oily with quantitative yield.This crude product continues on for the next step without being further purified soon.

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

(9.65g 40.4mmol) mixes with triethyl-silicane (41mmol), and uses solid PdCl with above-mentioned bromine compounds ₂(177mg, 4mmol) this reactant mixture is handled on sub-fraction sub-fraction ground.After a few minutes, violent exothermic reaction taking place then, notes by installing back the content of flow condenser backflow flask.At room temperature, stir this reactant mixture 6h again, and make this content leave standstill 16h.Topple over crude liquid product then carefully, soon it continues on for the next step without being further purified.Suppose that this reaction carries out with quantitative yield.

Step D: 1-ethyl-3,4,5-three fluoro-2-nitrobenzene:

0-5 ℃ with 1,2, (6.46g 40.4mmol) adds dense H to 3-three fluoro-5-methylbenzene ₂SO ₄(50ml).Use dense HNO then ₃(3.39ml, 48.44mmol, 90%) handles this reactant mixture lentamente, keeps internal temperature to be lower than 20 ℃ simultaneously.At room temperature stir this reactant mixture 16h, it is poured onto on ice (300g), and use CH ₂Cl ₂(2x125ml) extraction oil reservoir.Organic layer water (2x200ml), salt solution (200ml) washing, dry (MgSO ₄), and the evaporation obtain crude product, obtain title product (6.6g, 79%) through this crude product of fast silica gel chromatogram method purifying. ¹H NMR (CDCl ₃): δ 6.98 (heptet, 1H), 2.68 (q, 2H), 1.26 (t, J=7.8﹠amp; 7.2Hz, 3H).

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

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

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

Use condition described in the embodiment 1 (step B),

reduction

1,2, (2.47g 5.85mmol) forms title compound to 3-three fluoro-5-methyl-4-nitrobenzene.M-H ⁺：393。

Step G: 1-pi-allyl-N-(6-ethyl-3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) cyclopropane-1-sulfonamide:

According to general step B, make 1-pi-allyl-cyclopropane sulfonic acid chloride (230mg, 1.27mmol) with 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl)-3-methylbenzene-1, the 2-diamines (100mg, 0.255mmol) reaction obtains title product (72mg, 53%); M/z=535[M-1].

Step H: 1-(2, the 3-dihydroxypropyl)-N-(6-ethyl-3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) cyclopropane -1-sulfonamide:

(70mg, 0.13mmol) (15mg 0.13mmol) is dissolved among the THF (2mL) cyclopropane-1-sulfonamide with 4-methyl morpholine N-oxide with 1-pi-allyl-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-aminomethyl phenyl).(4% at H for 0.013mmol, 0.075mL at room temperature to add osmium tetroxide ₂Among the O), and at room temperature stirred this reactant mixture 16 hours.Add EtOAc, organic facies washes with water, dry (MgSO ₄), and under reduced pressure concentrate.(eluant, eluent: EtOAc/MeOH) the purifying residue obtains title product through silica gel chromatography. ¹H?NMR(300MHz，CDCl ₃)：δ7.38(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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-(2-methoxy ethoxy) phenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide:

Steps A: 1,2,3-three fluoro-5-(2-methoxy ethoxy)-4-nitrobenzene:

At 0 ℃, to 3,4,5-three fluoro-2-nitrophenols (1.93,10mmol), Ph ₃P (3.93g, 15mmol) (1.18ml 15mmol) in the mixture in anhydrous THF (25ml), adds diisopropyl azodiformate (2.91ml with 2-methoxyl group-ethanol, 15mmol) the solution in THF (5ml), and at room temperature stir this reactant mixture 16h.Evaporation of volatile substances, and residue is dissolved in CH ₂Cl ₂(100ml), organic layer water (100ml), salt solution (100ml) washing, dry (MgSO ₄), and evaporation.Obtaining yield through fast silica gel chromatogram method purifying gained residue is 68% title product (1.70g). ¹H?NMR(300MHz，CDCl ₃)：δ6.78(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: 2,3-two fluoro-N-(2-fluoro-4-iodophenyl)-5-(2-methoxy ethoxy)-6-nitroaniline:

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

Step C: 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl)-3-(2-methoxy ethoxy) benzene-1,2-diamines:

Use the condition described in the embodiment 1 (step B), reductase 12, (1.017g 2.17mmol) forms title compound to 3-two fluoro-N-(2-fluoro-4-iodophenyl)-5-(2-methoxy ethoxy)-6-nitroaniline; M/z=337[M-1].

Step D: 1-pi-allyl-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-(2-methoxy ethoxy) phenyl) ring third Alkane-1-sulfonamide:

According to general step B, (450mg is 2.5mmol) with 5 to make 1-pi-allyl-cyclopropane sulfonic acid chloride, 6-two fluoro-N1-(2-fluoro-4-iodophenyl)-3-(2-methoxy ethoxy) benzene-1, the 2-diamines (219mg, 2.5mmol) reaction obtains title product (230mg, 78%); M/z=581[M-1].

Step e: N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-(2-methoxy ethoxy) phenyl)-1-(2, the 3-dihydroxy Propyl group) cyclopropane-1-sulfonamide:

(230mg, 0.395mmol) (46mg 0.395mmol) is dissolved among the THF (2mL) cyclopropane-1-sulfonamide with 4-methyl morpholine N-oxide with 1-pi-allyl-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-(2-methoxy ethoxy) phenyl).(4% at H for 0.039mmol, 0.25mL at room temperature to add osmium tetroxide ₂Among the O), and at room temperature stirred this reactant mixture 16 hours.Add EtOAc, organic facies washes with water, dry (MgSO ₄), and under reduced pressure concentrate.(eluant, eluent: EtOAc/MeOH) the purifying residue obtains title product through silica gel chromatography. ¹H?NMR(300MHz，CDCl ₃)：δ7.36(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

2,4-two chloro-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) benzsulfamide:

Use suitable sulfonic acid chloride synthetic, m/z=571[M-1] by method A.

Embodiment 66

2-chloro-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-4-(trifluoromethyl) benzsulfamide:

Use suitable sulfonic acid chloride synthetic, m/z=605[M-1] by method A.

Embodiment 67

N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-2-(trifluoromethoxy) benzsulfamide:

Use suitable sulfonic acid chloride synthetic, m/z=587[M-1] by method A.

Embodiment 68

4-(N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) sulfamoyl) benzoic acid:

Use suitable sulfonic acid chloride synthetic, m/z=584[M-1] by method A.

Embodiment 69

N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl) benzsulfamide:

Use suitable sulfonic acid chloride synthetic, m/z=503[M-1] by method A.

Embodiment 70

N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-2-fluorobenzene sulfonamide:

Use suitable sulfonic acid chloride synthetic, m/z=521[M-1] by method A.

General step D: replace the iodine atom:

In microwave reactor, comprise 1eq. aryl iodide, 1.5eq. boric acid or borate, 0.25eq.PdCl in the deoxidation mixture with Zai diox and water (3: 1) ₂(dppf) x DCM and 10eq. anhydrous K ₂CO ₃The suspension of powder is at 115 ℃ of heating 60min.Use aq.NH ₄The Cl/THF extraction, and use Na ₂SO ₄Dry organic moiety.Use flash column chromatography (Si, EtOAc/ hexane or CHCl ₃/ MeOH) purifying crude reaction product.Yield: 20-40%.

Embodiment 71

N-(3,4-two fluoro-2-(2-fluoro-4-aminomethyl phenyl amino) phenyl) cyclopropane sulfonamide;

General step D: ¹H-NMR (500MHz, CDCl ₃): δ=7.38-7.36 (m, 1H), 7.06-7.03 (q, 1H), 6.92-6.90 (1H), and 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), and 0.94-0.90 (m, 2H); M/z=355[M-1].

Racemic mixture at chipal compounds has been split under the situation of independent enantiomer, and phrase used herein " essentially no " epimer means enantiomeric excess at least 90%.

Embodiment 72

N-(3,4-two fluoro-2-(2-fluoro-4-(1H-pyrazoles-4-yl) phenyl amino) phenyl) cyclopropane sulfonamide

Steps A: 2,3-two fluoro-N-(2-fluoro-4-iodophenyl)-6-nitroaniline:

At 0 ℃, (11.40g 47mmol) drips the 1M solution (47ml) of LHMDS in THF (47mmol) in the solution in the anhydrous THF of 100ml to 2-fluoro-4-Iodoaniline.The color of solution becomes mulberry.Solution is transferred to dropping funel through sleeve pipe, and at 0 ℃ this solution (comprising the amine free alkali) sub-fraction sub-fraction ground is added 2,3, (8.321g is 47.0mmol) in the solution in anhydrous THF (50ml) for the 4-trifluoronitrobenzene.After adding finishes, at room temperature, under argon gas, stirred this mixture 15 hours.Reduce the volume of solvent, then with ethyl acetate and salt solution extraction.Through the dried over sodium sulfate organic layer, remove and desolvate, and by flash chromatography (EtOAc/ hexane 1: 5, R _f=0.58) purifying gained dark oil obtains crude product, and it becomes brown solid (yield: 6.23g, 33.6%) through vacuum drying.m/z＝393[M-1] ^-。

Step B: 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamines

To nitro-diaryl amine (6.23g, 15.8mmol) add in the solution in 300ml ethanol iron powder (13.74g, 246mmol) and ammonium chloride (13.59g 254mmol), and follows this mixture of agitating heating 14 hours under 100 ℃ of oil bath temperatures.Filter, and with twice of washing with alcohol filter residue.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 salt water washing that merges, and through dried over sodium sulfate.Remove and desolvate, and from CHCl ₃/ hexane (1: 50) recrystallization crude product.Obtain brown needle-like product (2.094g, 66%).R _f＝0.44(EtOAc/Hex?1∶3)。 ¹H-NMR(500MHz，CDCl ₃)：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，NH ₂，br)；LRMS(ESI)：m/z＝365[M+H] ⁺。

Step C: N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl oxygen base) phenyl) cyclopropane sulfonamide:

According to general step A, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1, the product that 2-diamines and the reaction of cyclopropane sulfonic acid chloride obtain expecting.(500MHz，CDCl ₃)：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-(3,4-two fluoro-2-(2-fluoro-4-(1H-pyrazoles-4-yl) phenyl amino) phenyl) cyclopropane sulfonamide:

General step C: ¹H-NMR (500MHz, CDCl ₃): 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-(3,4-two fluoro-2-(2-fluoro-4-(1-methyl isophthalic acid H-pyrazoles-4-yl) phenyl amino) phenyl) cyclopropane sulfonamide

General step C: ¹H-NMR (500MHz, CDCl ₃): 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-(3,4-two fluoro-2-(2-fluoro-4-(1H-pyrazole-3-yl) phenyl amino) phenyl) cyclopropane sulfonamide

General step C: ¹H-NMR (500MHz, CDCl ₃): 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-(3,4-two fluoro-2-(2-fluoro-4-(pyridin-4-yl) phenyl amino) phenyl) cyclopropane sulfonamide

General step C: ¹H-NMR (500MHz, CDCl ₃): 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-(3,4-two fluoro-2-(2-fluoro-4-(pyridin-3-yl) phenyl amino) phenyl) cyclopropane sulfonamide

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-fluorophenyl amino)-3,4-difluorophenyl) cyclopropane sulfonamide

In microwave reactor, will in the 1ml dry DMF, comprise aryl iodide (75.5mg, 0.161mmol), CuCN (46.6mg, 0.520mmol) and Pd (OAc) ₂Suspension (0.47mg) is heated to 130 ℃ of lasting 60min.Use salt solution/THF to extract this mixture, and use Na ₂SO ₄Dry organic moiety.With after flash column chromatography generates the semi-solid product (R of kermesinus _f=0.42 (EtOAc/ hexane 1: 1)).Yield: 15%.m/z＝366[M-1] ^-。

Embodiment 78

N-(3,4-two fluoro-2-(3-fluorine biphenyl-4-base is amino) phenyl) cyclopropane sulfonamide

General step C: ¹H-NMR (500MHz, CDCl ₃): 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), and 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 is amino)-3, the 4-difluorophenyl) the cyclopropane sulfonamide

General step C: ¹H-NMR (500MHz, CDCl ₃): δ=8.6 (s, 1H), 7.86-7.85 (d, 1H), 7.68-7.66 (d, 1H), and 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), and 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 is amino)-3, the 4-difluorophenyl) the cyclopropane sulfonamide

General step C: ¹H-NMR (500MHz, CDCl ₃): 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), and 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 is amino)-3, the 4-difluorophenyl) the cyclopropane sulfonamide

General step C: ¹H-NMR (500MHz, CDCl ₃): 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-(3,4-two fluoro-2-(3-fluoro-4 '-(methanesulfonamido) biphenyl-4-base is amino) phenyl) the cyclopropane sulfonamide

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-(3,4-two fluoro-2-(2-fluoro-4-aminomethyl phenyl amino) phenyl) cyclopropane sulfonamide

General step C: ¹H-NMR (500MHz, CDCl ₃): δ=7.38-7.36 (m, 1H), 7.06-7.03 (q, 1H), 6.92-6.90 (1H), and 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), and 0.94-0.90 (m, 2H); M/z=355[M-1] ^-

Embodiment 84

4 '-(6-(cyclopropane sulfonamido)-2,3-difluorophenyl amino)-3 '-fluorine biphenyl-3-carboxylic acid

General step C: ¹H-NMR (500MHz, and [D4]-MeOH): δ=8.21 (s, 1H), 7.93-7.91 (d, 1H), and 7.73-7.72 (d, 1H), 7.47-7.43 (m, 2H), and 7.33-7.31 (d, 2H), 7.15-7.12 (q, 1H), and 6.71-6.68 (m, 1H), 2.51-2.46 (m, 1H), 0.94-0.93 (m, 2H), and 0.88-0.87 (m, 2H); M/z=499[M-1] ^-

Embodiment 85

N-(3,4-two fluoro-2-(3-fluoro-3 '-(methanesulfonamido) biphenyl-4-base is amino) phenyl) the cyclopropane sulfonamide

General step C: ¹H-NMR (500MHz, and [D4]-MeOH): δ=7.92 (s, 1H), 7.46-7.34 (m, 5H), and 7.34-7.31 (d, 1H), 7.29-7.22 (m, 1H), and 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), and 0.91-0.90 (m, 2H); M/z=510[M-1] ^-

Embodiment 86

N-(3,4-two fluoro-2-(3-fluoro-2 '-(methanesulfonamido) biphenyl-4-base is amino) phenyl) the cyclopropane sulfonamide

General step C: ¹H-NMR (500MHz, and [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-(3,4-two fluoro-2-(3-fluoro-4 '-(trifluoromethoxy) biphenyl-4-base is amino) phenyl) the cyclopropane sulfonamide

General step C: ¹H-NMR (500MHz, and [D4]-MeOH): δ=7.69-7.67 (d, 2H), 7.46-7.43 (d, 1H), 7.36-7.33 (m, 4H), and 7.30-7.29 (q, 1H), 6.73-6.72 (m, 1H), 2.51-2.49 (m, 1H), and 0.94-0.92 (m, 2H), 0.91-0.90 (m, 2H); M/z=501[M-1] ^-

Embodiment 88

N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-2-(methylamino) ethyl sulfonamide

General step D: ¹HNMR (300MHz, CDCl ₃): δ 9.01 (br s, D ₂O is commutative, 1H), and 7.36 (dd, J=2.1﹠amp; 10.5Hz, 1H), 7.27 (m, 1H), 7.17 (m, 1H), 7.03 (dd, J=9.0﹠amp; 16.8Hz, 1H), 6.48 (s, D ₂O is tradable, 1H), and 6.31 (dt, J=3.0,8.7﹠amp; 17.4Hz, 1H), and 3.45 (br t.2H) .3.31 (br s, 2H), 2.65 (s.3H) .1.80 (br s, D ₂O is commutative, 1H).

Embodiment 89

N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-2-(2-(dimethylamino) ethylamino) ethyl sulfonamide

General step D. ¹H?NMR(300MHz，CDCl ₃)：δ7.35(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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-2-(ethyl (methyl) amino) ethyl sulfonamide

General step D. ¹H?NMR(300MHz，(CDCl ₃+D ₂O))：δ7.39(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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-2-(4-methyl piperazine-1-yl) ethyl sulfonamide

General step D. ¹H?NMR(300MHz，CD ₃OD)：δ7.45(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)。

The external biological activity

Embodiment 92

The generation of IC50 data

Material and reagent preparation: with human GST-MEK1 and composition activation allelomorph GST-MEK1 ^CA(have sudden change Ser218Asp and Ser222Asp) from the human MEK1cDNA subclone of wild type to yeast expressed carrier pGEM4Z (Promega, Madison, WI) in.At expression in escherichia coli GST-MEK1 ^CA, and (Amersham Pharmacia Biotech, Piscataway NJ) carries out partial purification to it to use the affine resin of glutathione agarose 4B.With ERK2 allelomorph from pUSEamp (Upstate Biotechnology, Inc., Waltham, MA) MAPK2/Erk2cDNA in (wild type) subclone is to carrier pET21a (Novagen, Madison, WI) in, produce the mouse ERK2 allelomorph of the terminal histidine mark of N-.Expression ERK2 also is purified to homogeneous [Zhang, 1993#33].Myelin basic protein (MBP) available from Gibco BRL (Rockville, MD).EasyTides adenosine 5'-triphosphate (ATP) ([γ- ³³P]) (NEN Perkin Elmer, Wellesley MA) are the radioactive label source of all kinase reactions.The map kinase 2/ERK2 of Raf-1 (brachymemma) that activates and activation is available from Upstate, and Inc. (Lake Placid, NY).4-20%Criterion Precast gel available from Bio-Rad (Hercules, CA).

Measure enzymic activity: compound is diluted to 1xHMNDE (20mMHEPES pH 7.2,1mM MgCl from methyl-sulfoxide (DMSO) stock solution ₂, 100mM NaCl, 1.25mM DTT, 0.2mM EDTA) in.Typical 25 microlitres are measured and are comprised 0.002 nanomole MEK1 ^CA, 0.02 nanomole ERK2,0.25 nanomole MBP, the unlabelled ATP of 0.25 nanomole and 0.1 μ Ci[γ ³³P] ATP.This Screening test consists essentially of 4 interpolations.The compound of 5 μ l dilution is dispensed to 96-hole assay plate.Then, add 10 μ l 2.5x enzyme cocktails (MEK1 only to each hole ^CAAnd ERK2), precincubation 30 minutes at ambient temperature subsequently.Add 10 μ l 2.5x substrate mixed liquors (substratecocktail) (the adding MBP of mark) then, subsequently incubation 60 minutes at ambient temperature with unlabelled ATP.At last, add 100 μ l, 10% trichloroacetic acids (TCA), and at room temperature incubation stopped this reaction in 30 minutes and makes radiolabeled proteins product precipitation.Product is collected on the glass fibre 96 hole filters that water and 1% pyrophosphate prewet.Wash this filter 5 times then with water.Replace water with absolute ethyl alcohol, and at room temperature made this plate air-dry 30 minutes.Seal the back by hand, and the scintillation solution (scintillation cocktail) of 40 μ l is dispensed to each hole.Carry out top seal and in TopCount this plate is counted, speed is 2 seconds/hole.

For some experiment, use need be by the truncated-type MEK of Raf kinase activator.

Embodiment 93

The generation of EC50 data

Detect the effect of compound in the cell by the ERK of immunoblotting mensuration phosphorylation.With 20,000 cells/well the MDA-MB-231 breast cancer cell is plated in 48 orifice plates, and at the CO of 37 ° of humidifications ₂Cultivate in the incubator.Second day, remove growth medium (DMEM+10% hyclone), and substitute with hungry medium (starve media) (DMEM+0.1% hyclone).The incubation cell is 16 hours in hungry medium, uses the compound treatment 30 minutes of a series of concentration then.Behind the compound incubation, use 100ng/ml EGF irritation cell 5 minutes.Dissolved cell then, and use anti-phosphorylation ERK monoclone antibody by the immunoblotting analysis.Use the second antibody enhancing signal combine with nir dye, and on Licor Odyssey scanner detection signal.The amount of measured signal intensity, these data are used to generate dose-effect curve and EC50 calculates.

Legend: A, EC ₅₀=＜2.0nM; B, EC ₅₀=2.0-15nM; C, EC ₅₀=15nM-100nM; D, EC ₅₀＞100nM, IC ₅₀＜20 μ M; F, EC ₅₀＞100nM, IC ₅₀＞20 μ M

Legend: A, EC ₅₀=＜2.0nM; B, EC ₅₀=2.0-15nM; C, EC ₅₀=15nM-100nM; D, EC ₅₀=100nM-200nM; E, EC ₅₀＞200nM; The ND=undetermined

Biologically active in the body

Embodiment 94

Compound as herein described and composition are used for the treatment of or prevent one or more diseases, described disease to include but not limited to cancer, inflammatory bowel disease (IBD), psoriasis and rheumatoid arthritis (RA).Compound as herein described and composition also be used for once a day or every day twice oral medication or prevention include but not limited to one or more diseases of cancer, IBD, psoriasis and RA.

The in vivo studies of the compound (compd A of preparation as described herein) of following structure has been described in the present embodiment:

Human tumor is implanted in the nu/nu mouse.In case the tumour size is about 100mm ³, promptly the oral administration compd A continues 14 days.Treat after 14 days, with tumour size in the treatment group reduce with vehicle Control in suppress (TGI) to recently measuring tumor growth.Any one Time Calculation that arrives earlier of final Japan and China that reaches time of specific terminal point volume or research with tumour reaches the time (TTE) of terminal point.Measure the result who treats from % tumor growth delay (%TGD), it is defined as the control mice contrast with vehicle treated, the growth % of the TTE intermediate value of the mouse of receiving treatment.Also the retrograde reaction (regression response) of animal is monitored.Measure pERK level in tumour and the brain by immunoblotting, and be associated with the blood plasma level of compd A for pharmacodynamics/Study on pharmacokinetics makes this pERK level.Estimate some tumor models with different dosage and dosage regimen.In A375 melanoma tumour, Colo205 colon cancer knurl and A431 epiderm-like tumour with 25 or the 50mg/kg treatment of (QD) once a day demonstrate the significant %TGD of statistics.With 25mg/kg QD oral administration, observe the significant TGI of statistics to these tumor models and in HT29 colon cancer tumour.In the A375 xenograft, estimate the effect of different dosing regimes.Though per two days one time oral administration 100mg/kg compd A demonstrates the significant %TGD of statistics (91%), it is ineffective with the QD treatment of 25mg/kg (143%TGD) or 50mg/kg (233%TGD).According to the %TGI that measures, every day, twice (BID) administration was also more effective than the QD administration.Cause 79.5%TGI with 12.5mg/kg BID administration, by contrast, cause 51.7%TGI with 25mg/kg QD administration compd A.Cause 110.1%TGI with 25mg/kg BID administration, by contrast, obtain 69.9%TGI with 50mg/kg QD administration.Pharmacodynamics/Study on pharmacokinetics in the Colo205 xenograft shows that pERK formation is suppressed and observes minimum inhibition in the tumour in brain, and this shows the effective antitumor activity with limited CNS penetrability.

Compd A is effective MEK1/2 inhibitor, and it suppresses external and the interior tumor cell growth.BRAF state decision anchorage dependence growth but not in the growth of adherent not dependence, the perhaps growth inhibiting susceptibility that in the xenograft compound is caused.Because administration is frequent more, validity is high more, therefore keeps enough MEK and suppress more even more important than keeping the peak level in whole dosing interval.According to the xenograft result, in the mankind, use the therapeutic dose 20-40mg/ day of design, compd A has favourable pk feature in the mankind.

Embodiment 94A

Anticancer growth (GI ₅₀)

In with compd A processing 384-orifice plate, behind the cultured cells 48hr, use CellTiterGlo reagent to measure the anchorage dependence growth inhibition.Processing be incubated in the medium that comprises 0.15% agarose or non-adhesive plate (A431) on cell after 7 days, adherent not dependence growth measurement uses MTS (methyl thiosulfonates) reagent.Be growth inhibiting value (GI shown in the following table ₅₀).

Tumor cell line	The BRAF state	Anchorage dependence GI ₅₀(nM±sd)	Adherent not dependence GI ₅₀(nM±sd)
Tumor cell line	The BRAF state	Anchorage dependence GI ₅₀(nM±sd)	Adherent not dependence GI ₅₀(nM±sd)	The A375 melanoma	??V600E	??67±12	??68±34
The Colo205 colon	??V600E	??74±45	??33±16	The A375 melanoma	??V600E	??67±12	??68±34
The Colo205 colon	??V600E	??74±45	??33±16	The HT29 colon	??V600E	??70±12	Undetermined
The A431 epiderm-like	Normally	??＞10,000	??65±19	The HT29 colon	??V600E	??70±12	Undetermined

Embodiment 94B

Antitumor xenograft activity

A375 melanoma, Colo205 colon tumor, A431 epiderm-like tumour or HT-29 colon tumor cell are implanted female nu/nu mouse, make these tumor growths to 100-200mm ³Oral administration compd A or carrier (25mg/kg, 50mg/kg or 100mg/kg) continue 14 days once a day.To the mean tumour volume mapping of vehicle group and treatment group, and in Fig. 1, represent to provide.

Embodiment 94C

Tumor growth suppresses (TGI) 25mg/kg QD

For the tumor xenogeneic graft of pointing out, calculate tumor growth inhibition through the group of 25mg/kg compd A treatment.When administration once a day finished in 14 days, measure tumor growth and suppress, and calculate according to following formula:

The scope of A375 and Colo205 is represented the numerical value from 2 independent studies.

Tumor xenogeneic graft	??％TGI	The P value
Tumor xenogeneic graft	??％TGI	The P value	The A375 melanoma	??52-72 ^**	??＜0.001
The Colo205 colon	??70-123 ^**	??＜0.001	The A375 melanoma	??52-72 ^**	??＜0.001
The Colo205 colon	??70-123 ^**	??＜0.001	The HT29 colon	??56	??＜0.001
The A431 epiderm-like	??67	??＜0.001	The HT29 colon	??56	??＜0.001

^*Record degeneration at duration of test

Embodiment 94D

ED in the Colo205 xenograft ₅₀

The Colo205 tumour cell is implanted male nu/nu mouse.After 10 days, by tumour size (scope 126-256mm ³) with the animal randomization, and with taxol (IV, QODx5), carrier or compd A (PO, QDx14) treatment.

Obtain pharmacokinetic parameters from the Balb/c mouse of administration 25mg/kg compd A with than the extrapolated value of low dose group, and in following table, provide.

^*P＜0.001

Embodiment 94E

The tumor growth that has the A375 xenograft suppresses

To A375 heterograft mouse administration compd A 50mg/kg QD, 25mg/kg BID, 50mg/kg QD and 12.5mg/kg BID.%TGI and provides in Fig. 2 as calculated and mapping.

Embodiment 94F

Plasma concentration in the mouse

The A375 tumour cell is implanted female nu/nu mouse, make tumor growth to 100-200mm ³(QD) or every day twice (BID) oral administration compd A or carrier (50mg/kg QD, 25mg/kg BID, 50mg/kg QD and 12.5mg/kg BID) once a day.When administration once a day finished in 14 days, measure tumor growth and suppress, and calculate according to following formula:

??AUC(μg·hr/ml)	??132.5	??117.0	??66.5	??78.0
??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 _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

The inhibition of mouse heterograft tumour and brain MEK activity

The carrier or 2.5,5,10 or the compd A of 25mg/kg that the female nu/nu mouse administration single dose of Colo205 tumour cell is arranged to implantation.Measure compound level in the plasma sample, and measure after the

administration

2,6,12 and 24hr tumour of gathering and the pERK level in the brain sample.Use the LI-COR Odyssey will be quantitative, it is normalized into total ERK level, and suppress recently measuring %MEK with level through vehicle treated from the pERK level of immunoblotting.Plasma concentration mapping to corresponding compounds A in inhibition of the MEK in each mouse tumor or the brain and the animal.Nonlinear regression draws the EC that MEK suppresses in the tumour ₅₀Be 73nM.Brain EC ₅₀＞5000nM.

It shown in Fig. 3 the chart that plasma concentration (log nM) suppresses with respect to pERK%.

The preparation of capsule

Embodiment 95A

Preparation comprises blue size 1 hard gelatin capsule of dry powder blend composition, and wherein structure is

The concentration of compd A (referring to the table shown in the above embodiment 93) be 1mg and 10mg.

Preparation compd A as described herein, use then fluid energy mill with its micronizing (Spiral Jet Mill, electrical ground, the grinding chamber diameter is 50mm; 50 ° of .4x0.8mm nozzle rings; Injector nozzle diameter 0.8mm, injector nozzle is apart from 3mm).Compd A and part microcrystalline cellulose are mixed,, and add in the diffusion drum mixer (diffusion-tumble blender) (V-mixer) by the screening of #20 mesh sieve.By the remaining microcrystalline cellulose of #20 mesh sieve screening, add in the material in the mixer, mix.By #20 mesh sieve screening cross-linked carboxymethyl cellulose sodium and lauryl sodium sulfate, add in the material in the mixer, mix.Make pulverulent mixture by the vane type grinder (QuadroCoMil) in rotating, be added back in the mixer, continue to mix.Sieve dolomol by #20 mesh sieve, and mix with pulverulent mixture.Pulverulent mixture is packed in size 1 capsule.In order to discern, with the colligation of 10mg capsule.

Be the composition of capsule shown in the following table:

^aThe target filling weight of adjusting according to the practical effect of mixture.

It is as follows that the typical case of 10,000 batches 1mg capsule criticizes prescription:

Criticize formula components	Every batch amount (g) (10,000 unit)
Criticize formula components	Every batch amount (g) (10,000 unit)	Compd A	??10.0
Microcrystalline cellulose, NF (Avicel PH302)	??2222	Compd A	??10.0
Microcrystalline cellulose, NF (Avicel PH302)	??2222	Cross-linked carboxymethyl cellulose sodium, (Ac-two-Sol) for NF	??120.0
Lauryl sodium sulfate, NF	??24.0		??120.0
Lauryl sodium sulfate, NF	??24.0	Dolomol, NF	??24.0
Total filling weight ^a	??2400	Dolomol, NF	??24.0
Total filling weight ^a	??2400	Blue size 1 hard gelatin capsule shell	??10,000

It is as follows that the typical case of 10,000 batches 10mg capsule criticizes prescription:

Criticize formula components	Every batch amount (g) (10,000 unit)
Criticize formula components	Every batch amount (g) (10,000 unit)	Compd A	??100.0
Microcrystalline cellulose, NF (Avicel PH302)	??2132	Compd A	??100.0

Criticize formula components	Every batch amount (g) (10,000 unit)
Criticize formula components	Every batch amount (g) (10,000 unit)	Cross-linked carboxymethyl cellulose sodium, (Ac-two-Sol) for NF	??120.0
Lauryl sodium sulfate, NF	??24.0		??120.0
Lauryl sodium sulfate, NF	??24.0	Dolomol, NF	??24.0
Total filling weight ^a	??2400	Dolomol, NF	??24.0
Total filling weight ^a	??2400	Blue size 1 hard gelatin capsule shell ^b	??10,000

Embodiment 95B

The concentration of compd B (referring to the table shown in the above embodiment 93) be 1mg and 10mg.

Preparation compd B as described herein, and use fluid energy mill with its micronizing (Spiral Jet Mill, electrical ground, the grinding chamber diameter is 50mm; 50 ° of .4x0.8mm nozzle rings; Injector nozzle diameter 0.8mm, injector nozzle is apart from 3mm).Compd B and part microcrystalline cellulose are mixed,, and add in the diffusion drum mixer (V-mixer) by the screening of #20 mesh sieve.By the remaining microcrystalline cellulose of #20 mesh sieve screening, add in the material in the mixer, mix.By #20 mesh sieve screening cross-linked carboxymethyl cellulose sodium and lauryl sodium sulfate, add in the material in the mixer, mix.Make pulverulent mixture by the vane type grinder in rotating (Quadro CoMil), be added back in the mixer, continue to mix.By #20 mesh sieve screening dolomol, and mix with pulverulent mixture through grinding.It is heavy that pulverulent mixture is packed into size 1 capsule.In order to discern, the 10mg capsule is tied up.

Following table is depicted as the composition of capsule:

Activity in vivo in the mankind

Embodiment 96

The capsule described in the administration embodiment 95A in the human cancer patient

The capsule composition of above-described 1mg or 10mg in the embodiment 95A of human cancer patient administration single dose.For 2mg dosage, to patient's administration 2x1mg capsule; For 4mg dosage, to patient's administration 4x1mg capsule; For 6mg dosage, to patient's administration 6x1mg capsule; For 10mg dosage, to patient's administration 1x10mg capsule; For 20mg dosage, to patient's administration 2x10mg capsule.

Monitoring concentration-time diagram, and in Fig. 4 and following table, provide:

Dosage (mg)	My god	??T _max??(hr)	??C _max??(ng/mL)	??C _12hr??(ng/mL)	??AUC _0-12hr??(ng·hr/mL)	??AUCτ??(ng·hr/mL)
Dosage (mg)	My god	??T _max??(hr)	??C _max??(ng/mL)	??C _12hr??(ng/mL)	??AUC _0-12hr??(ng·hr/mL)	??AUCτ??(ng·hr/mL)	??2	??1	??2.0	??0.111	??0.0378	??0.700	??NA
	??35	??2.0	??0.202	??0.0756	??NA	??2.07	??2	??1	??2.0	??0.111	??0.0378	??0.700	??NA
	??35	??2.0	??0.202	??0.0756	??NA	??2.07	??4	??1	??1.5	??0.292	??0.134	??2.26	??NA
	??35	??1.0	??0.544	??0.310	??NA	??5.12	??4	??1	??1.5	??0.292	??0.134	??2.26	??NA
	??35	??1.0	??0.544	??0.310	??NA	??5.12	??10	??35	??NA	??1.57	??1.01	??NA	??14.3
??20	??35	??NA	??3.28	??2.19	??NA	??29.5	??10	??35	??NA	??1.57	??1.01	??NA	??14.3

Crystalline polymorph

Embodiment 97: preparation N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide

Prepare N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino) phenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide according to above-mentioned steps (referring to the International Patent Application WO of announcing 2007/014011) and following general introduction.

Steps A: 2-fluoro-N-(2,3,5-three fluoro-6-nitrobenzophenones)-4-Iodoaniline

At-78 ℃, under nitrogen, with 1.0M hexamethyl two silica-based lithium amide (LiN (SiMe ₃) ₂) (15.37mL, (3.64g 15.37mmol) in the solution through stirring in anhydrous THF (100mL), and continues to stir 1 hour at-78 ℃ " LHMDS " solution again 15.37mmol) to add 2-fluoro-4-

Iodoaniline lentamente.Add

2,3,4,6-tetrafluoro nitrobenzene makes this reactant mixture be warmed to room temperature, and continues to stir 16 hours again.Add ethyl acetate (200mL), organic facies washes with water, through dried over sodium sulfate, and is further purified by column chromatography and generates yellow solid product (3.75g, 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:2-fluoro-N-(2,3-two fluoro-5-methoxyl group-6-nitrobenzophenones)-4-Iodoaniline

Under nitrogen, with (2-fluoro-4-iodo-phenyl)-(2,3,5-three fluoro-6-nitro-phenyl)-amine (1.23g, 3mmol) solution through stirring in anhydrous THF (25ml) is cooled to-78 ℃, and add lentamente 25% sodium methoxide solution (0.68ml, 0.3mmol).Make this reactant mixture be warmed to room temperature, and continue again to stir 16 hours.TLC shows not complete reaction.(100mL) adds in this reactant mixture with ethyl acetate, and organic layer washes with water, through dried over sodium sulfate, and is further purified the expecting compound (0.6g, 47.6%) that generates yellow solid by column chromatography.m/z＝424[M+H] ⁺。

Step C:5,6-two fluoro-N1-(2-fluoro-4-iodophenyl)-3-methoxybenzene-1,2-diamines

With ammonium chloride (1.18g, 20.16mmol) and iron powder (1.15g, (0.57g is 1.34mmol) in the solution through stirring in ethanol (20mL) 21.44mmol) to add (2,3-two fluoro-5-methoxyl group-6-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine.Backflow stirred the mixture 16 hours, was cooled to room temperature, through diatomite filtration, and filtrate was concentrated into dried.With the molten ethyl acetate that places of the residue of gained, wash with water, through dried over sodium sulfate, and by be further purified generation pale solid (0.47g, 90.3%) from alcohol crystal.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-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl) cyclopropane-1-sulfonamide

To 5,6-two fluoro-N ¹Add 1-pi-allyl-cyclopropane sulfonic acid chloride (1-5eq) in-(2-fluoro-4-iodophenyl)-3-methoxybenzene-1,2-diamines (1eq) the solution in anhydrous pyridine (5ml/mmole) through stirring.Stirred this reactant mixture 48 hours at 40 ℃.Water and ethyl acetate distribute this reactant mixture.Organic layer salt water washing, dry (MgSO ₄), and under reduced pressure concentrate.Obtain title product by flash column chromatography through the silica gel purification residue. ¹H?NMR(CDCl ₃，300MHz)：δ7.417(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，1H)，5.668(m，1H)，5.11(t，1H)，3.9(s，3H)，2.75(d，2H)，1.21(m，2H)，0.767(m，2H)。

Step e: N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide

(97mg, 0.18mmol) (21mg 0.18mmol) is dissolved among the THF (8mL) cyclopropane-1-sulfonamide with 4-methyl morpholine N-oxide with 1-pi-allyl-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl).(4% at H for 0.018mmol, 0.13mL at room temperature to add osmium tetroxide ₂Among the O), and at room temperature stirred this reactant mixture 16 hours.Add ethyl acetate, organic facies washes with water, dry (MgSO ₄), and under reduced pressure concentrate.(eluant, eluent: EtOAc/MeOH) the purifying residue obtains title product (0.80g, 78%) through silica gel chromatography. ¹H?NMR(CDCl ₃，300MHz)：δ7.38(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)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide

By chirality HPLC separation of racemic mixture, obtained pure S isomer. ¹H?NMR(CDCl ₃，300MHz)：δ7.38(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)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide

By chirality HPLC separation of racemic mixture, obtained pure R isomer. ¹H?NMR(CDCl ₃，300MHz)：δ7.38(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: the crystalline polymorph A of preparation N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide

Preparation i) with N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide (216.10g) adds the 4L conical flask that big magnetic stirring bar and magnetic stirring apparatus/heating plate are installed.Add ethyl acetate (about 600mL is available from Fisher).Begin heating and stirring to form brown suspension.Make the faint backflow of this mixture, additionally add ethyl acetate (about 200mL) again to realize that dissolving generates dark-brown solution fully.Speed so that the whole precipitations that add fashionable formation are dissolved fast and backflow is kept at every turn adds heptane (available from Acros) in the solution that is refluxing with slowly pursuing part.When this solution adds the 2L heptane, the dissolving under refluxing of the solid of formation is very slow.Stop the heating, and make this crystalline mixture under agitation through the 16h balance to room temperature.During seasoning, around glass surface, form the crystalline material of thick-layer.Be accompanied by stirring, break even income suspension in ice/water-bath.On the 25cm Buchner funnel of being furnished with Whatman #1 filter medium, filter this suspension.With the crystallization of heptane (1L) washing collection, and under vacuum, make it air-dry.Under 40 ℃/＜1 holder, further dry this crystallization 20h generates pink crystalline solid product (160.99g, 77.2%).

Preparation is ii) with N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide (13.2g) and ethyl acetate (30mL) add the conical flask that big magnetic stirring bar and magnetic stirring apparatus/heating plate are installed.Begin to stir and be heated to faint backflow and generate dark-brown solution to realize dissolving fully.Speed so that the whole precipitations that add fashionable formation are dissolved fast and backflow is kept at every turn in the heptane solution that adding is refluxing with slowly pursuing part, causes that until add heptane in solution the solid of formation dissolves very slow (～90mL heptane) under backflow.Stop the heating, and make this crystalline mixture under agitation through the 16h balance to room temperature.During seasoning, around glass surface, form the crystalline material of thick-layer.Be accompanied by stirring, break even income suspension in ice/water-bath.On the Buchner funnel of being furnished with Whatman #1 filter medium, filter this suspension.With the crystallization of heptane wash collection, and under vacuum, make it air-dry.Under 40 ℃/＜1 holder, further dry this crystallization 20h generates pink crystalline solid product.

Preparation is iii) with N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide (44.8g) and ethyl acetate (750mL) add the conical flask that big magnetic stirring bar and magnetic stirring apparatus/heating plate are installed.Begin to stir and be heated to faint backflow and generate dark-brown solution to realize dissolving fully.Speed so that the whole precipitations that add fashionable formation are dissolved fast and backflow is kept at every turn in the hexane solution that adding is refluxing with slowly pursuing part, causes that until add hexane in solution the solid of formation dissolves very slow (～2L hexane) under backflow.Stop the heating, and make this crystalline mixture under agitation through the 16h balance to room temperature.During seasoning, around glass surface, form the crystalline material of thick-layer.Be accompanied by stirring, break even income suspension in ice/water-bath.On the Buchner funnel of being furnished with Whatman #1 filter medium, filter this suspension.The crystallization that washing is collected, and under vacuum, make it air-dry.Under 40 ℃/＜1 holder, further dry this crystallization 20h generates pink crystalline solid product.

Embodiment 101: the crystalline polymorph of preparation N-(R)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide

With N-(R)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide (216.10g) adds the 4L conical flask that big magnetic stirring bar and magnetic stirring apparatus/heating plate are installed.Add ethyl acetate (about 600mL).Begin heating and stir to form brown suspension.Make the faint backflow of this mixture, additionally add ethyl acetate (about 200mL) again to realize that dissolving obtains dark-brown solution fully.With the speed that the whole precipitations that add fashionable formation are dissolved fast and backflow is kept at every turn, heptane is slowly pursued in part solution that the ground adding is refluxing.When this solution adds the 2L heptane, the dissolving under refluxing of the solid of formation is very slow.Stop the heating, and make this crystalline mixture under agitation through the 16h balance to room temperature.During seasoning, around glass surface, form the crystalline material of thick-layer.Be accompanied by stirring, break even income suspension in ice/water-bath.On the 25cm Buchner funnel of being furnished with Whatman #1 filter medium, filter this suspension.With the crystallization of heptane (1L) washing collection, and under vacuum, make it air-dry.Under 40 ℃/＜1 holder, further dry this crystallization 20h.

Embodiment 102: the generation of IC50 data

Material and reagent preparation: with the allelomorph GST-MEK1 of human GST-MEK1 and composition activation ^CA(have sudden change Ser218Asp and Ser222Asp) from the human MEK1cDNA subclone of wild type to yeast expressed carrier pGEM4Z (Promega, Madison, WI) in.At expression in escherichia coli GST-MEK1 ^CA, and (Amersham Pharmacia Biotech, Piscataway NJ) carries out partial purification to it to use the affine resin of glutathione agarose 4B.With ERK2 allelomorph from pUSEamp (Upstate Biotechnology, Inc., Waltham, MA) MAPK2/Erk2cDNA in (wild type) subclone is to carrier pET21a (Novagen, Madison, WI) in, produce the mouse ERK2 allelomorph of the terminal histidine mark of N-.Expression ERK2 also is purified to homogeneous [Zhang, 1993#33].Myelin basic protein (MBP) available from Gibco BRL (Rockville, MD).EasyTides adenosine 5'-triphosphate (ATP) ([γ- ³³P]) (NEN Perkin Elmer, Wellesley MA) are the radioactive label source of all kinase reactions.The map kinase 2/ERK2 of Raf-1 (brachymemma) that activates and activation is available from Upstate, and Inc. (Lake Placid, NY).4-20%Criterion Precast gel available from Bio-Rad (Hercules, CA).

Measure enzymic activity: compound is diluted to 1xHMNDE (20mMHEPES pH 7.2,1mM MgCl from methyl-sulfoxide (DMSO) stock solution ₂, 100mM NaCl, 1.25mM DTT, 0.2mM EDTA) in.Typical 25 microlitres are measured and are comprised 0.002 nanomole MEK1 ^CA, 0.02 nanomole ERK2,0.25 nanomole MBP, the unlabelled ATP of 0.25 nanomole and 0.1 μ Ci[γ ³³P] ATP.This Screening test consists essentially of 4 interpolations.The compound of 5 μ l dilution is dispensed to 96-hole assay plate.Then, add 10 μ l 2.5x enzyme cocktails (MEK1 only to each hole ^CAAnd ERK2), precincubation 30 minutes at ambient temperature subsequently.Add 10 μ l 2.5x substrate mixed liquors (the adding MBP of mark) then, subsequently incubation 60 minutes at ambient temperature with unlabelled ATP.At last, add 100 μ l, 10% trichloroacetic acids (TCA), and at room temperature incubation stopped this reaction in 30 minutes and makes radiolabeled proteins product precipitation.Product is collected on the glass fibre 96 hole filters that water and 1% pyrophosphate prewet.Wash this filter 5 times then with water.Replace water with absolute ethyl alcohol, and at room temperature made this plate air-dry 30 minutes.Seal the back by hand, and the scintillation solution of 40 μ l is dispensed to each hole.Carry out top seal and in TopCount this plate is counted, speed is 2 seconds/hole.For some experiment, use need be by the truncated-type MEK of Raf kinase activator.

Embodiment 103: the generation of EC50 data

Detect the effect of compound in the cell by the ERK of immunoblotting mensuration phosphorylation.With 20,000 cells/well the MDA-MB-231 breast cancer cell is plated in 48 orifice plates, and at the CO of 37 ° of humidifications ₂Cultivate in the incubator.Second day, remove growth medium (DMEM+10% hyclone), and substitute with hungry medium (DMEM+0.1% hyclone).The incubation cell is 16 hours in hungry medium, uses the compound treatment 30 minutes of a series of concentration then.Behind the compound incubation, use 100ng/ml EGF irritation cell 5 minutes.Dissolved cell then, and use anti-phosphorylation ERK monoclone antibody by the immunoblotting analysis.Use the second antibody enhancing signal combine with nir dye, and on Licor Odyssey scanner detection signal.The amount of measured signal intensity, these data are used to generate dose-effect curve and EC50 calculates.

Embodiment 104: the activity data of compound

In said determination, tested the compound described in the

embodiment

1,2 and 3.The result is summarized in (A, EC in the following table ₅₀=＜2.0nM; B, EC ₅₀=2.0-15nM):

Embodiment 105: the XRPD data

Have in configuration on the Inel XRG-3000 diffractometer of curve location sensitive detector (curved position-sensitive detector) of 120 ° of 2 θ scope and carry out XPRD.Under the resolution of 0.03 ° of 2 θ, use Cu K α radiation to gather real time data.The voltage and current intensity of pipe is set to 40kV and 30mA respectively.From 2.5 to 40 ° of 2 θ demonstration figure is so that directly compare figure.By sample being filled in the thin-walled glass capillary, and (S) N-that preparation is used to analyze (3, the sample of 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide (as described herein synthetic).Each capillary is moved on the vehicularized goniometer head, thereby allow data acquisition period rotation capillary.Analytic sample 5 minutes.Use the silicon reference standard to carry out instrument calibration every day.Fig. 5 is powder x-ray diffraction (PXRD) figure of N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide A type thing.Fig. 7 is powder x-ray diffraction (PXRD) figure of N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide A type (last figure) and amorphous substance (figure below).

Embodiment 106: differential scanning calorimetry (DSC)

On TA instrument differential scanning calorimetry (DSC) Q1000, analyze.Use indium as the reference material calibration instrument.Sample is placed the standard aluminum matter DSC dish with corrugationless lid (non-crimped lid) structure, and write down weight exactly.In order to measure the glass transition temperature (T of amorphous substance _g), make the sample cell several times that between-40 ℃ to 140 ℃, circulate.Make final temperature rise to 150 ℃.Report T from the flex point that last circulation transforms _gFig. 6 is the modulation DSC thermal analysis curue of N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide (A type).In order to watt/gram (W/g) for the normalized heat flow of unit to ℃ being the sample temperature that the records mapping of unit.

Embodiment 107: dynamic steam absorption/desorption (DVS)

On VTI SGA-100 steam adsorption analysis instrument, gather water adsorption/desorption data.With 10%RH at interval, under purging with nitrogen gas, between 5% to 95% relative moisture (RH) scope, gather absorption/desorption data.Before analysis, the sample undried.The tension metrics that is used to analyze is lower than 0.0100% for weight change in 5 minutes, if less than lumping weight amount standard, then maximum equilibration time is 3 hours.The original water content of sample not being carried out data proofreaies and correct.Use sodium chloride and polyvinylpyrrolidine (polyvinypyrrolidine) as calibration standard.Figure 8 shows that the DVS isotherm of N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide (A type).At experimental session, this material demonstrates insignificant weight change.

Embodiment 108: DTG (TG)

On TA instrument 2950 DTG analyzers, analyze.Calibration standard is nickel and Alumel ^TMEach sample is placed aluminium quality sample dish, and be inserted in the TG smelting furnace.At 25 ℃ of balance samples, the rate of heat addition with 10 ℃/min flows down heating at nitrogen then, is 350 ℃ until final temperature.Figure 9 shows that N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) the TG thermal analysis curue of cyclopropane-1-sulfonamide (A type) demonstrates the insignificant loss in weight until 140 ℃, shows that polymorph A type is non-solvation.

Embodiment 109: external cancer screening

In comprising RPMI 1640 medium of 5% hyclone and 2mM L-glutaminate, cultivate the human tumour cell line.With the scope that depends on each cell-line doubling time is the bed board density of 5,000 to 40,000 cells/well, with 100 μ L with cell inoculation in 96 hole microwell plates.Behind the cell inoculation, at 37 ℃, 5%CO ₂, under 95% air and 100% relative moisture, these microwell plates of incubation 24h adds N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide then.

Add N-(S)-(3 in order to represent, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) measured value of the cell mass of each cell-line during cyclopropane-1-sulfonamide (Tz) is behind 24h, with two plates of each cell-line of TCA anchored in place.With 400 times to required final full test concentration, with N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide is dissolved in the methyl-sulfoxide, and freezing before use preservation.Add fashionable, the frozen concentrated liquid of the aliquot of thawing, and with the complete medium that comprises 50 μ g/ml gentamicins it is diluted to and doubles required final full test concentration.5 kinds of concentration add contrast in order to provide altogether, have prepared the dilution of 4 times, 10 times or 1/2 logarithm series in addition.The separatory such as 100 μ l of these different diluent are added in the suitable microtiter well that comprises 100 μ l medium, obtain required ultimate density.

After adding N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide, at 37 ℃, 5%CO ₂, under 95% air and 100% relative moisture, these plates of incubation 48h in addition again.For adherent cell, stop measuring by adding cold TCA.By leniently adding cold 50% (w/v) TCA of 50 μ l (ultimate density, 10%TCA) anchored in place cell, and 4 ℃ of incubations 60 minutes.Abandoning supernatant is used running water wash plate 5 times, and the sector-style of going forward side by side is done.0.4% (w/v) sulphonyl rhodamine (SulforhodamineB) that will be in 1% acetate (SRB) solution (100 μ l) adds in each hole, and these plates of incubation 10 minutes at room temperature.After the dyeing, remove unconjugated dyestuff 5 times by washing with 1% acetate, and air-dry these plates.Thereafter use the dyestuff of 10mM three (hydroxymethyl) aminomethane (trizmabase) dissolving combination, and use and read the plate device automatically, the place reads absorbance at the 515nm wavelength.For suspension cell, except by leniently add 50 μ l 80%TCA (ultimate density, 16%TCA) cell that is secured in the sedimentation of hole bottom is with outside stopping measuring, method is identical.Use 7 absorbance measuring values [N-(S)-(3 of zero-time (Tz), contrast growth (C) and 5 kinds of concentration levels, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) test vector generation for testing IC (Ti) under cyclopropane-1-sulfonamide exists], calculate the growth % under each drug concentration level.Growth inhibition % is calculated as follows:

Three kinds of dose response parameters have been calculated.Calculate 50% growth inhibition (GI50) by [(Ti-Tz)/(C-Tz)] x100=50, it is between the medicine incubation period, causes that clean albumen growth (recording by SRB dyeing) reduces by 50% concentration in the control cells.Calculate N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide concentration that causes complete growth inhibition (TGI) by Ti=Tz.Calculate the LC50 that expression handles the clean reduction of back cell (cause protein that drug treating records when finishing is compared when initial reduce by 50% drug concentration) by [(Ti-Tz)/Tz] x100=-50.If reach activity level, then calculate each value of these three kinds of parameters; But if do not meet or exceed this effect, then this parameter is represented with the highest or least concentration that is higher or lower than test.

Corresponding to the group of leukemia, non-small cell lung cancer, colon cancer, CN cancer, melanoma, oophoroma, kidney, prostate cancer and breast cancer, cell-line shown in having detected also provides following result.

Group	Cell-line	??GI50??(μM)	??LC50??(μM)	??TGI??(μM)
Group	Cell-line	??GI50??(μM)	??LC50??(μM)	??TGI??(μM)	Leukemia	??CCRF-CEM	??17.378	??100.000	??60.256
Leukemia	??HL-60(TB)	??0.010	??100.000	??100.000	Leukemia	??CCRF-CEM	??17.378	??100.000	??60.256
Leukemia	??HL-60(TB)	??0.010	??100.000	??100.000	Leukemia	??K-562	??6.607	??100.000	??100.000
Leukemia	??MOLT-4	??10.965	??100.000	??69.183	Leukemia	??K-562	??6.607	??100.000	??100.000
Leukemia	??MOLT-4	??10.965	??100.000	??69.183	Leukemia	??RPMI-8226	??26.915	??100.000	??100.000
Leukemia	??SR	??38.019	??100.000	??100.000	Leukemia	??RPMI-8226	??26.915	??100.000	??100.000
Leukemia	??SR	??38.019	??100.000	??100.000	Non-small cell lung cancer	??A549/ATCC	??0.589	??100.000	??64.565
Non-small cell lung cancer	??EKVX	??0.214	??61.660	??13.804	Non-small cell lung cancer	??A549/ATCC	??0.589	??100.000	??64.565
Non-small cell lung cancer	??EKVX	??0.214	??61.660	??13.804	Non-small cell lung cancer	??HOP-62	??0.069	??42.658	??12.589
Non-small cell lung cancer	??HOP-92	??0.047	??58.884	??0.324	Non-small cell lung cancer	??HOP-62	??0.069	??42.658	??12.589
Non-small cell lung cancer	??HOP-92	??0.047	??58.884	??0.324	Non-small cell lung cancer	??NCI-H226	??3.311	??74.131	??24.547
Non-small cell lung cancer	??NCI-H23	??0.056	??74.131	??2.884	Non-small cell lung cancer	??NCI-H226	??3.311	??74.131	??24.547
Non-small cell lung cancer	??NCI-H23	??0.056	??74.131	??2.884	Non-small cell lung cancer	??NCI-H322M	??0.162	??46.774	??15.488
Non-small cell lung cancer	??NCI-H460	??3.631	??52.481	??19.498	Non-small cell lung cancer	??NCI-H322M	??0.162	??46.774	??15.488
Non-small cell lung cancer	??NCI-H460	??3.631	??52.481	??19.498	Non-small cell lung cancer	??NCI-H522	??5.248	??100.000	??29.512
Colon cancer	??HCC-2998	??0.010	??0.457	??0.035	Non-small cell lung cancer	??NCI-H522	??5.248	??100.000	??29.512
Colon cancer	??HCC-2998	??0.010	??0.457	??0.035	Colon cancer	??HCT-116	??0.195	??67.608	??12.589

Group	Cell-line	??GI50??(μM)	??LC50??(μM)	??TGI??(μM)
Group	Cell-line	??GI50??(μM)	??LC50??(μM)	??TGI??(μM)	Colon cancer	??HCT-15	??0.603	??60.256	??16.982
Colon cancer	??HT29	??0.026	??29.512	??3.090	Colon cancer	??HCT-15	??0.603	??60.256	??16.982
Colon cancer	??HT29	??0.026	??29.512	??3.090	Colon cancer	??KM12	??0.229	??48.978	??13.490
Colon cancer	??SW-620	??0.039	??66.069	??12.589	Colon cancer	??KM12	??0.229	??48.978	??13.490
Colon cancer	??SW-620	??0.039	??66.069	??12.589	The CNS cancer	??SF-268	??2.570	??100.000	??25.704
The CNS cancer	??SF-295	??9.333	??53.703	??23.442	The CNS cancer	??SF-268	??2.570	??100.000	??25.704
The CNS cancer	??SF-295	??9.333	??53.703	??23.442	The CNS cancer	??SF-539	??1.514	??60.256	??20.417
The CNS cancer	??SNB-19	??0.251	??75.858	??24.547	The CNS cancer	??SF-539	??1.514	??60.256	??20.417
The CNS cancer	??SNB-19	??0.251	??75.858	??24.547	The CNS cancer	??SNB-75	??0.302	??34.674	??4.467
The CNS cancer	??U251	??0.891	??44.668	??17.378	The CNS cancer	??SNB-75	??0.302	??34.674	??4.467
The CNS cancer	??U251	??0.891	??44.668	??17.378	Melanoma	??LOXIMVI	??0.195	??38.905	??10.715
Melanoma	??MALME-3M	??0.010	??19.953	??0.014	Melanoma	??LOXIMVI	??0.195	??38.905	??10.715
Melanoma	??MALME-3M	??0.010	??19.953	??0.014	Melanoma	??M14	??0.015	??29.512	??0.166
Melanoma	??SK-MEL-28	??0.028	??22.387	??0.214	Melanoma	??M14	??0.015	??29.512	??0.166
Melanoma	??SK-MEL-28	??0.028	??22.387	??0.214	Melanoma	??SK-MEL-5	??0.062	??38.905	??13.804
Melanoma	??UACC-257	??0.020	??66.069	??10.233	Melanoma	??SK-MEL-5	??0.062	??38.905	??13.804
Melanoma	??UACC-257	??0.020	??66.069	??10.233	Melanoma	??UACC-62	??0.014	??20.893	??0.170
Oophoroma	??IGROV1	??0.018	??19.055	??0.295	Melanoma	??UACC-62	??0.014	??20.893	??0.170
Oophoroma	??IGROV1	??0.018	??19.055	??0.295	Oophoroma	??OVCAR-3	??2.512	??48.978	??17.783
Oophoroma	??OVCAR-4	??0.562	??72.444	??16.218	Oophoroma	??OVCAR-3	??2.512	??48.978	??17.783
Oophoroma	??OVCAR-4	??0.562	??72.444	??16.218	Oophoroma	??OVCAR-5	??0.017	??40.738	??12.023
Oophoroma	??SK-OV-3	??12.882	??100.000	??41.687	Oophoroma	??OVCAR-5	??0.017	??40.738	??12.023

Group	Cell-line	??GI50??(μM)	??LC50??(μM)	??TGI??(μM)
Group	Cell-line	??GI50??(μM)	??LC50??(μM)	??TGI??(μM)	Kidney	??786-0	??5.129	??63.096	??23.442
Kidney	??A498	??0.191	??44.668	??4.169	Kidney	??786-0	??5.129	??63.096	??23.442
Kidney	??A498	??0.191	??44.668	??4.169	Group	Cell-line	??GI50??(μM)	??LC50??(μM)	??TGI??(μM)
Kidney	??ACHN	??0.275	??83.176	??21.878	Group	Cell-line	??GI50??(μM)	??LC50??(μM)	??TGI??(μM)
Kidney	??ACHN	??0.275	??83.176	??21.878	Kidney	??CAKI-1	??0.389	??100.000	??26.915
Kidney	??SN12C	??0.851	??47.863	??18.621	Kidney	??CAKI-1	??0.389	??100.000	??26.915
Kidney	??SN12C	??0.851	??47.863	??18.621	Kidney	??TK-10	??0.224	??100.000	??23.442
Kidney	??UO-31	??0.158	??40.738	??11.482	Kidney	??TK-10	??0.224	??100.000	??23.442
Kidney	??UO-31	??0.158	??40.738	??11.482	Prostate cancer	??PC-3	??8.128	??100.000	??37.154
Prostate cancer	??DU-145	??2.138	??95.499	??22.387	Prostate cancer	??PC-3	??8.128	??100.000	??37.154
Prostate cancer	??DU-145	??2.138	??95.499	??22.387	Breast cancer	??MCF7	??10.965	??85.114	??30.903
Breast cancer	??NCI/ADR-RES	??3.467	??100.000	??25.704	Breast cancer	??MCF7	??10.965	??85.114	??30.903
Breast cancer	??NCI/ADR-RES	??3.467	??100.000	??25.704	Breast cancer	??MDA-MB-231	??0.069	??35.481	??10.471
Breast cancer	??HS?578T	??0.617	??85.114	??13.490	Breast cancer	??MDA-MB-231	??0.069	??35.481	??10.471
Breast cancer	??HS?578T	??0.617	??85.114	??13.490	Breast cancer	??MDA-MB-435	??0.035	??41.687	??12.303
Breast cancer	??BT-549	??5.754	??47.863	??20.893	Breast cancer	??MDA-MB-435	??0.035	??41.687	??12.303
Breast cancer	??BT-549	??5.754	??47.863	??20.893	Breast cancer	??T-47D	??4.898	??100.000	??38.019
Breast cancer	??MDA-MB-468	??0.019	??54.954	??10.233	Breast cancer	??T-47D	??4.898	??100.000	??38.019

Embodiment 110: external antiproliferative activity

In the present embodiment, detected N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-and the following effect of 1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide: (1) is to the inhibition activity (GI of some tumor cell lines growths of having different sudden changes ₅₀); (2) the inhibition activity (GI that some B-Raf mutational cell lines are grown ₅₀); (3) effect that adherent not dependent cell is grown; (4) effect of cell cycle; (5) to the toxic effect of primary hepatocyte and nephrocyte.

Cell culture/growth inhibition is measured

(Manassas VA) obtains from ATCC for human melanoma A375 cell and human colon's cancer Colo205 cell.In the DMEM that adds 10% hyclone, glutamine (2mM), penicillin (100U/ml) and streptomycin (100 μ g/ml), cultivate the A375 cell.At 37 ℃, 5%CO ₂With cultured cell under 100% humidity.In the RPMI that adds 10% hyclone, glutamine (2mM), penicillin (100U/ml) and streptomycin (100 μ g/ml), cultivate the Colo205 cell.For growth inhibition test,, cell is plated in the microtest plate of white 384-hole with 1000 cells/20 μ l/ holes.Behind the 24hr, add 5 μ l 5X medicine storage solution.At first all medicines all are mixed with the 200X stock solution among the DMSO, making final DMSO concentration is 0.5%.At 37 ℃ of incubation cell 48hr, and (Promega, Madison WI) measure the ATP level to use CellTiterGlo.(Cambrex, Walkersville MD) measure adenylate kinase (AK) and discharge to use Toxilight.(GraphPad Software, San Diego CA) carry out non-linear curve fitting to use GraphPad Prism 4.((2R, 3R, 4S, 5R)-3,4-dihydroxy-5-(hydroxymethyl) oxolane-2-yl) pyrido [2,3-d] pyrimidines-5 (8H)-ketone (VRX-14686) is the cytotoxic agent as reference compound to 4-amino-8-.

Growth inhibition(%)=(vehicle Control (RLU)-N-(S)-(3 only, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide RLU)/(vehicle Control RLU-1 μ MN-(S)-(3 only, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide RLU); According to by N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) growth retardation that cyclopropane-the 1-sulfonamide causes, wherein measured the ATP level.

Cell viability(%)=(N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide RLU-10 μ M VRX-14686RLU)/(only vehicle Control RLU-10 μ M Tamoxifen RLU); According to the cell killing that causes by VRX-14686, wherein measure the ATP level.

Cell killing(%)=(N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide RLU-is vehicle Control RLU only)/(10 μ M Tamoxifen RLU-are vehicle Control carrier RLU only); According to the cell killing that causes by Tamoxifen, wherein measure AK and discharge.

The relative flat light emission of RLU=

Estimate cell cycle arrest

With 10,000 cells/200 μ l/ holes the A375 cell is plated in the 96 hole microtest plates.Behind the 24hr, cell about 50% converges, and adds 50 μ l 5X medicine storage solution.Again behind the 24hr, cell is through trypsin acting, be fixed in 200 μ l Prefer (Anatech, Battle Creek, MI) in, and 4 ℃ of store overnight.In PBS, clean cell then, carry out permeableization processing, the ribalgilase and 25 μ g/ml iodate, third ingot (the Molecular Probes that do not have deoxyribonuclease at 0.1%Triton X-100,200 μ g/ml, Sunnyvale, CA) dyeing in, and in Guava PCA-96 (Guava Technologies, Foster City, CA) upward analysis.Use ModFit LT (3.0 editions, Verity, Topsham ME) analyzes data.

(1) the assess attachment growth inhibition of dependent cell not

Make the hole of " ultralow adhesiveness " plate (Corning, Acton MA) be full of 0.15% agarose solution in complete RPMI of 60 μ l.Then, the complete RPMI of 60 μ l that will comprise 9000 Colo205 cells in 0.15% agarose adds each hole.Behind the 24hr, add the 3X drug solution in the complete RPMI of no agarose of 60 μ l.After 7 days, (Madison WI) adds each hole for CellTiter 96Aqueous, Promega with 36 μ l 6X MTS reagent.Behind 37 ℃ of following 2hr, M5 read the plate device (Molecular Devices, Sunnyvale, CA) on, measure absorbance at the 490nm place.Use GraphPad Prism 4 to carry out non-linear curve fitting.

(2) to the growth inhibition (GI of MEK dependence growth of cancer cells ₅₀)

B-Raf mutant cell A375 (human melanoma), A431 (melanoma), Colo205 (colon cancer), HT29 (knot rectal adenocarcinoma), MDA-MB231 (adenocarcinoma of breast) and BxPC3 (pancreas adenocarcinoma) and N-(S)-(3 that logarithmic phase is being divided, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide contact 48hr, and measure ATP content.Use 1 μ M N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide to measure 100% growth retardation.

Following table is depicted as the average GI of each cell-line that derives from least three tests ₅₀Value, and show N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide causes the growth inhibition in three kinds of B-Raf mutational cell lines (A375, Colo205 and HT29) and a kind of ras/raf/MEK/MAPK approach wild-type cell system (A431), its have average effectiveness 79nM (± 9nM).

Cell-line	Mean value	Standard deviation	??C.V.
Cell-line	Mean value	Standard deviation	??C.V.	??A375	??71nM	??12.1nM	??17％
??A431	??86nM	??25.4nM	??30％	??A375	??71nM	??12.1nM	??17％
??A431	??86nM	??25.4nM	??30％	??Colo205	??89nM	??40.1nM	??45％
??HT29	??70nM	??12.2nM	??18％	??Colo205	??89nM	??40.1nM	??45％
??HT29	??70nM	??12.2nM	??18％	??MDA	??＞1uM
??BxPC3	??＞1uM			??MDA	??＞1uM

In independently studying, B-Raf mutant cell A375 (human melanoma), SKMel28 (human melanoma) and Colo205 (human colon's cancer) and N-(S)-(3 that logarithmic phase is being divided, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide contact 48hr, and measure ATP content.Following table is depicted as the GI of each cell-line ₅₀, showing that N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide causes growth inhibition, it has and is similar to its MEK and suppresses EC ₅₀The effectiveness of value.

Cell-line	??GI ₅₀(nM)
Cell-line	??GI ₅₀(nM)	??A375	??56
??SK?Mel?28	??105	??A375	??56

Cell-line	??GI ₅₀(nM)
Cell-line	??GI ₅₀(nM)	??Colo205	??27

Figure 10 A and Figure 10 B are depicted as the N-(S)-(3 that increases with concentration, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-growth retardation of the A375 cell that the logarithmic phase of 1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide contact is dividing.Analysis of cells is measured ATP content.Use 1 μ M N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide to measure 100% growth retardation.

Discharge by measuring adenylate kinase (AK), the analysis of cells supernatant is measured the cytotoxicity lysis.A375 cell and N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide that logarithmic phase is being divided contact 48hr with PD-325901.(using 20 μ M Tamoxifen to measure 100% cell killing).In Figure 11, demonstrate the result.These data show N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide causes the non-toxicity growth retardation in some neurological susceptibility human cancer cell-lines, and this is by i) growth retardation measured value (ATP is quantitative); Ii) lacking cytotoxic cell lysis (AK release) proves.For all cells system of test, confirm to lack AK and discharge.

Adherent not dependence growth inhibition

Estimate quantitatively and N-(S)-(3 with 96 hole microtest plate patterns, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide contacts 7 days Colo205, A375 and the adherent not dependence of MDA-MB231 cell is grown.By MTS assay determination vigor.GI ₅₀Be worth as follows:

Cell-line	Mean value	Standard deviation	??C.V.
Cell-line	Mean value	Standard deviation	??C.V.	??Colo205	??40nM	??8.1nM	??20％
??A375	??84nM	??17.2nM	??21％	??Colo205	??40nM	??8.1nM	??20％
??A375	??84nM	??17.2nM	??21％	??MDA-MB231	??81nM	??55.6nM	??69％

Figure 12 A-12C is depicted as the growth inhibition (GI of N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide (A) to human colorectal cancer Colo205 cell ₅₀=11nM); (B) to the growth inhibition (GI of A375 cell ₅₀=22nM) with (C) to the MDA-MB231 cell inhibiting, it does not demonstrate N-(S)-(3 in two-dimentional anchorage dependence is measured, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) growth retardation that cyclopropane-the 1-sulfonamide causes.

A375 cell and N-(S)-(3 that logarithmic phase is being divided, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide (1uM) contact 48hr, and the analysis of cells supernatant is measured growth inhibition (ATP content) and cytotoxicity lysis (AK release).In vehicle Control hole only, measure 100% vigor (ATP assay).Result shown in the following table shows that N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide causes suddenly change non-toxicity growth retardation in the human melanoma A375 cell of B-Raf.

	The % contrast
	The % contrast	ATP, cell viability	??27％
AK, cell killing	??4％	ATP, cell viability	??27％

Adherent not dependence growth inhibition

With the not dependence growth of assess attachment quantitatively of 96 hole microtest plate patterns.Figure 13 A is depicted as the growth inhibition to human colorectal cancer Colo205 cell, GI ₅₀Be worth non-Wei 6nM and 11nM.Figure 13 B is depicted as the growth inhibition to the A375 cell, GI ₅₀Value is 5nM and 22nM.

N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1- The cell cycle analysis of the growth retardation that sulfonamide causes

Shown that MEK suppresses to cause G1/S phase cell cycle arrest in the A375 cell.

A375 cell and N-(S)-(3 that logarithmic phase is being divided, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide contact 24hr, and use cells were tested by flow cytometry to measure the percentage of the cell that dyes because of DNA in the stage dependent cell.

Following table is depicted as through N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-be in the distribution percentage of the cell in each vegetative period in the cell that 1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide and contrast (only carrier) are handled.

Figure 14 A and Figure 14 B are depicted as N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) effect of cyclopropane-1-sulfonamide cell cycle process, this explanation makes A375 cell and N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) in the phase, it is all exhausted by the cell that is in G2 phase and S phase and shows cyclopropane-1-sulfonamide contact causing cell cycle arrest in G1.

Estimate primary hepatocyte and nephrocyte toxicity

(Austin TX) obtains cryopreserved rat hepatocytes, and according to the specification of manufacturer it is plated in 96 orifice plates that scribble collagen from CellzDirect.4hr behind the bed board adds medicine (final DMSO concentration 0.5%).

The human hepatocytes of bed board obtains from CellzDirect, and handles according to the specification of manufacturer.

(renal proximal tubule epithelial cell RPTEC) obtains from Cambrex cryopreserved human kidney proximal tubule epithelial cell, and handles according to the specification of manufacturer.Made cell proliferation 4 days, and be plated on 50,000 cells/well then and be used for medicine contact in 96 orifice plates.

Behind the 48hr, use Toxilight to measure supernatant A K level, and use CellTiterGlo to measure the cell ATP level.Use 15 μ M VRX-14686 to measure the total kill value.

The result is as follows.Observe few cell lysis.In former generation of just bed board human hepatocytes, observe the minimum toxicity (81% survival rate) under 30 μ M N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide.The RPTEC cell shows dose dependent ATP loss and tangible cell lysis under 30 μ M.

Above data show (1) N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cell growth and the division among the human cancer cell that cyclopropane-inhibition of 1-sulfonamide is selected, in the anchorage dependence proliferation assay, its GI ₅₀Value is in the 70-89nM scope, as the not toxigenicity of measuring in the analysis of cell lysis; (2) N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cell growth and the division in the human cancer cell that cyclopropane-inhibition of 1-sulfonamide is selected, in anchorage dependence and non-dependence proliferation assay, GI ₅₀Value is respectively 51nM and 22nM; (3) N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide causes the adherent not dependence growth in G1 stagnation and the inhibition A375 cell, and active anticancer evidence in the relevant external model of physiology is provided; (4) N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide to former generation normal human subject liver cell, human kidney proximal tubule epithelial cell and rat hepatocytes show cytotoxicity hardly.

Embodiment 111: the pharmacokinetics of N-among the cancer patient behind the multiple dosing (S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide

R _Ac: index of bunching

^*Because it is inaccurate that estimate limited sample time

With 2,4 or 6mg/ experimenter's multiple dosing N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) behind cyclopropane-1-sulfonamide, N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide easily is absorbed, its average T _MaxScope is 1.33 to 1.50hr.Average C _Max, C _τIncrease with dosage in the mode that is directly proportional with dosage with the AUC value.For C _Max, the index of bunching scope is 1.49 to 1.76, and for AUC, the index of bunching scope is 1.90 to 2.07, and this shows the accumulation appropriateness.Though owing to sample time behind the multiple dosing is limited, can not measure the half life period exactly, according to index of bunching, the half life period is longer than 22hr behind the expection multiple dosing.These elimination half life values are longer than observed value in the mouse effectiveness models (observed common scope be 2 to 3hr) significantly.In addition, under all dosage, observe challenging peak-to-valley ratio.

Embodiment 112: the pharmacokinetics of N-(S) among the healthy volunteer behind the multiple dosing-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide

R _a: index of bunching

^*Because limited evaluation sample time is inaccurate

With 10 or 20mg/ experimenter's multiple dosing N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) behind cyclopropane-1-sulfonamide, N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide easily is absorbed, its average T _MaxScope is 2.00 to 2.25hr.Average C _Max, C _τIncrease with dosage with the AUC value.For C _Max, the index of bunching scope is 1.14 to 1.23, for AUC, and index of bunching scope 1.24 to 1.29, this shows that accumulation is not remarkable.The half life period of two kinds of dosage regimens is similar, and its scope is 13 to 15hr.These elimination half life values are shorter than the observed value among the cancer patient.

Embodiment 113: external antiproliferative activity

In cell proliferation test, in coming from the cell-line of human cancer of the stomach, detect N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide to suppressing the effect of cell proliferation.

Cell culture/growth inhibition test: (Manassas VA) obtains human cancer of the stomach Hs746t cell from ATCC.In the DMEM that adds 10% hyclone, penicillin (100U/ml) and streptomycin (100 μ g/ml), cultivate the Hs746t cell.At 37 ℃, 5%CO ₂With cultured cell under 100% humidity.For cell proliferation test, cell is plated in white 96 orifice plates with clear bottom with 3000 cells/100 μ l/ holes.Behind the 24hr, remove cell culture medium, and substitute with the medium that comprises various dosage N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide.Behind 37 ℃ of incubation 48hr, (Promega, Madison WI) measure the ATP level, and (Sunnyvale CA) reads luminous value to use LJL Biosystems Analyst HT to use CellTiterGlo.Use hole independently to measure the ATP level of each dosage in triplicate.

Relative cell number=(average RLU (handling))/(average RLU is vehicle Control only) through N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide.

Figure 19 shows that cell number (with respect to carrier) is to N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) chart of cyclopropane-1-sulfonamide concentration, and show after handling 48 hours, N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide suppresses the propagation of human cancer of the stomach Hs746t cell.

Embodiment 114: external antiproliferative activity

In cell proliferation test, in the cell-line that comes from human sdenocarcinoma of stomach (" cancer of the stomach "), detect N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide is to suppressing the effect of cell proliferation.

Cell culture/growth inhibition test

(Manassas VA) obtains human sdenocarcinoma of stomach ags cell from ATCC.In the DMEM/F12 that adds 10% hyclone, penicillin (100U/ml) and streptomycin (100 μ g/ml), cultivate ags cell.At 37 ℃, 5%CO ₂With cultured cell under 100% humidity.For cell proliferation test, cell is plated in white 96 orifice plates with clear bottom with 3000 cells/100 μ l/ holes.Behind the 24hr, remove cell culture medium, and substitute with the medium that comprises various dosage N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide.After 3 days, (Promega, Madison WI) measure the ATP level, and (Sunnyvale CA) reads luminous value to use LJL Biosystems Analyst HT to use CellTiterGlo at 37 ℃ of incubations.Use hole independently to measure the ATP level of each dosage in triplicate.In another experiment, bed board 1000 cells/100ul/ hole were handled cell 6 days, and as above measured.

Figure 15 A and Figure 15 B are depicted as and N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) contact of cyclopropane-1-sulfonamide is after 3 days (A) and after 6 days (B), N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) chart of cyclopropane-1-sulfonamide concentration pair cell number (with respect to carrier), this shows N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide suppresses the propagation of human sdenocarcinoma of stomach ags cell system.

Embodiment 115: the human Hep3B growth of tumor reaction of original position in the nude mice of the N-of difference amount (S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide treatment

5 FU 5 fluorouracil contrast with dose,optimum (75mg/kg), in BALB/c nu/nu mouse, estimate N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the dose response usefulness of the inhibition that 1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide (" compd A ") take place original position Hep3B2.1-7 human liver cancer.

Animal: female BALB/c nu/nu mouse (University of Adelaide, Waite Campus, SA, Australia), in age in 10-14 week, weight range: 19.1-29.94g (average 22.95g) is used to research.Mouse is divided into following 6 seminar (4 treatment groups and 2 control groups):

Number of mice/group: comprise that in the 1-5 group be 10

In " absorption ratio " control group (the 6th group) is 15

In controlled environment (target zone: 21 ± 3 ℃ of temperature, humidity 30-70%, 10-15 ventilation/hour), under barrier (quarantine) condition, with 12 hours illumination/12 hour dark cycles, the raising mouse.Routinely monitoring temperature and relative moisture.Optionally supply with commodity rodent (Rat and Mouse Cubes, Speciality Feeds PtyLtd, Glen Forrest, Western Australia) and running water to animal.Food and water supply are all sterilized by autoclaving.

Tumor inoculation: cultivate Hep3B human liver cancer cell (from active redundancy VP-Stock 353 go down to posterity 2) in the RPMI1640 cell culture medium, described medium is added 10%FBS and penicillin-streptomycin (50IU/mL ultimate density).By the trypsin acting collecting cell, in HBSS, clean twice, and counting.Then, with cell be suspended in once more HBSS: Matrigel (1: 1, v/v) in, and it transferred to comprise 1x10 ⁸The final volume of cell/mL.Before the inoculation, with alcohol wiping cutting part fully, and open abdomen exposes liver.Insert a needle into liver surface, inject 10 μ L cell (1x10 herein ⁶Cell).Leak out in the abdominal cavity for fear of tumour cell, pin is remained on that this position kept about 30 seconds so that

Polymerization.

Inoculate back 14 days begin treatments.In the 7th day (inoculation back the 21st day) of research, kill all mouse of " absorption ratio " control group, the visual assessment liver detects the existence of tumour.

Material: following material obtains from each supplier.

Sterile saline solution (0.9%NaCl (aq)) is from Baxter Healthcare Australia, Old Toongabbie, and NSW, Australia obtains.Cremophor EL is from Sigma-Aldrich Pty Ltd, Castle Hill, and NSW, Australia obtains.The 5 FU 5 fluorouracil clinical preparation of the colourless liquid of clarification obtains from Mayne Pharma Pty Ltd.RPMI1640 cell culture medium, FBS and HBSS are from Invitrogen Australia Pty Ltd, Mt Waverley, VIC, Australia's acquisition.Penicillin-streptomycin and trypan blue be from Sigma-Aldrich, Castle Hill, and NSW, Australia obtains.Hep3B2.1-7 human liver cancer cell derives from American type culture collection (American Type CultureCollection) (ATCC), Rockville, MD, USA.

From BD Biosciences, North Ryde, NSW, Australia obtains.

In inoculation suspension, use

Improve the absorption ratio of tumour and reduce the changeability of tumour size, and the growth of Hep3B2.1-7 human liver cancer cell is more stable when inoculating in the presence of this extracellular matrix.

Compound preparation and administration: according to following timetable administration cremophor EL: salt solution (1: 9, v/v; Vehicle Control), N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide (" compd A ") or 5 FU 5 fluorouracil (compound contrast):

Group	Compound	Dosage (mg/kg)	Treatment regularly	Drug treatment
Group	Compound	Dosage (mg/kg)	Treatment regularly	Drug treatment	??1	Vehicle Control	??10mL/kg	Once a day, 21 days (the 0th day to the 20th day)	Once a day, 19 days (the 0th day to the 18th day)
??2	Compd A	??0.2mL@??10mL/kg＝2mg/kg	Once a day, 21 days (the 0th day to the 20th day)	Once a day, 19 days (the 0th day to the 18th day)	??1	Vehicle Control	??10mL/kg	Once a day, 21 days (the 0th day to the 20th day)	Once a day, 19 days (the 0th day to the 18th day)
??2	Compd A	??0.2mL@??10mL/kg＝2mg/kg	Once a day, 21 days (the 0th day to the 20th day)	Once a day, 19 days (the 0th day to the 18th day)	??3	Compd A	??1.0mL@??10mL/kg＝10mg/kg	Once a day, 21 days (the 0th day to the 20th day)	Once a day, 19 days (the 0th day to the 18th day)
Group	Compound	Dosage (mg/kg)	Treatment regularly	Drug treatment	??3	Compd A	??1.0mL@??10mL/kg＝10mg/kg	Once a day, 21 days (the 0th day to the 20th day)	Once a day, 19 days (the 0th day to the 18th day)
Group	Compound	Dosage (mg/kg)	Treatment regularly	Drug treatment	??4	Compd A	??5.0mL@??10mL/kg＝50mg/kg	Once a day, 21 days (the 0th day to the 20th day)	Once a day, 19 days (the 0th day to the 18th day)
??5	5 FU 5 fluorouracil	??7.5mL@??10mL/kg＝75mg/kg	Once in a week, 21 days (the 0th, 7 and 14 day)	Once in a week, 3 weeks (the 0th, 7 and 14 day)	??4	Compd A	??5.0mL@??10mL/kg＝50mg/kg	Once a day, 21 days (the 0th day to the 20th day)	Once a day, 19 days (the 0th day to the 18th day)
??5	5 FU 5 fluorouracil	??7.5mL@??10mL/kg＝75mg/kg	Once in a week, 21 days (the 0th, 7 and 14 day)	Once in a week, 3 weeks (the 0th, 7 and 14 day)	??6	" absorption ratio " contrast	There is not treatment	??-	??-

With the administration volume of 10mL/kg, continue 21 days (the 0th day to the 20th day) oral administration vehicle Control cremophor ELs once a day: salt solution (1: 9, v/v).

At cremophor EL: salt solution (1: 9, v/v) in preparation N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide.Prepare stock solution weekly, and preserve down at 4 ℃.Prepare to drug solns the every day in administration.With the administration volume of 10mL/kg, continue 21 days (the 0th day to the 20th day) oral administration N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide once a day.With 2,10 and the described compound of dosed administration of 50mg/kg.

Dilution 5 FU 5 fluorouracil clinical preparation in Sterile Saline, and under concentration 75mg/kg,, continue 3 weeks (at the 0th day, the 7th day and the 14th day) once in a week with the administration volume of 10mL/kg, carry out intravenous administration via the tail vein.

The mouse in the 6th group (" absorption ratio " contrast) is not applied treatment.The 7th day (inoculating back 21 days) of research, kill mouse, and expose liver to measure the tumour size in " absorption ratio " and the liver wall.

Before administration, measure the body weight of each animal at once.Calculate and adjust dosage according to body weight to each mouse.

Measurement of tumor: when expiration date of research when after death excising each liver and tumour, measure liver and tumour weight in wet base.When research finishes, hepatectomize and weigh from all mouse of each seminar.If visible tumour exists, then count its quantity.Remove these tumours and weigh from liver.

DATA REASONING and sample acquisition time table

DATA REASONING	Timetable
DATA REASONING	Timetable	Body weight	For comprising 1-5 group, the 0th day, time (Monday, Wednesday and Friday) on every Wendesdays then, and the expiration date of research.
Liver weight and tumor weight	The expiration date of research after death from whole mouse of comprising 1-5 group and die from the liver of a mouse excision of the 5th group of final treatment day and the weight in wet base of tumour.	Body weight
Liver weight and tumor weight		Sample is gathered
Liver and tumour	Whole mouse from research the 7th day the 6th group (" absorption ratio " contrast).	Sample is gathered
Liver and tumour		Liver and tumour	From research expiration date whole mouse that comprise a 1-5 group after death and mouse of the 5th group that dies from final treatment day.
Liver	From research expiration date whole mouse that comprise a 1-5 group after death and mouse of the 5th group that dies from final treatment day.	Liver and tumour

Data acquisition and calculating: before image data, use at once bar code reader (LabMax I, DataMars, Switzerland) scan each animal responder (Bar Code Data Systems Pty Ltd, Botany Bay, NSW).With identical hand-held caliper (Absolute Digimatic Model CD-6 " CS, Mitutoyo Corporation Japan) obtains all measured values.Use Pendragon Forms 4.0 ( Software Corporation, Libertyville, IL U.S.A.) as transmitting software, makes data sync with vivoPharm ' s security relationship database.AIDAM v2.4 is used for data report and data computation.

Statistics and calculating: use SigmaStat 3.0. (SPSS Australasia Pty Ltd, North Sydney, NSW, Australia) to carry out all statistical calculations.

The significance of use two sample t-to check to be determined at research the 0th day body weight change to the treatment group between the expiration date.Not under the situation by test of normality or homogeneity test of variance, carry out the Mann-Whitney rank test in data.

When research finishes, to liver weight and tumor weight data carry out one-way analysis of variance (ANOVA) (all paired multiple comparison methods (All Pairwise Multiple Comparison Procedure) and with the control group multiple ratio).Not under the situation by homogeneity test of variance, carry out Kruskal-Wallis one-way analysis of variance (ANOVA) in this check according to grade.Data to tumor-bearing mice in the research are carried out identical statistical analysis.

The P value is lower than 0.05 and is considered to have significance.

The liver of every group every mouse of the liver weight of tumor-bearing mice and tumor weight data and tumor-bearing mice and the average weight of tumour

Group	Treatment	Average liver weight (g)	??SEM	Average tumor weight (g)	??SEM	Tumor-bearing mice number (/ 10)
Group	Treatment	Average liver weight (g)	??SEM	Average tumor weight (g)	??SEM	Tumor-bearing mice number (/ 10)	??1	Vehicle Control	??4.560	??0.673	??3.382	??0.979	??4
??2	Hua HewuA @2mg/kg	??2.775	??0.475	??1.776	??0.576	??6	??1	Vehicle Control	??4.560	??0.673	??3.382	??0.979	??4
??2	Hua HewuA @2mg/kg	??2.775	??0.475	??1.776	??0.576	??6	??3	Hua HewuA @10mg/kg	??2.551	??0.446	??1.407	??0.465	??7
??4	Hua HewuA @50mg/kg	??1.677	??0.161	??0.624	??0.257	??4	??3	Hua HewuA @10mg/kg	??2.551	??0.446	??1.407	??0.465	??7
??4	Hua HewuA @50mg/kg	??1.677	??0.161	??0.624	??0.257	??4	??5	??5FUTM@75??mg/kg	??1.217	??0.051	??0.143	??0.078	??4

Not from mouse (it is killed during the studying) collected specimens of the 5th group (75mg/kg 5 FU 5 fluorouracil).Owing in some mouse, there is big tumour (indicated), after initial treatment, stopped this research in 18 days as belly swelling outward appearance.

In N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide-treatment group, the dose dependent trend that liver and tumor weight reduce is obvious.When only considering tumor-bearing mice, discovery is at the N-(S)-(3 through maximum dose level (the 4th group with 50mg/kg), 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-group of 1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide and 5 FU 5 fluorouracil (the 5th group with 75mg/kg) treatment in the average weight of liver with respect to (the 1st group of vehicle Control group; P＜0.05) has significant difference.And find through N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-group of 1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide (the 3rd and the 4th group respectively with 10mg/kg and 50mg/kg) and 5 FU 5 fluorouracil (the 5th group with 75mg/kg) treatment in the average weight of tumour have significant difference with respect to the vehicle Control group.

In Figure 16 (average liver weight-only tumor-bearing mice) and Figure 17 (liver neoplasm weight-only tumor-bearing mice), provide these results by chart.

Embodiment 116: the growth response of the human HT-29 colon tumor of original position in the nude mice of the N-of difference amount (S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide treatment

5 FU 5 fluorouracil (75mg/kg) contrast with dose,optimum, in BALB/c nu/nu mouse, estimate N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the dose response usefulness of the inhibition that 1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide (" compd A ") take place the human knot of original position HT-29 rectal adenocarcinoma.

Animal: female BALB/c nu/nu mouse (University of Adelaide, Waite Campus, SA, Australia), in age in 7-12 week, weight range: 16.58-25.39g (average 21.52g) is used to research.Mouse is divided into following 6 seminar (4 treatment groups and 2 control groups):

Number of mice/group: comprise that in the 1-5 group be 10

In " absorption ratio " control group (the 6th group) is 9

Tumor inoculation: cultivate HT-29 human colon rectal adenocarcinoma cell (from going down to posterity 4 from active redundancy VP-Stock 325) in the RPMI1640 cell culture medium, described medium is added 10%FBS and penicillin-streptomycin (50IU/mL ultimate density).By the trypsin acting collecting cell, in HBSS, clean twice, and counting.Then, cell is suspended among the HBSS once more, and transfers to and comprise 2x10 ⁸The final volume of cell/mL.Before the inoculation, with alcohol wiping cutting part fully, and open abdomen exposes the caecum wall.Insert a needle into the caecum wall surface, inject 5 μ L cell (1x10 herein ⁶Cell).

Material: following material obtains from each supplier.

Sterile saline solution (0.9%NaCl (aq)) is from Baxter Healthcare Australia, Old Toongabbie, and NSW, Australia obtains.Cremophor EL is from Sigma-Aldrich Pty Ltd, Castle Hill, and NSW, Australia obtains.The 5 FU 5 fluorouracil clinical preparation of the colourless liquid of clarification obtains from Mayne Pharma Pty Ltd.RPMI1640 cell culture medium, FBS and HBSS are from Invitrogen Australia Pty Ltd, Mt Waverley, VIC, Australia's acquisition.Penicillin-streptomycin and trypan blue be from Sigma-Aldrich, Castle Hill, and NSW, Australia obtains.The human knot of HT-29 rectal adenocarcinoma cell derives from American type culture collection (ATCC), Rockville, MD, USA.

Compound preparation and administration: according to following timetable administration cremophor EL: salt solution (1: 9, v/v; Vehicle Control), N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide or 5 FU 5 fluorouracil (compound contrast):

Group	Compound	Dosage (mg/kg)	Treatment regularly	Drug treatment
Group	Compound	Dosage (mg/kg)	Treatment regularly	Drug treatment	??1	Vehicle Control	??10mL/kg	Once a day, 21 days (the 0th day to the 20th day)	Once a day, 19 days (the 0th day to the 18th day)
??2	Compd A	??0.2mL@??10mL/kg＝2mg/kg	(the 0th day to the 20th day) once a day, 21 days	Once a day, 19 days (the 0th day to the 18th day)	??1	Vehicle Control	??10mL/kg	Once a day, 21 days (the 0th day to the 20th day)	Once a day, 19 days (the 0th day to the 18th day)
??2	Compd A	??0.2mL@??10mL/kg＝2mg/kg	(the 0th day to the 20th day) once a day, 21 days	Once a day, 19 days (the 0th day to the 18th day)	??3	Compd A	??1.0mL@??10mL/kg＝10mg/kg	Once a day, 21 days (the 0th day to the 20th day)	Once a day, 19 days (the 0th day to the 18th day)
??4	Compd A	??5.0mL@??10mL/kg＝50mg/kg	Once a day, 21 days (the 0th day to the 20th day)	Once a day, 19 days (the 0th day to the 18th day)	??3	Compd A	??1.0mL@??10mL/kg＝10mg/kg	Once a day, 21 days (the 0th day to the 20th day)	Once a day, 19 days (the 0th day to the 18th day)
??4	Compd A	??5.0mL@??10mL/kg＝50mg/kg	Once a day, 21 days (the 0th day to the 20th day)	Once a day, 19 days (the 0th day to the 18th day)	??5	5 FU 5 fluorouracil	??7.5mL@??10mL/kg＝75mg/kg	Once in a week, 21 days (the 0th, 7 and 14 day)	Once in a week, 3 weeks (the 0th, 7 and 14 day)
Group	Compound	Dosage (mg/kg)	Treatment regularly	Drug treatment	??5	5 FU 5 fluorouracil	??7.5mL@??10mL/kg＝75mg/kg	Once in a week, 21 days (the 0th, 7 and 14 day)	Once in a week, 3 weeks (the 0th, 7 and 14 day)
Group	Compound	Dosage (mg/kg)	Treatment regularly	Drug treatment	??6	" absorption ratio " contrast	There is not treatment	??-	??-

At cremophor EL: salt solution (1: 9, v/v) in preparation N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide.Prepare stock solution weekly, and preserve down at 4 ℃.Prepare to drug solns the every day in administration.With 2,10 and the dosage of 50mL/kg, administration volume with 10mL/kg, continue 21 days (the 0th day to the 20th day) oral administration N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide once a day.

The mouse in the 6th group (" absorption ratio " contrast) is not applied treatment.The 7th day (inoculating back 21 days) of research, kill mouse, and expose colon to measure the tumour size in " absorption ratio " and the caecum wall.

Measurement of tumor: when expiration date of research when after death excising each caecum and tumour, measure caecum and tumour weight in wet base.When research finishes, intactly weigh from all mouse excision caecums of each seminar and with tumour.Then from the caecum tumor resection and weigh.

DATA REASONING and sample acquisition time table

DATA REASONING	Timetable
DATA REASONING	Timetable	Body weight	For comprising 1-5 group, the 0th day, time (Monday, Wednesday and Friday) on every Wendesdays then, and the expiration date of research.
Caecum weight and tumor weight	Excise caecum and tumour from each mouse that comprises the 1-5 group during end.	Body weight
Caecum weight and tumor weight		Sample is gathered
Caecum and tumour	Whole mouse from research the 6th group (" absorption ratio " contrast) after death in the 7th day.	Sample is gathered
Caecum and tumour		Caecum and tumour	From the research expiration date after death the whole mouse that comprise 1-5 group and die from research during mouse.
Liver	From the research expiration date after death the whole mouse that comprise 1-5 group and die from research during mouse.	Caecum and tumour

Data acquisition and calculating: before image data, use at once bar code reader (LabMax I, DataMars, Switzerland) scan each animal responder (Bar Code Data Systems Pty Ltd, Botany Bay, NSW).With identical hand-held caliper (Absolute Digimatic Model CD-6 " CS, Mitutoyo Corporation Japan) obtains all measured values.Use Pendragon Forms 4.0 (

Software Corporation, Libertyville, IL U.S.A.) as transmitting software, makes data sync with vivoPharm ' s security relationship database.AIDAM v2.4 is used for data report and data computation

The significance of use two sample t-to check to be determined at research the 0th day body weight change to the treatment group between the expiration date.In the group of 2 and 50mg/kg N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide treatment, because excessive body weight loss therapy discontinued.In these groups, use two sample t-to check to be determined at research the 0th day between the final treatment day and in the significance of the last treatment of research day body weight change to the treatment group between the expiration date.Not under the situation by test of normality or homogeneity test of variance, carry out the Mann-Whitney rank test in data.

When research finishes, to caecum weight and tumor weight data carry out one-way analysis of variance (ANOVA) (all paired multiple comparison methods (All Pairwise Multiple Comparison Procedure) and with the control group multiple ratio).Not under the situation by test of normality, before carrying out the method, convert numerical value to natural logrithm in data.。

The P value is lower than 0.05 and is considered to have significance.

Observe: comprise in all seminar and measure the average weight loss in the vehicle Control group.Comprise in the vehicle Control in all seminar, observe the sign (skin elasticity disappearance) of diarrhoea and dehydration.Early stage serious body weight loss causes accepting lowest dose level (2mg/kg) and maximum dose level (50mg/kg) N-(S)-(3 in the 9th day and the 7th day respectively in research during studying, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-treatment in the group of 1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide stops.Because accepting 10mg/kg N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) in the group of cyclopropane-1-sulfonamide, body weight loss is more not serious, so as per the schedule this group is implemented all treatments.For this group and 5 FU 5 fluorouracil treatment group, when research finished, the average weight loss had significance.

Though in inoculation back 21 days, the absorption ratio of HT-29 tumour was 100% in " absorption ratio " group, the size of these tumours is far below desired value.This may cause average caecum and tumor weight there was no significant difference between N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide treatment group and the vehicle Control group.5 FU 5 fluorouracil does not have influence to the weight of caecum and HT-29 tumour yet.

Measured body weight result (± SEM) (final treatment day and the research Close Date)

Do not collect the weight data of the 6th group (" absorption ratio " contrast).Whether kill this group mouse in the 7th day (postvaccinal the 21st day) of research comes the visual assessment tumor growth abundant for the purpose of this research.

Because the body weight that the mouse loss is excessive, the 2nd group of (2mg/kg N-(S)-(3 of interruption in the 9th day in research, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) treatment cyclopropane-1-sulfonamide), the 4th group of (50mg/kg N-(S)-(3 of interruption in the 7th day in research, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide) in treatment.Remaining set is all accepted all regular treatments during studying.

Shown in Figure 18 the average tumor weight of each group.The average tumor weight of each group only comprises that survival is to research mouse the most all day.The numerical value of dead mouse is not included in the mean value of calculating during studying.

Caecum weight and tumor weight data

The shade lattice represent to gather the sample of the mouse during dying from research.The mean value as calculated of caecum weight and tumor weight does not comprise these values.Trend shows that after 10mg/kg N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide treatment, the data of HT-29 tumour and caecum weight reduce.

Embodiment 117: have the tumor growth delay in the nude mice of human A375 melanoma xenograft

Use 6 groups of (n=9) tumor-bearing mices.Control group comprise through port lumen feeding (po) continue once a day 14 days (qd x14) accept 10% cremophor EL/saline vehicle mouse and with 30mg/kg every other day continue 5 times (qod x5) by tail vein injection (iv) administration as the another mouse of the taxol of reference medicament.4 experimental group are accepted 25mg/kg or 50mg/kg, qd x14, perhaps 12.5 or 25mg/kg, the oral N-(S)-(3 of bid x14,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide (" compd A ").Estimate treatment results by TGD, it is defined as with control group and compares, and reaches the difference of the time intermediate value of terminal point gross tumor volume in the treatment group.Estimate toxicity by measured body weight and clinical observation.

Animal: the 1st day of research, female athymic nude mice (nu/nu, Harlan) be 10-11 week greatly, and body weight (BW) scope is 19.3 to 25.5g.With these animals of purpose feed water (reverse osmosis, 1ppm Cl) and NIH 31Modified and Irradiated Lab This feed is made up of 18.0% thick protein, 5.0% crude fat and 5.0% raw fiber.Under 12 hours periodicity of illuminations, under 21-22 ℃ (70-72) and 40-60% humidity, raise in the case (microisolator), at ALPHA-through radiation in static little isolation

Bed-o '

Raise mouse on the laboratory animal bedding and padding.Follow management of laboratory animal and guide for use (Guide for Care and Use of Laboratory Animals) suggestion about restriction, animal feeding management, surgical procedure, feed and liquid regulation and veterinary care.

Tumour is implanted: transplant by the series in the athymic nude mice, begin heterograft from the human melanoma tumour of A375.With A375 tumor fragment (～1mm ³) subcutaneous implantation respectively tests in the right flank of mouse, and when mean size near 100-150mm ³The time, the monitoring tumor growth.After 13 days, be appointed as research the 1st day, animal is divided into 6 groups, every group is 63 to 221mm by each gross tumor volume scope ³And the group mean tumour volume is 125.3 to 125.9mm ³9 mouse (reducing) from 10 form.Use following formula to calculate gross tumor volume:

The length (mm) of width of w=A375 tumour (mm) and l=A375 tumour wherein.

Material: with the concentration of 5mg/mL with N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide is dissolved in 10% cremophor EL in the salt solution, is accompanied by ultrasonic processing, jolts and is heated to 35 ℃ and come hydrotropy.5mg/mL solution is as the drug solns of giving of 50mg/kg treatment, and is used for the drug solns of giving of 25mg/kg and 12.5mg/kg treatment by the serial dilution preparation.Under the room temperature lucifuge, storage reached for 1 week to drug solns.

By at 5% ethanol, 5% cremophor EL in 5% D/W (D5W), the 30mg/mL stock solution is diluted to the taxol (NPI) that 3mg/mL preparation uses every day gives drug solns.Dose of paclitaxel is 30mg/kg.

Treatment: following table is depicted as therapeutic scheme.

The 1st group mouse, through port lumen feeding (po) is accepted 14 doses of every days the carrier be made up of 10% cremophor EL in the salt solution (qd x14), and as the contrast of tumor development.With 30mg/kg, every other day one time 5 doses (qod x5) to the 2nd treated animal intravenous (iv) administration as the taxol of reference reagent.According to following each timetable, the mouse of 3-6 group is accepted oral N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide: 50mg/kg, qd x14; 25mg/kg, at twice, 14 day every day was at the 1st day and last 1 day administration single dose (bid x14); 25mg/kg, qd x14; And 12.5mg/kg, bid x14.With 0.2mL volume/all agent of 20g body weight administration, and by the body weight adjustment of animal.

Terminal point: the use caliper is measured the tumour in all groups semiweekly.When the tumour of each animal reaches terminal point size 2000mm ³The time, perhaps in (the 60th day) the most all day of research, whichever earlier extremely makes each animal euthanasia.Calculate the time (TTE) that each mouse reaches terminal point from following equation:

Wherein b is that straight line intercept and m are the slopes of straight line, and the linear regression of the tumor growth data group that described straight-line pass log transforms obtains.

The data group comprises observes the first time that surpasses research terminal point volume, and three observations continuously before reaching the terminal point volume at once.Specify the TTE value of the last day that equals to study for the animal that does not reach terminal point.Be not included in the TTE calculating (with all further analyses) owing to accident (NTRa) or owing to unknown cause (NTRu) is classified as the dead animal of NTR (non-treatment correlation).The TTE value that appointment classifies as the dead animal of TR (treatment correlation) death or NTRm (because of the non-treatment correlation due to shifting) equal death day.

(TGD) determines treatment results from tumor growth delay, and it is defined as with control group and compares, and reaches the increase of time (TTE) intermediate value of terminal point: TGD=T-C in the treatment group, expresses with fate, perhaps is expressed as the percentage of the TTE intermediate value that accounts for control group:

Wherein: the TTE intermediate value of T=treatment group, the TTE intermediate value of C=control group (the 1st group).

Treatment may cause that the part of tumour in the animal is degenerated (PR) or degeneration (CR) fully.In PR response, in research process, the gross tumor volume of three continuous measurements be the 1st day volume 50% or littler, and the gross tumor volume that one or many is measured in measuring for these 3 times is equal to or greater than 13.5mm ³In the CR response, in research process, the gross tumor volume of three continuous measurements is less than 13.5mm ³When research finished, the animal with CR response additionally was classified as no tumor survival person (TFS).Monitoring and record tumour regression.

Side effect:, weigh for twice weekly afterwards preceding 5 day weighing every day animal of research.Observe the obvious sign of the side effect any bad, that treatment is relevant of mouse continually, and when observing, write down clinical sign.Acceptable tolerance is defined as the test period group average weight loss in weight and is lower than 20%, and treats dead no more than 1 of correlation in the animal groups.Any dosage regimen that does not satisfy these standards is considered to exceed maximum tolerated dose (MTD).If be attributable to treat side effect through clinical sign and/or postmortem proof, then death is classified as TR, if perhaps during administration or in 10 days of administration in the end because unknown cause, then death can be classified as TR.If do not have death and the relevant evidence of treatment side effect, then death is classified as NTR.

The statistics and the analysis of drawing: use sequence check to analyze the significance of difference between the TTE value of treatment group and control group.At significance P=0.05, carry out two tail statistical analysis.

The intermediate value tumor growth curve shows that group gross tumor volume intermediate value is the function of time.When animal because tumour size or TR death when withdrawing from research, comprise the final gross tumor volume of animal of record and the group gross tumor volume intermediate value that data are used to calculate later time point.50% animal in group is owing to after tumour progression withdraws from research, block curve.Making Kaplan-Meier figure represents the percentage as residue animal in the research of the function of time, and the use data group identical with sequence check.Prism (GraphPad) Windows 3.03 is used for all diagrams and statistical analysis.

The treatment response is summed up

A375 growth of tumor in the control mice (the 1st group): animals received 10% cremophor EL/saline vehicle of the 1st group, po, qd x14.The tumour of control mice grows to 2000mm progressively ³Terminal point volume, TTE intermediate value are that 22.8 days (having determined the T-C of maximum possible in 37.1 days research) or TGD are 163%.

Effect with taxol (the 2nd group) treatment: to the taxol of the 2nd animals administer as reference reagent, 30mg/kg, iv, qod x5.9 whole animals reach the gross tumor volume terminal point.Tumor growth is parallel, and the contrast control group moves right slightly.The TTE intermediate value is 28.8 days, and corresponding to 26%TGD, the result has significance through Time-Series analysis (table 2, P=0.0088 G1vs.G2).No tumour regression is relevant with paclitaxel treatment.

Through N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) effect of cyclopropane-1-sulfonamide (3-6 group) treatment: the 3-6 winding is subjected to the N-(S)-(3 as monotherapy, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide oral administration.According to the qdx14 timetable to the 3rd treated animal administration 50mg/kg.9 tumours in the group reach the volume terminal point.At 1-10 days, the gross tumor volume intermediate value of group experienced the net change of a little, continued to increase with research afterwards.An animal experience tumour PR.The TTE intermediate value is 27.5 days, and perhaps 21%TGD is remarkable result (P=0.0054 G1 vs.G).

The 4th group animal is accepted 25mg/kg N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide according to bid x14 timetable.At the 60th day, 4 residues in the group in 9 animals all were TFS.In the previous day that research finishes, the tumour of 2/9 animal in addition reaches the volume terminal point.This group has 4/9PR, 5/9CR and 4/9TFS.At initial several days of research, the gross tumor volume intermediate value began to reduce, and continues about 30 days.Tumor regrowth in 5/9 animal causes originating in the reproduction of about the 32nd day tumor growth intermediate value, and continues to the research end.This group TTE intermediate value is 59.9 days, represents maximum possible 163%TGD (P＜0.0001, Table A 1).

The 5th group of mouse also accepted 25mg/kg N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide, but according to more unstrained qd x14 timetable.Whole 9 animals of the 5th group reach the gross tumor volume terminal point, no tumour regression.Tumor growth closely changes along the tumor growth track of control group.The TTE intermediate value is 25.6 days, or 12%TGD, is non-significant result (P=0.0662 G1 vs.G5).

According to bid x14 timetable, to the 6th treated animal administration 12.5mg/kg N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide.All tumours in the group all reach the volume terminal point.As the 4th group, early stage what study, the 6th group gross tumor volume intermediate value reduces, but this reduction has only continued about 9 days, and relevant with single PR response.Finish from the 10th day to studying, gross tumor volume increases.The TTE intermediate value of this group is 27.5 days, corresponding to the 21%TGD with significance (P=0.0424 G1 vs.G6).

In a word, with once a day with twice oral administration N-every day (S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide all demonstrates the dosage correlation antitumor activity to human A375 melanoma xenograft.At the TGD size that produces and the quantitative aspects of target response, every day, twice administration was better than administration once a day.Therefore, the antitumor activity of N-(S)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide be dose dependent also be that timetable is dependent.

Embodiment 118: the activity that suppresses subcutaneous COLO 205 human colon's cancer xenograft

Animal: the 1st day of research, female athymic nude mice (nu/nu, Harlan) be 12-13 week greatly, and body weight (BW) scope is 18.3 to 27.3g.With these animals of purpose feed water (reverse osmosis, 1ppm Cl) and NIH 31Modified and Irradiated Lab

This feed is made up of 18.0% thick protein, 5.0% crude fat and 5.0% raw fiber.Under 12-hour periodicity of illumination, under 21-22 ℃ (70-72) and 40-60% humidity, raise in the case in static little isolation, at ALPHA-through radiation

Bed-o '

Raise mouse on the laboratory animal bedding and padding.Follow the suggestion of management of laboratory animal and guide for use about restriction, animal feeding management, surgical procedure, feed and liquid regulation and veterinary care.

Tumour is implanted: begin heterograft from COLO 205 human colon's cancer cells.In 10% heat-killed hyclone, 100 units/mL novocillin, 100 μ g/mL streptomycin sulphates, 0.25 μ g/mL amphotericin B and 25 μ g/mL gentamicins, 2mM glutamine, 1mM Sodium Pyruvate, 10mM HEPES and 0.075% sodium bicarbonate, cultivate tumour cell.At 37 ℃, at 5%CO ₂In the atmosphere of 95% air, in the incubator of humidification, cultured cell in tissue culture flasks.In the day of tumour cell implantation, during logarithmic growth, collect Colo 205 cells, and with 5x10 ⁶The concentration of cell/mL is suspended in the 50%Matrigel matrix (BD Biosciences) among the PBS once more.Each tests the 1x 10 that mouse is implanted subcutaneously in the acceptance of right flank place ⁶Individual Colo 205 cells, and when mean size near 80 to 120mm ³The time, the monitoring tumor growth.After 14 days, be appointed as research the 1st day, animal is divided into 8 groups (n=9), each gross tumor volume scope is 63 to 196mm ³And the group mean tumour volume is 118 to 119mm ³Use following formula to calculate gross tumor volume:

The length (mm) of the width (mm) of w=COLO 205 tumours and l=COLO 205 tumours wherein.Suppose that 1mg is equivalent to 1mm ³Gross tumor volume, can estimate tumor weight.

Material: be dissolved in 100% cremophor EL by compound, prepare the drug solns of giving of fresh compd A every day, then with 10 times of physiological saline dilutions with requirement.In order to provide 25,50,100 or the dosage of 200mg/kg respectively in 10mL/kg administration volume, final administration solution concentration is 2.5,5,10 or 20mg/mL.In the every day of administration, in the carrier of forming by 5% cremophor EL among 5% ethanol and the 90%D5W (5%EC carrier), prepare fresh taxol (Natural Pharmaceuticals, Inc.).

Treatment: following table is depicted as therapeutic scheme.

The 1st winding is subjected to preparations carrier (10% cremophor EL in the salt solution), and as the tumor growth control group.The 2nd winding is subjected to the reference drug taxol according to its suitableeest timetable administration (30mg/kg i.v.qod x5) in the nude mouse.3-6 group accepts 25,50,100 and the compd A with p.o.qd x14 administration of 200mg/kg dosage respectively, because toxicity was interrupted the 6th group administration (200mg/kg) after 6 days.Adjust all dosage (0.2mL/20g body weight) according to the weight of animal.

Terminal point: use caliper to measure tumour semiweekly.When the tumour of each animal reaches predetermined terminal point size 2000mm ³The time, perhaps in (the 74th day) the most all day of research, whichever earlier extremely makes each animal euthanasia.But, reaching the about 800mm of size ³The time, control tumor does not demonstrate the logarithmic growth feature.Therefore, terminal point tumour size 800mm ³Be used to analyze tumor growth delay (TGD).Calculate the time (TTE) that each mouse reaches terminal point from following equation:

Wherein b is that straight line intercept and m are the slopes of straight line, and the linear regression of the tumor growth data group that described straight-line pass log transforms obtains.The data group comprises observes the first time that surpasses research terminal point volume, and three observations continuously before reaching the terminal point volume at once.The last day of specifying the TTE value of the animal do not reach terminal point to equal to study.Be not included in the TTE calculating (with all further analyses) owing to accident (NTRa) or owing to unknown cause (NTRu) is classified as the dead animal of NTR (non-treatment correlation).The TTE value that appointment classifies as the dead animal of TR (treatment correlation) death or NTRm (because of the non-treatment correlation due to shifting) equal death day.

Estimate treatment results by tumor growth delay (TGD), it is defined as with control group and compares, and reaches the increase of the time intermediate value of terminal point (TTE): TGD=T-C in the treatment group, represents with fate, perhaps is expressed as the percentage of the TTE intermediate value that accounts for control group:

Wherein: the TTE intermediate value of T=treatment group, the TTE intermediate value of C=control group.

Control group is designated as the 1st group of mouse.

Treatment may cause that the part of tumour in the animal is degenerated (PR) or degeneration (CR) fully.In PR response, in research process, the gross tumor volume of three continuous measurements be the 1st day volume 50% or littler, and the gross tumor volume that one or many is measured in measuring for these 3 times is equal to or greater than 13.5mm ³In the CR response, in research process, the gross tumor volume of three continuous measurements is less than 13.5mm ³Monitoring and record are degenerated and are responded.

Side effect:, weigh for twice weekly afterwards preceding 5 day weighing every day animal of research.Observe the obvious sign of the side effect any bad, that treatment is relevant of mouse continually, and when observing, write down the clinical sign of toxicity.The loss of group average weight was lower than 20% during acceptable toxicity was defined as research, and treated dead no more than 1 of correlation (TR) in the animal of 10 treatments, caused any dosage regimen of bigger toxicity to be considered to exceed maximum tolerated dose (MTD).If be attributable to treat side effect through clinical sign and/or postmortem proof, then death is classified as TR, if perhaps during administration or in 10 days of administration in the end because unknown cause, then death can be evaluated as TR.If do not have death and the relevant evidence of treatment side effect, then death is classified as NTR.Measure the side effect of monitoring animal by frequent observation and BW.BW changes not remarkable, and except that the 6th group, all treatments all are to tolerate acceptably.Once a day, the 200mg/kg compd A of 6 p.o. dosage caused 1 TR death at the 7th day that estimates, and at the 8th day, caused other 2 TR death.Whole mouse of the 6th group demonstrate the clinical symptoms of toxicity, comprise protuberance posture, hypoactivity and loose stool.

The intermediate value tumor growth curve shows that the group gross tumor volume intermediate value of logarithmic scale is the function of time.Because research is withdrawed from tumour size or TR death, comprise that the final gross tumor volume of animal of record and data are used to calculate the group gross tumor volume intermediate value at later time point when animal.50% animal in group is because after tumour progression withdraws from research, perhaps behind the 2nd TR, blocks curve in group.Make Kaplan-Meier figure represent to study in the residue animal percentage over time, and the use data group identical with sequence check.Prism (GraphPad) Windows 3.03 is used for all diagrams and statistical analysis.

The treatment response is summed up

COLO 205 growth of tumor in control mice (the 1st group)

The 1st group tumour demonstrates heterophyiesis growth slowly.The tumour of the 1st group of control mice of 7/9 vehicle treated reaches 800mm ³The gross tumor volume terminal point, and when research finishes, remain two mouse.The 1st group TTE intermediate value is 41.0 days, and therefore in this research of 74 days maximum possible TGD be 33.0 days (80%).

Effect (the 2nd group) with taxol treatment

At the 74th day, remaining under study for action 8 the 2nd group of mouse (n=9) of accepting paclitaxel treatment, it has MTV143mm ³On this possible TGD (33.0 days or 80%) and the statistics significant active (P=0.002) corresponding to maximum.5 PR responses have been write down.The intermediate value tumor growth curve shows the reduction until the 19th day MTV, slight variations subsequently, until the 47th day when tumor growth recovers.

Effect (group 3-6) with the compd A processing

3rd, 4,5 groups of TTE intermediate values that produce were respectively 47.9,59.1 and 74.0 days.The the 3rd and 4 group of sequence check result with non-significance, and the 5th group of sequence check check reaches edge significance (P=0.058).These treatments produce the degeneration of dose dependent quantity, and still, 74-days survivors' of degeneration respond style (PR vs.CR) and every group quantity and dosage are uncorrelated.The intermediate value tumor growth curve shows, and is active similar for 3 kinds of dosage levels in early stage (until the 29th day) of research, follows dose dependent delay by tumor regrowth.The 6th group produces 3 routine TR death, and stops administration after the 6th day.Therefore, think that the 200mg/kg treatment surpasses MTD, and can not estimate TGD.

Compd A demonstrates the dose dependent activity to COLO 205 colon cancer xenograft.When in the 25mg/kg administration, compd A demonstrates 3% TGD.At 50mg/kg, compd A produces 46% TGD.Tolerate the 100mg/kg treatment acceptably, and, cause the possible TGD of maximum in test, have the degeneration response of similar amt as paclitaxel treatment.The 200mg/kg treatment produces 3/9 routine TR death, and exceeds MTD.The contrast taxol for compd A, is observed the more significant initial reduction of lotus knurl; But the duration of effect is shorter.Contrast contrast, 25 and the 50mg/kg group in, initial tumor regrowth makes progress more quickly, and when finishing to research, the tumor regrowth that MTV approaches to contrast.The 100mg/kg treatment does not demonstrate this fast rapid regeneration, and still, the tumor regrowth of contrast taxol demonstrates tumor growth faster really.

Embodiment 119: the human clinical trial

To in suffering from (chemo-naive) late period of accepting chemotherapy first or the patient who shifts cancer of pancreas, carry out safety at random, double blinding, open label, historic contrast, single packet/human I clinical trial phase of validity with compd A contrast placebo.

The primary and foremost purpose of this research is safety and the tolerance of assessing compound A.Less important result estimates with the speed of response, clinical benefit and tumour after the compd A treatment to dwindle.In addition, this research will be designed to estimate the time of progression of disease and total survival rate of Pancreas cancer patients.And, estimate pharmacodynamics in the tumor vessel parameter by DCE-MRI and change (comprise as CBF, blood volume, reach time of ROC experimenter's characteristic working curve peak value).

And, will use biological marker for example MEK1 make the result related with MEK2 genetics polymorphism with the haemocyanin group.This also will allow to measure the resection rate of treatment back tumour and the MTD of assessing compound A.

During studying, with different dosed administration compd As, 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 criteria of this research will be based on following factor:

On the histology/the unresectable or unresectable cancer of pancreas in edge in local late period confirmed on the pathology, and the evidence of non-metastatic disease.

Based on evaluation (EUS described in appendix F), be diagnosed as the cancer of pancreas that to cut local late period by two-phase CT scan and/or EUS (EUS).

In preceding 14 days of agreement treatment registration, according to RECIST and the disease that can measure by two-phase CT scan gained result.

Through the two-phase computerized tomography, the tumour size is more than or equal to 2cm.

In 14 days of registration, put down in writing suitable organ dysfunction: absolute neutrophil cell number＞1500/mm3 by following evidence; Platelet count 100,000/mm3; Haemoglobin ³9gm/dL need not blood transfusion in preceding 4 weeks; 1.5 times of total bilirubin≤upper limits of normal value (ULN); Aminotransferase (AST and/or ALT)≤2.5x ULN; (patient who accepts the treatment of medicament such as warfarin or anticoagulant heparin will be allowed to participate in normal limits for PT (or INR)≤1.5x ULN and aPTT; For the patient who accepts warfarin, according to the qualification of local nursing standard, evaluation is at least weekly monitored closely, be stable until INR based on the measured value under predose; Creatinine clearance＞the 60ml/min that uses the Cockcroft-Gault formula to calculate.

Culling level comprises: register in preceding 6 months, treat with compd A in advance; Invaded the clinical evidence (as putting down in writing) of DM by endoscopy or EUS by tumour; Minor surgery operation (as fine needle aspiration biopsy or needle biopsy) in 14 days of research registration; In 21 days of research registration, big operation, tangible traumatic damage or serious not healing of wound, ulcer or fracture; In research 6 months before the drug administration, below any: angina pectoris (originating in nearest 3 months) or myocardial infarction, the congestive heart failure of serious/unsettled angina pectoris when static (angina pectoris symptom), new outbreak, need the cardiac ventricles arrhythmia cordis of antiarrhythmic therapy; In in the past 6 months, the medical history of thrombosis or embolism incident is cerebrovas-cularaccident or transient ischemic attack for example; The medical history of aneurysm or arteriovenous malformation; Known human immunodeficiency virus (HIV) infects or chronic hepatitis B or chronic hepatitis C; The active severe infections clinically that has that is higher than 2 grades of CTCAE; In 4 weeks of research registration, accept any research medicament; Although with through best medical supervision, shrink and still press greater than 150mmHg or diastolic pressure still greater than the uncontrolled hypertension of 90mmHg definition; In 4 weeks of research registration, the lung that is higher than 2 grades of CTCAE is lost blood/bleeding episode; In 4 weeks of research registration, any other that is higher than 3 grades of CTCAE lost blood/bleeding episode; The proof of hemorrhagic diathesis or coagulopathy or medical history; With aspirin or long-term treatment every day of other nonsteroidal and-inflammatory drugs; Use St. john's wort (St.John ' s Wort), rifampin, ketoconazole, Itraconazole, Ritonavir or grapefruit juice; Known or suspect to compd A allergy; Hinder the patient to swallow any patient's condition of the ability of whole pill; Any malabsorption problem; Acute or the chronic medical science that other are serious or the psychology patient's condition, the laboratory abnormalities that the risk relevant with participating in studying material or research drug administration increased, perhaps may The Study of Interference result's the laboratory abnormalities of explanation, and can make the patient be not suitable for participating in the laboratory abnormalities of this research according to researcher's judgement; The medical history of collagen vascular diseases; Accept any contraindication of magnetic resonance imaging.

Embodiment 120: the human clinical trial

Suffering from late period or shifting among the patient who accepts chemotherapy first of cancer of the stomach, double-blind study ground, open-label ground, historical control ground, single packet randomly,, use compd A, with with embodiment 117 described identical modes, carry out the human I clinical trial phase of safety/usefulness, except the patient who registers suffers from lymphoma, stomach stromal tumor or carcinoid of stomach knurl after diagnosing.

Embodiment 121: the pawl oedema (CPE) that carrageenan causes in the rat

The oral administration compd A (6,20﹠amp; 60mg/kg) or Indomethacin (3mg/kg), behind the 2hr, 1% carrageenan supensoid agent is injected in the right back vola of male Sprague-Dawley rat (N=6/ treatment group).Behind the 3hr, estimate corpus unguis by plethysmography and amass and measure the rear solid end oedema.The rear solid end oedema reduces by 30% or the bright significant acute anti-inflammatory activity of multilist more.Use Indomethacin (Indo) as positive control drug.Be the increase of each treatment group median claw volume shown in Figure 22, this shows that in all dosage groups, the oral administration compd A causes significant anti-inflammatory activity in the rat carrageenan pawl edema model.

Embodiment 122: the rat assist agent arthritis inflammation is measured

In the arthritis model that rat adjuvant causes, Freund's complete adjuvant (CFA) is injected in the right back pawl of rat and causes the symptom that is similar to rheumatoid arthritis among the mankind.With 2,6 and continuous 5 days of 20mg/kg oral administration compd A.In addition, with 5mg/kg oral administration dexamethasone 5 days.At the 1st day and the 4th day, with 10mg/kg by hypodermic injection administration Enbrel.At the 1st day, after the administration first time 1 hour, CFA is injected in the right back pawl.For acute stage, measured with respect to contrast at the 1st day and the 5th day through vehicle treatment, to the inhibition % of right back pawl swelling, and, measured with respect to contrast, to the inhibition % of left back pawl swelling through vehicle treatment at the 14th day and the 18th day for period of delay.When swelling exists in fore paw, afterbody, nose or the ear, polyarthritis is marked.

Figure 23 A is with to be different treatment groups shown in Figure 23 B suppress % with respect to the swelling of contrast.In acute stage and period of delay, compd A all shows the remarkable reduction of swelling under 20mg/kg.For polyarthritis scoring, fore paw of all 6 animals in the vehicle treatment group and the equal swelling of afterbody.For 20mg/kg compd A group, 2 not swelling of fore paw in 6 animals, 4 not swelling of afterbody in 6 animals.For enbrel group, all animals all do not avoid fore paw swelling, 3 not swelling of afterbody in 6 animals.

Embodiment 123: the inhibition of the arthritis that collagen antibodies causes in the mouse (CAIA)

At the 0th day, to the collagen antibodies mixed liquor (Chondrex) of male Balb/c mouse (N=8/ treatment group) intravenous injection (tail vein) 2mg.0-4 days, oral administration RDEA119 (1,3﹠amp; 10mg/kg QD) or dexamethasone (1mg/kg QD), and at the 1st day and the 3rd day, hypodermic injection Enbrel.At the 3rd day, to except reception test first

All mouse outside the animal give LPS the intraperitoneal injection of (50 μ g).Determine the arthritis score of all four limbs, and (the highest scoring 16) as shown in Figure 24.Write down the significant anti-inflammatory activity of all test substances and reference medicine.Use Enbrel and dexamethasone as positive control.

Embodiment 124: the cells in vivo proliferation assay

Be used for measuring the method for the cancer cell cell proliferating number of handling through the MEK kinases inhibitor, be methods known in the art, and be described in Kenny, L.M. etc., Positron Emission Tomography (PET) Imagingof Cell Proliferation in Oncology, Clinical Oncology, among the 16:176-185 (2004), it intactly quotes adding herein.Detect MEK kinases inhibitor (for example compd A) in the body and measure their effect cancer cell multiplication.This research of 50 patient's voluntary participations, they all suffer from the cancer of pancreas that is in the similar cancer development phase.Combination to 25 patient's administration compd As.To last 25 patient's administration placebos.To each patient's administration daily dose, continue 14 days, with radiolabeled tracer (for example fluoro-2-deoxidation of mark-DF-glucose (FDG)) coupling.

Handle after 14 days, the doctor through training uses atraumatic positron emission tomography (PET) imager to detect tumor cell proliferation.And the doctor through training can measure through the patient's of compd A and placebo treatment the tumour and the cell proliferating number of normal cell tissue.The result shows, the reduction of cell proliferating number between MEK kinases inhibitor (for example compd A) and placebo.This mensuration that cell proliferating number is measured in the tracer of usage flag and PET imaging is referred to herein as " cells in vivo enrichment procedure ".Other cells in vivo enrichment procedures are known in the art.

Similar analysis can be used to measure reducing of tumour size.

Embodiment 125: apoptosis is measured in the body

Detect mek inhibitor (for example compd A) in the body and determine its effect cancer cell-apoptosis.This research of 40 patient's voluntary participations, they all suffer from the cancer of pancreas that is in the similar cancer development phase.To 20 patient's administration compd As and to 20 patient's administration placebos.To each patient's administration daily dose, continue 14 days.

After 14 days, each patient will absorb the markd lipopolysaccharide binding protein of detectable coupling (LBP) reagent.According to WO/2006/054068 (it intactly quotes adding herein), then each patient is placed in the zone of scanner, scanner detects the medicament that is ingested that combines with dead cell.The dead cell number can be related with each patient's level of apoptosis.Can contrast the patient's of the patient of administration coupling medicine and administration single entities reagent level of apoptosis mutually, and with the administration placebo the same period group relatively.This mensuration of using lipopolysaccharide binding protein and scanner to detect level of apoptosis is referred to herein as " apoptosis method in the body ".

Embodiment 126: dissolution study

Capsule according to the inclusion compound of preparation described in above embodiment A.Use is used to measure USP＜711 of dissolution rate〉method obtains following dissolution data.

	The 1mg form	The 10mg form
	The 1mg form	The 10mg form	Time (min)	% discharges (%RSD)	% discharges (%RSD)
?15	??78(8.3)	?80(7.3)	Time (min)	% discharges (%RSD)	% discharges (%RSD)

	The 1mg form	The 10mg form
	The 1mg form	The 10mg form	?30	??82(7.1)	?87(9.2)
?45	??82(6.7)	?92(9.6)	?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)	?60	??88(6.3)	?92(7.2)

Claims

1. composition, it comprises and is selected from:

With

Compound.

2. the composition of claim 1, the 2-OH carbon on the wherein said compound is in the R configuration.

3. the composition of claim 1, the 2-OH carbon on the wherein said compound is in the S configuration.

4. the composition of claim 1, the S-isomer of the essentially no described compound of wherein said composition.

5. the composition of claim 1, the R-isomer of the essentially no described compound of wherein said composition.

6. the composition of claim 1, wherein said compound comprise the S-isomer that is less than 10% described compound.

7. the composition of claim 1, wherein said compound comprise the R-isomer that is less than 10% described compound.

8. the composition of claim 1, wherein said compound comprise the S-isomer that is less than 5% described compound.

9. the composition of claim 1, wherein said compound comprise the R-isomer that is less than 5% described compound.

10. the composition of claim 1, wherein said compound comprise the S-isomer that is less than 1% described compound.

11. the composition of claim 1, wherein said compound comprise the R-isomer that is less than 1% described compound.

Each composition during 12. aforesaid right requires, it comprises the compound that about 1-100mg has following structure:

13. the composition of claim 12, wherein said composition allow to improve the described compound of release.

14. the composition of claim 12, wherein said composition allow to continue to discharge described compound.

15. the composition of claim 12, wherein said composition allow to postpone to discharge described compound.

16. the composition of claim 12, wherein said compound exists with the amount of about 1-50mg.

17. the composition of claim 12, wherein said compound exists with the amount of about 1-10mg.

18. the composition of claim 12, wherein said compound exists with the amount of about 10-20mg.

19. the composition of claim 12, wherein said compound exists with the amount of about 20-40mg.

20. the composition of claim 12, wherein said compound exists with the amount of about 40-50mg.

21. each composition among the claim 1-15, it comprises: about 1-50mg has the compound of following structure

Wherein said composition allows to improve this medicine of release.

22. each composition among the claim 1-21, it also comprises microcrystalline cellulose.

23. each composition among the claim 1-22, it also comprises cross-linked carboxymethyl cellulose sodium.

24. each composition among the claim 1-23, it also comprises lauryl sodium sulfate.

25. each composition among the claim 1-24, it also comprises dolomol.

26. each composition among the claim 1-15, it comprises:

About 1mg structure is

Compound;

About 222.2mg microcrystalline cellulose;

About 12.0mg cross-linked carboxymethyl cellulose sodium;

About 2.4mg lauryl sodium sulfate; With

About 2.4mg dolomol.

27. each composition among the claim 1-15, it comprises:

About 10mg structure is

Compound;

About 213.2mg microcrystalline cellulose;

About 12.0mg cross-linked carboxymethyl cellulose sodium;

About 2.4mg lauryl sodium sulfate; With

About 2.4mg dolomol.

28. each composition among the claim 1-15, it comprises:

About 20mg structure is

Compound;

About 203.2mg microcrystalline cellulose;

About 12.0mg cross-linked carboxymethyl cellulose sodium;

About 2.4mg lauryl sodium sulfate; With

About 2.4mg dolomol.

29. each composition among the claim 1-15, it comprises:

About 40mg structure is

Compound;

About 183.2mg microcrystalline cellulose;

About 12.0mg cross-linked carboxymethyl cellulose sodium;

About 2.4mg lauryl sodium sulfate; With

About 2.4mg dolomol.

30. each composition among the claim 1-15, it comprises: the structure of about 0.4 weight % is

Compound; Pharmaceutically acceptable carrier or carrier with about 99.6 weight %.

31. the composition of claim 30, wherein said pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.

32. the composition of claim 31, wherein said microcrystalline cellulose account for about 92.6 weight % of described composition.

33. the composition of claim 32, it also comprises: cross-linked carboxymethyl cellulose sodium of about 5 weight %; The lauryl sodium sulfate of about 1 weight %; Dolomol with about 1 weight %.

34. each composition among the claim 1-15, it comprises: the structure of about 4.2 weight % is Compound; Pharmaceutically acceptable carrier or carrier with about 95.8 weight %.

35. the composition of claim 34, wherein said pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.

36. the composition of claim 35, wherein said microcrystalline cellulose account for about 88.8 weight % of described composition.

37. the composition of claim 36, it also comprises: cross-linked carboxymethyl cellulose sodium of about 5 weight %; The lauryl sodium sulfate of about 1 weight %; Dolomol with about 1 weight %.

38. each composition among the claim 1-15, it comprises: the about 2 weight % extremely structure of about 10 weight % are Compound; With pharmaceutically acceptable carrier or the carrier of about 98 weight % to about 90 weight %.

39. the composition of claim 38, wherein said pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.

40. the composition of claim 39, wherein said microcrystalline cellulose account for about 85 weight % of described composition to about 95 weight %.

41. the composition of claim 40, it also comprises: about 1 weight % is to cross-linked carboxymethyl cellulose sodium of about 6 weight %; About 0.1 weight % is to the lauryl sodium sulfate of about 2 weight %; With the dolomol of about 0.25 weight % to about 1.5 weight %.

42. each composition among the claim 1-15, it comprises:

About 1mg structure is

Compound;

About 222.2mg microcrystalline cellulose;

About 12.0mg cross-linked carboxymethyl cellulose sodium;

About 2.4mg lauryl sodium sulfate; With

About 2.4mg dolomol.

43. each composition among the claim 1-15, it comprises:

About 10mg structure is

Compound;

About 213.2mg microcrystalline cellulose;

About 12.0mg cross-linked carboxymethyl cellulose sodium;

About 2.4mg lauryl sodium sulfate; With

About 2.4mg dolomol.

44. each composition among the claim 1-15, it comprises:

About 20mg structure is

Compound;

About 203.2mg microcrystalline cellulose;

About 12.0mg cross-linked carboxymethyl cellulose sodium;

About 2.4mg lauryl sodium sulfate; With

About 2.4mg dolomol.

45. each composition among the claim 1-15, it comprises:

About 40mg structure is

Compound;

About 183.2mg microcrystalline cellulose;

About 12.0mg cross-linked carboxymethyl cellulose sodium;

About 2.4mg lauryl sodium sulfate; With

About 2.4mg dolomol.

46. each composition among the claim 1-15, it comprises: the structure of about 0.4 weight % is

47. the composition of claim 46, wherein said pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.

48. the composition of claim 47, wherein said microcrystalline cellulose account for about 92.6 weight % of described composition.

49. the composition of claim 48, it also comprises: cross-linked carboxymethyl cellulose sodium of about 5 weight %; The lauryl sodium sulfate of about 1 weight %; Dolomol with about 1 weight %.

50. each composition among the claim 1-15, it comprises: the structure of about 4.2 weight % is

Compound; Pharmaceutically acceptable carrier or carrier with about 95.8 weight %.

51. the composition of claim 50, wherein said pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.

52. the composition of claim 51, wherein said microcrystalline cellulose account for about 88.8 weight % of described composition.

53. the composition of claim 52, it also comprises: cross-linked carboxymethyl cellulose sodium of about 5 weight %; The lauryl sodium sulfate of about 1 weight %; Dolomol with about 1 weight %.

54. each composition among the claim 1-15, it comprises: the about 2 weight % extremely structure of about 10 weight % are

Compound; With pharmaceutically acceptable carrier or the carrier of about 98 weight % to about 90 weight %.

55. the composition of claim 54, wherein said pharmaceutically acceptable carrier or carrier comprise microcrystalline cellulose.

56. the composition of claim 55, wherein said microcrystalline cellulose account for about 85 weight % of described composition to about 95 weight %.

57. the composition of claim 56, it also comprises: about 1 weight % is to cross-linked carboxymethyl cellulose sodium of about 6 weight %; About 0.1 weight % is to the lauryl sodium sulfate of about 2 weight %; With the dolomol of about 0.25 weight % to about 1.5 weight %.

Each composition during 58. aforesaid right requires, it also comprises at least a pharmaceutically acceptable carrier.

(59.N--)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl-1-(2, the 3-dihydroxypropyl) the crystalline polymorph A of cyclopropane-1-sulfonamide, it demonstrates the x-ray diffractogram of powder that comprises the peak of being identified in the x-ray diffractogram of powder shown in Fig. 5 of at least 50%.

60. the crystalline polymorph A of claim 59, wherein said x-ray diffractogram of powder comprise the peak of being identified in the x-ray diffractogram of powder shown in Fig. 5 of at least 70%.

61. the crystalline polymorph A of claim 59, wherein said x-ray diffractogram of powder comprise the peak of being identified in the x-ray diffractogram of powder shown in Fig. 5 of at least 90%.

62. the crystalline polymorph A of claim 59, the x-ray diffractogram of powder shown in wherein said x-ray diffractogram of powder and Fig. 5 is basic identical.

63. each crystalline polymorph among the claim 59-62, wherein said crystalline polymorph have 143 ℃ the fusing point starting point of being about through determine with dsc method.

64. each crystalline polymorph among the claim 59-62, wherein said crystalline polymorph is anhydrous basically.

65. each crystalline polymorph among the claim 59-62, the essentially no solvent of wherein said crystalline polymorph.

66. pharmaceutical composition, it comprises among the claim 59-62 of effective dose each crystalline polymorph and at least a excipient or carrier.

(67.N--)-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) the crystalline polymorph A of cyclopropane-1-sulfonamide, it demonstrates and the essentially identical differential scanning calorimetric of the calorimetric of differential scanning shown in Fig. 6 figure figure.

68. the crystalline polymorph of claim 67, wherein said crystalline polymorph have 143 ℃ the fusing point starting point of being about through determine with dsc method.

69. the crystalline polymorph of claim 67 or 68, wherein said crystalline polymorph is anhydrous basically.

70. each crystalline polymorph among the claim 67-69, the essentially no solvent of wherein said crystalline polymorph.

71. pharmaceutical composition, it comprises among the claim 67-70 of effective dose each crystalline polymorph and at least a excipient or carrier.

72.N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) polymorph of cyclopropane-1-sulfonamide, it makes unbodied N-(3 by comprising, 4-two fluoro-2-(2-fluoro-4-iodophenyl amino)-6-methoxyphenyl)-the method preparation of the step of 1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide crystallization.

73. the polymorph of claim 72, wherein said crystallisation step comprises crystallization from the mixture of ethyl acetate and heptane.

74. the polymorph of claim 73, the ratio of the mixture of wherein said ethyl acetate and heptane are that about 1-4 part ethyl acetate is than about 2-10 part heptane.

75. the polymorph of claim 73, the ratio of the mixture of wherein said ethyl acetate and heptane are that about 2 parts of ethyl acetate are than about 5 parts of heptane.

76. suppress the method for MEK enzyme, it comprises makes described MEK enzyme contact with each compound or composition among the claim 1-75, there is the amount of described enzyme inhibition 25% in wherein said compound being enough at least.

77. the method for claim 76, wherein said MEK enzyme is the MEK kinases.

78. the method for claim 76, wherein said contact occurs in the cell.

79. treatment suffers from the method for illness described in the individuality of illness of MEK mediation, it comprises in the claim 1-75 of described individual effective dosage each compound or composition.

80. the method for claim 79 is with other therapy couplings.

81. the method for claim 80, wherein said other therapies are radiotherapy, non-MEK kinase inhibition agent therapy, chemotherapy, operation, glucocorticoid, methotrexate (MTX), biological response modifier, or their any combination.

82. the method for claim 79, the illness of wherein said MEK mediation is selected from inflammatory disease, infection, autoimmune disease, apoplexy, ischemic, cardiac conditions, neurological disorders, fibrillatable illness, proliferative disorders, excess proliferative illness, tumour, leukemia, knurl, cancer, cancer, metabolic disease and malignant diseases.

83. the method for claim 79, the illness of wherein said MEK mediation is an excess proliferative disease.

84. the method for claim 79, the illness of wherein said MEK mediation is cancer, tumour, leukemia, knurl or cancer.

85. the method for claim 79, the illness of wherein said MEK mediation is an inflammatory disease.

86. the method for claim 85, wherein said inflammatory disease are rheumatoid arthritis or multiple sclerosis.

87. the method for proliferative diseases in treatment or the prevention individuality, it comprises in the claim 1-75 of described individual effective dosage each compound or composition.

88. the method for claim 87, wherein said proliferative diseases are cancer, psoriasis, ISR, disease or atherosclerotic.

89. the method for claim 87, wherein said proliferative diseases is a cancer.

90. the method for claim 89, wherein said cancer are the cancer of the brain, breast cancer, lung cancer, oophoroma, cancer of pancreas, prostate cancer, kidney, colorectal cancer, leukemia, myeloid leukemia, glioblastoma, folliculus type lymphoma, preceding B acute leukemia, chronic lymphocytic B leukemia, cancer of the stomach, celiothelioma or small-cell carcinoma of the lung.

91. each method among the claim 87-90, it also comprises at least a therapeutic agent of administration.

92. each method among the claim 87-90, it also comprises uses at least a other cancer therapies.

93. the method for claim 92, wherein said other therapies are radiotherapy, non-MEK kinase inhibition agent therapy, chemotherapy, operation, glucocorticoid, methotrexate (MTX), biological response modifier, or their any combination.

94. the method for inflammatory disease in treatment or the prevention individuality, it comprises the compound compositions that comprises among the claim 1-75 each to described individual effective dosage.

95. the method for claim 94, wherein said inflammatory disease are rheumatoid arthritis or multiple sclerosis.

96. make that cancer cell is degenerated, the method for anticancer growth or kill cancer cell, it comprise make described cell with make effectively that cancer cell is degenerated, anticancer is grown or the claim 1-75 of the amount of kill cancer cell in each compound or composition contact.

97. the method for claim 96, wherein said cancer cell comprise brain cancer cell, breast cancer cell, lung carcinoma cell, ovarian cancer cell, pancreatic cancer cell, prostate gland cancer cell, kidney cancer cell, hepatoma carcinoma cell, stomach cancer cell or colorectal cancer cell.

98. suppress the method that the tumour size increases, reduces the tumour size, reduces tumor proliferation or prevention tumor proliferation in individuality, it comprises that each compound or composition increases, reduces the tumour size to suppress the tumour size, reduces tumor proliferation or prevention tumor proliferation in the claim 1-75 of described individual effective dosage.

99. the method for claim 98 is used to suppress the increase of tumour size or reduces the tumour size, wherein said tumour appears in brain, mammary gland, lung, ovary, pancreas, prostate, kidney, liver, stomach, colon or the rectum.

100. the method for claim 98 is used to suppress the increase of tumour size or reduces the tumour size, wherein said individuality is a mammal.

101. the method for treatment or prevention ankylosing spondylitis, gout, myotenositis, bursal synovitis or sciatica, it comprises formula (I) compound or pharmaceutically acceptable salt thereof to experimenter's effective dosage that these needs are arranged:

Wherein:

Z is H or F;

X is F, Cl, CH ₃, CH ₂OH, CH ₂F, CHF ₂Or CF ₃

Y is I, Br, Cl, CF ₃, C ₁-C ₃Alkyl, C ₂-C ₃Thiazolinyl, C ₂-C ₃Alkynyl, cyclopropyl, OMe, OEt, SMe, phenyl or Het, wherein Het is 5 to 10 yuan of monocyclic heterocycles groups or bicyclic heterocyclic groups that comprise 1-5 the ring hetero atom that is independently selected from N, O and S, described heterocyclic group is saturated, olefinic or aromatics; Wherein

Whole described methyl groups are randomly by 1,2 or 3 F atoms replacements;

G ₁Be C ₃-C ₈The Diaminoalkyl group;

R _1cBe (CH ₂) _nO _mR ' wherein

M is 0 or 1; And wherein

When m was 0, n was 1 or 2;

When m was 1, n was 2 or 3;

R _1dBe C (A) (A ') (B)-; Wherein

B is H or C _1-4Alkyl, it is randomly replaced by one or two OH group;

A and A ' are H or C independently _1-4Alkyl, it is randomly replaced by one or two OH group;

Perhaps

R _1eBe

Wherein

Q is 1 or 2;

R ₅Be H, F, Cl or methyl;

R ₆Be H, F, Cl or methyl;

Ar ₁Be

Wherein

U and V are N, CR independently ₂Or CR ₃

R ₅And R ₆Be H, F, Cl or methyl independently;

Ar ₂Be

Wherein

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

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

When U be-during N=, V is-CH=,-CCl=, or-N=;

R ₇Be H or methyl;

R ₈Be H, acetylamino, methyl, F or Cl;

Ar ₃Be

Wherein

U is-NH-,-NCH ₃-or-O-;

R ₇And R ₈Be H, F, Cl or methyl independently.

102. the method for claim 101, the compound or pharmaceutically acceptable salt thereof of wherein said formula (I) is selected from:

103. the method for claim 101, the compound or pharmaceutically acceptable salt thereof of wherein said formula (I) is selected from

With

Wherein 2-OH carbon is in the R configuration.

104. the method for claim 101, the compound or pharmaceutically acceptable salt thereof of wherein said formula (I) is selected from

With

Wherein 2-OH carbon is in the S configuration.

105. the method for claim 167, the compound or pharmaceutically acceptable salt thereof of wherein said formula (I) is

106. the method for claim 167, the compound or pharmaceutically acceptable salt thereof of wherein said formula (I) is

107. by each the compound or the method for combination treatment cancer of the stomach among the claim 1-75 of drug treatment effective dose.

108. by each the compound or the method for combination treatment leukemia melanoma or hepatoma among the claim 1-75 of drug treatment effective dose.

109. by each the compound or the method for combination treatment non-small cell lung cancer among the claim 1-75 of drug treatment effective dose.

110. by each the compound or the method for combination treatment colon cancer among the claim 1-75 of drug treatment effective dose.

111. by each compound or combination treatment CNS method for cancer among the claim 1-75 of drug treatment effective dose.

112. by each the compound or the method for combination treatment oophoroma among the claim 1-75 of drug treatment effective dose.

113. by each the compound or the method for combination treatment kidney among the claim 1-75 of drug treatment effective dose.

114. by each the compound or the method for combination treatment prostate cancer among the claim 1-75 of drug treatment effective dose.

115. by each the compound or the method for combination treatment breast cancer among the claim 1-75 of drug treatment effective dose.

116. each method among the claim 107-115, it also comprises at least a therapeutic agent of administration.

117. each method among the claim 107-115, it also comprises uses at least a other cancer therapies.

118. the method for claim 117, wherein said other cancer therapies are radiotherapy, chemotherapy, operation or their any combination.

119. each method among the claim 76-118, wherein described compound of oral administration or composition.

120. each method among the claim 76-118, wherein once a day or described compound of twice administration every day or composition.

121. each method among the claim 76-118, wherein described compound of administration once a day or composition continue at least one week.

122. by with among the claim 1-75 of topical formulations drug treatment effective dose each compound or combination treatment or prevent psoriatic method.

123. each method among the claim 76-121 is wherein to the T that reaches described compound behind the described composition of experimenter's administration of fasting between 1 hour to 3 hours _Max

124. each compound, composition or method wherein when to experimenter's administration, reached C at the 1st day described compound during aforesaid right required _MaxAbout 0.01 μ g/ml is to about 1.0 μ g/ml.

125. the compound of claim 124, composition or method wherein when to experimenter's administration, reach C at the 1st day described compound _MaxAbout 0.01 μ g/ml is to about 0.8 μ g/ml.

126. the compound of claim 124, composition or method wherein when to experimenter's administration, reach C at the 1st day described compound _MaxAbout 0.03 μ g/ml is to about 0.5 μ g/ml.

127. each compound, composition or method wherein when to one group of 10 experimenter's administration, reached average C at the 1st day described compound during aforesaid right required _MaxAbout 0.01 μ g/ml is to about 1.0 μ g/ml.

128. the compound of claim 127, composition or method wherein when to one group of 10 experimenter's administration, reach average C at the 1st day described compound _MaxAbout 0.01 μ g/ml is to about 0.8 μ g/ml.

129. the compound of claim 127, composition or method wherein when to one group of 10 experimenter's administration, reach average C at the 1st day described compound _MaxAbout 0.03 μ g/ml is to about 0.5 μ g/ml.

130. each compound, composition or method among the claim 124-126, wherein the AUC of described compound is that about 0.1 μ g/hr/mL is to about 5.0 μ g/hr/mL between 0-12 hour.

131. the compound of claim 130, composition or method, the AUC of wherein said compound is that about 0.1 μ ghr/mL is to about 4.0 μ g hr/mL.

132. the compound of claim 130, composition or method, the AUC of wherein said compound is that about 0.5 μ ghr/mL is to about 3.0 μ g hr/mL.

133. each compound, composition or method among the claim 127-129, the average A UC of wherein said compound is that about 0.1 μ g hr/mL is to about 5.0 μ g hr/mL.

134. the compound of claim 134, composition or method, the average A UC of wherein said compound is that about 0.1 μ g hr/mL is to about 4.0 μ g hr/mL.

135. the compound of claim 134, composition or method, the average A UC of wherein said compound is that about 0.5 μ g hr/mL is to about 3.0 μ g hr/mL.

136. each compound, composition or method among claim 124-126 and the 130-132, the T of wherein said compound _MaxBetween 0.5 to 5.0 hour.

137. the compound of claim 133, composition or method, the T of wherein said compound _MaxBetween 1.0 to 3.0 hours.

138. the compound of claim 133, composition or method, the T of wherein said compound _MaxBetween 1.0 to 2.5 hours.

139. each compound, composition or method among claim 127-129 and the 133-135, the average T of wherein said compound _MaxBetween 0.5 to 5.0 hour.

140. the compound of claim 139, composition or method, the average T of wherein said compound _MaxBetween 1.0 to 3.0 hours.

141. the compound of claim 139, composition or method, the average T of wherein said compound _MaxBetween 1.0 to 2.5 hours.

142. each compound, composition or method among claim 124-126,130-132 and the 136-138, wherein the plasma concentration at single-dose described compound after 5 hours is higher than about 0.01mg/mL.

143. each compound, composition or method among claim 124-126,130-132 and the 136-138, wherein the plasma concentration at single-dose described compound after 10 hours is higher than about 0.01mg/mL.

144. each compound, composition or method among claim 124-126,130-132 and the 136-138, wherein the plasma concentration at single-dose described compound after 15 hours is higher than about 0.01mg/mL.

145. each method among the claim 76-141, wherein at the described medicine of administration every day after 5 days, described gross tumor volume reduces at least about 25%.

146. each method among the claim 76-141, wherein at the described medicine of administration every day after 5 days, described gross tumor volume reduces at least about 50%.

147. each method among the claim 76-141, wherein at the described medicine of administration every day after 5 days, described gross tumor volume reduces at least about 20-70%.

148. each method among the claim 76-141, wherein at the described medicine of administration every day after 15 days, described gross tumor volume reduces at least about 25%.

149. each method among the claim 76-141, wherein at the described medicine of administration every day after 15 days, described gross tumor volume reduces at least about 50%.

150. each method among the claim 76-141, wherein at the described medicine of administration every day after 15 days, described gross tumor volume reduces at least about 20-70%.

151. each method among the claim 76-141, wherein at the described medicine of administration every day after 30 days, described gross tumor volume reduces at least about 25%.

152. each method among the claim 76-141, wherein at the described medicine of administration every day after 30 days, described gross tumor volume reduces at least about 50%.

153. each method among the claim 76-141, wherein at the described medicine of administration every day after 30 days, described gross tumor volume reduces at least about 20-70%.

154. each method among the claim 76-141, wherein behind the described medicine of administration, described tumor growth is suppressed at least about 20%.

155. each method among the claim 76-141, wherein behind the described medicine of administration, described tumor growth is suppressed at least about 40%.

156. each method among the claim 76-141, wherein behind the described medicine of administration, described tumor growth is suppressed at least about 60%.

157. each method among the claim 76-141, wherein behind the described medicine of administration, described tumor growth is suppressed at least about 80%.

158. each method among the claim 76-141, wherein behind the described medicine of administration, described tumor growth is suppressed about 20% to about 100%.

159. each method among the claim 76-141, wherein behind the described medicine of administration, described tumor growth is suppressed substantially.

160. each method among the claim 145-159, the wherein described medicine of twice administration every day.

161. each method among the claim 145-159, the wherein described medicine of administration once a day.

162. each method among the claim 76-157, wherein said mek inhibitor does not disturb the administering drug combinations of another kind of tumor inhibitor.

Each compound, composition or method during 163. aforesaid right requires, wherein said composition is the form of tablet, capsule, soft capsule, ingot, bolus or particle.

164. the compound of claim 163, composition or method, wherein said composition are to have about 50mg to the capsule of about 1000mg gross weight or the form of Tabules.

165. the compound of claim 163, composition or method, wherein said composition are the form with capsule or tablet of the gross weight that is selected from 50mg, 75mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg and 500mg.

166. the compound of claim 163, composition or method, wherein said composition are the form with capsule or tablet of about 240mg gross weight.

167. claim 1-58,66,71 or 76-166 in each composition or method, wherein said composition also comprises at least a filler that is selected from microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sompressible sugar, xylitol, sorbierite, mannitol, pregelatinized starch, maltodextrin, calcium phosphate, calcium carbonate, starch and calcium silicates.

168. claim 1-58,66,71 or 76-166 in each composition or method, wherein said composition also comprises at least a disintegrant that is selected from cross-linked carboxymethyl cellulose sodium, primojel, Crospovidone, methylcellulose, alginic acid, mosanom, starch derivatives, bentonite and aluminium-magnesium silicate.

169. claim 1-58,66,71 or 76-166 in each composition or method, wherein said composition also comprises at least a dolomol, metallic stearate, talcum, sodium stearyl fumarate and the stearic lubricant of being selected from.

170. claim 1-58,66,71 or 76-166 in each composition or method, wherein said composition also comprises at least a wetting agent or the surfactant that is selected from lauryl sodium sulfate, glycerine, sorbitan monooleate, Span60, polyoxyethylene anhydrous sorbitol dodecylate, palmitate, stearate, oleate or six oleates, the pure and mild anhydrous sorbitol list of polyoxyethylene stearyl dodecylate.

171. claim 1-58,66,71 or 76-170 in each composition or method, wherein said composition is the preparation of capsule or tablet, and use American Pharmacopeia (USP) apparatus II under 50rpm, as dissolution medium, described capsule or tablet discharged at least 60% described medicine in 30 minutes with 1% lauryl sodium sulfate in the water.

172. the compound of claim 171, composition or method, wherein said composition is the preparation of capsule or tablet, and use American Pharmacopeia (USP) apparatus II under 50rpm, as dissolution medium, described capsule or tablet discharged the described medicine of about 60-100% in 30 minutes with 1% lauryl sodium sulfate in the water.

173. the compound of claim 171, composition or method, wherein said composition is the preparation of capsule or tablet, and use American Pharmacopeia (USP) apparatus II under 50rpm, as dissolution medium, described capsule or tablet discharged the described medicine of about 60-90% in 30 minutes with 1% lauryl sodium sulfate in the water.

174. the compound of claim 171, composition or method, wherein said composition is the preparation of capsule or tablet, and use American Pharmacopeia (USP) apparatus II under 50rpm, as dissolution medium, described capsule or tablet discharged the described medicine of about 60-80% in 30 minutes with 1% lauryl sodium sulfate in the water.

175. a collection of capsule or tablet, it respectively comprises in about 1 to about 50mg claim 1-75 each compound, and has and be lower than about 15 content uniformity USP admitted value.

176. by each the compound or the method for combination treatment liver cancer among the claim 1-75 of drug treatment effective dose.