CN101495118B - N-(arylamino)-sulfonamide inhibitors of MEK - Google Patents

N-(arylamino)-sulfonamide inhibitors of MEK Download PDF

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CN101495118B
CN101495118B CN2006800349355A CN200680034935A CN101495118B CN 101495118 B CN101495118 B CN 101495118B CN 2006800349355 A CN2006800349355 A CN 2006800349355A CN 200680034935 A CN200680034935 A CN 200680034935A CN 101495118 B CN101495118 B CN 101495118B
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chemical compound
fluoro
phenyl
methyl
iodophenyl
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CN101495118A (en
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A·马德纳
J·-M·韦尼耶
D·巴劳卡
V·查马库拉
H·E·阿布德劳伊
Z·洪
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Ardea Biociences Inc
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Abstract

This invention concerns N-(2-arylamino) aryl sulfonamides, which are inhibitors of MEK and are useful in treatment of cancer and other hyperproliferative diseases.

Description

The N-of MEK (arylamino) sulfonamide inhibitors
Cross reference to related application
The application requires to be filed in the U.S. Provisional Application series No.60/701 on July 21st, 2005; 814, be filed in the U.S. Provisional Application series No.60/706 on August 8th, 2005; 719 with the U.S. Provisional Application series No.60/731 that is filed on October 28th, 2005; 633 priority, their full content is hereby incorporated by.
Invention field
The present invention relates to N-(2-arylamino) aryl sulfonic acid amides for mek inhibitor.Said chemical compound can be used for the treatment of cancer and other hyperproliferation disease.
Background of invention
Oncogene (gene that helps cancer to form) is the mutant form of some normal cell gene (" proto-oncogene ") normally.Oncogene is the anomaly pattern of coded signal pathway component usually, such as receptor tyrosine kinase, serine-threonine kinase or downstream signaling molecule.The downstream signaling molecule at center is a Ras protein, and they are anchored on the inner surface of cytoplasmic membrane and the bonded GTP of hydrolysis (GTP) is guanosine diphosphate (GDP).When carrying out activation through somatomedin, growth factor receptors causes a series of activatory reaction of the exchange activity of guanylic acid on Ras that causes.Ras has active " opening " state (hereinafter " Ras.GTP ") that combines GTP and is having alternate between nonactive " pass " state that combines GDP.Active " opening " state, Ras.GTP combine and the activation control cell is grown and the protein of differentiation.
For example, in " mitogen-activated protein kinase (map kinase) cascade ", Ras.GTP causes the activation of serine/threonine kinase cascade.It is Raf family that known autoactivation needs one group in several groups of kinases of Ras.GTP.Raf protein activates for " MEK1 " and " MEK2 " of mitogen-activated ERK-activated protein kinase abbreviation (wherein ERK is a protein kinase of regulating extracellular signal, the another kind name of MAPK).MEK1 and MEK2 are two sense serine/threonines and tyrosine protein matter kinases, and are known as the map kinase kinases.Thus, Ras.GTP activation Raf, its activation MEK1 and MEK2 (its activation map kinase (MAPK)).The activation of the map kinase that produces through mitogen is seemingly requisite to propagation, and this kinase whose structural activation is enough to bring out cell transformation.Blocking-up through utilizing dominant negative Raf-1 protein to carry out downstream Ras can suppress mitogenesis fully, no matter is the mitogenesis that the mitogenesis brought out of cell surface receptor or carcinogenic Ras mutation are brought out.
The interaction of Raf and Ras is the crucial set-up procedure in the control cell proliferation.Up to now, do not identify the substrate of the MEK that is not MAPK; Yet, report expression recently, MEK can also carry out activation through other stream signal protein, such as MEK kinases or MEKK1 and PKC.Activation MAPK is shifted in nucleus and accumulates, and it can carry out phosphorylation and activating transcription factor (such as Elk-1 and Sap 1a) at this, causes enhanced gene expression, such as c-fos gene expression.
In case obtain activation, Raf and other kinases are with the MEK of phosphorylation on two adjacent serine residues, and two adjacent serine residues are S in the situation of MEK-1 218And S 222For will be as kinase activation MEK, these phosphorylations need.And then the MEK phosphorylation is through the map kinase on isolating two residues of single amino acids: tyrosine, Y 185And threonine, T 183Before it, it is relevant strongly with map kinase that MEK seems in phosphorylation, and this shows phosphorylation that map kinase carries out through MEK strong in advance interaction the between maybe two kinds of protein of needs.Two kinds of factors (the unusual specificity of MEK and before phosphorylation, need have strong interaction with map kinase) show that the mechanism of action of MEK possibly fully be different from other about considering and the mechanism of the protein kinase of MEK selective depressant.Said inhibitor maybe with through allosterism rather than through relate to stop up ATP-binding site than general mechanism work.
Thus, MEK1 and MEK2 are the conclusive evidence of antiproliferative therapy and the target body of approval, even when the Cancer-causing mutation body does not influence the MEK structure or expresses, also be like this.Referring to, for example people's such as Barrett United States Patent (USP) disclose 2003/0149015 with people's such as Boyle 2004/0029898.
Reported that the 1-of MEK replaces several instances of-2 (the p-substituted 4-phenyl is amino)-aryl inhibitor.United States Patent(USP) Nos. 6; 440; 966 and 6,750,217 and accordingly openly WO00/42003 sulfonamide-replacements-2-(4-iodophenyl the amino)-benzoate that plays the mek inhibitor effect and carboxylic acid and the Hydroxamates and the N substituted amide derivant of N-substituted benzamide have been described.Sulfonamide can also be replaced by N-.
United States Patent (USP) 6; 545; 030 has described the mek inhibitor for 1-heterocyclic radical-2 (the 4-iodophenyl is amino)-benzene with corresponding openly WO 00/42029; Wherein heterocycle is five yuan and contains azo-cycle, such as pyrazoles, triazole, azoles, different
Figure 2006800349355_7
azoles and different
Figure 2006800349355_8
azoles quinoline ketone.Recently; United States Patent (USP) discloses 2005/004186 and has described related compound; Wherein ' the 4-iodine substituent group of 030 patent is replaced with very wide in range structure division classification, comprises alkyl, alkoxyl, acyloxy, thiazolinyl, carbamoyl, carbamoyl alkyl, carboxyl, carboxyalkyl and N-acyl group sulfoamido and other group.
United States Patent (USP) 6; 469; 004 has described the carboxylic acid and the Hydroxamates of one group of heterocyclic fused phenylene chemical compound, i.e. benzimidazole, benzo
Figure 2006800349355_9
azoles, benzothiazole, diazosulfide, quinazoline or the like with corresponding openly WO 00/42022.Said heterocyclic compound is 7-F-6-(4-iodo-phenyl amino)-5-carboxylate, carboxylic acid amide or Hydroxamates.Nearest disclosed U.S.2005/0026970 has described similar compound, and wherein 4-iodine substituent group is replaced by very wide in range structured sort.Related compound is described among patent open WO 03/077855, WO 03/77914 and the US2005/0554701.It is reported and to be found among the WO 2005/028426 as other instance of the 2-of mek inhibitor (the 4-iodophenyl is amino)-phenyl hydroximic acid ester.
Open WO 02/06213 of patent and corresponding U. S. application series No.10/333,399 (U S.2004/0054172) have been described 1-oxamidic acid .-2 (the 4-halogenophenyl is amino)-3, the substituted acid esters of the hydroxyl of 4-difluoro-benzene.United States Patent(USP) No. 6,891,066 has described similar compound with corresponding openly WO 03/62191, and wherein the 4-halogenic substituent is replaced by very wide in range structured sort.In the 4-bit substituent, be methyl, ethyl, acetenyl and 2-ethoxy.Concrete related compound is described in United States Patent(USP) No. 6,770, in 778.
The open WO 04/083167 (Japanese) of patent that is disclosed on JIUYUE 30th, 2004 discloses above 2,000 chemical compounds; But only to 400 1-(N-replaces sulfonylureas)-2-(2; The 4-dihalogenated phenyl is amino)-3, the 4-difluoro-benzene provides the NMR data and has declared that they can be used as mek inhibitor.Only the Asia group of 12 chemical compounds is appeared and show the data that suppress MEK.Except the second month in a season or tertiary amine, these 12 chemical compounds all contain one of following group: N, the dibasic sulfonylureas of N-, N-piperazine sulfonamide, N-piperidine sulfonamide or N-pyrrolidine sulfonamide.
The MEK cascade also has complicated relation with inflammatory diseases and disease.The open No.2006/0030610 of people's such as Koch U. S. application, the open No.2006/0140872 of people's such as Furue U. S. application.This comprises acute and chronic inflammation.The instance of said disease is contact dermatitis, rheumatic arthritis, osteoarthritis, inflammatory bowel disease, chronic infraction property pneumonopathy, psoriasis, multiple cerebral sclerosis, asthma, the disease relevant with diabetic complication and the inflammatory complication (such as acute coronary artery syndrome) of disease and cardiovascular system.In inflammatory bowel disease, comprise Crohn disease and ulcerative colitis.
All all are hereby incorporated by at this file of quoting.
Summary of the invention
The present invention provides formula I chemical compound
Figure S2006800349355D00041
Wherein G is R 1a, R 1b, R 1c, R 1d, R 1e, Ar 1, Ar 2Perhaps Ar 3
R 0Be H, halogen, C 1-C 6Alkyl, C 1-C 4Alkoxyl, C 3-C 6Cycloalkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, said alkyl, cycloalkyl, thiazolinyl and alkynyl group are optional to be replaced and said C by 1～3 substituent group that is independently selected from halogen, OH, CN, cyanogen methyl, nitro, phenyl and trifluoromethyl 1-C 6Alkyl and C 1-C 4Alkoxyl is also optional by OCH 3Perhaps OCH 2CH 3Replace;
X is F, Cl or methyl;
Y is I, Br, Cl, CF 3, C 1-C 3Alkyl, C 2-C 3Thiazolinyl, C 2-C 3Alkynyl, cyclopropyl, phenyl, pyridine radicals, pyrazolyl, OMe, OEt or SMe, wherein all said methyl, ethyl, the C of X and Y 1-C 3Alkyl and cyclopropyl group are optional by the OH replacement, and the said phenyl of all of Y, pyridine radicals, optional all the said methyl by halogen, acetyl group, methyl and trifluoromethyl replacement and X and Y of pyrazolyl groups are chosen wantonly by one, two or three fluorine atoms replacements; With Z be H or F,
R wherein 1aBe methyl, optional by 1-3 fluorine atom or 1-3 chlorine atom replacement, perhaps by OH, ring propoxyl group or C 1-C 4Alkoxyl replaces, wherein said C 1-C 4The C of alkoxyl 1-C 4Moieties is optional to be replaced and said C by a hydroxyl or methoxyl group 1-C 4All C in the alkoxyl 2-C 4Alkyl is optional further to be replaced by second OH group;
R 1bBe CH (CH 3)-C 1-3Alkyl or C 3-C 6Cycloalkyl, said methyl, alkyl and group of naphthene base are optional to be independently selected from F, Cl, Br, I, OH, C by 1-3 1-C 4The substituent group of alkoxyl and CN replaces;
R 1cBe (CH 2) nO mR ', wherein m is 0 or 1; Wherein, when m was 1, n was 2 or 3 and when m is 0, and n is 1 or 2; Wherein R ' is C 1-C 6Alkyl, optional by individual F, Cl, OH, the OCH of being independently selected from of 1-3 3, OCH 2CH 3And C 3-C 6The substituent group of cycloalkyl replaces;
R 1dFor C (A) (A ') (B)-, wherein B, A and A ' are H or C independently 1-4Alkyl; Optional by one or two OH groups or halogen atom replacement; Perhaps A forms 3-6 unit saturated rings altogether with the carbon atom that A ' is connected together with them, and said ring is optional to be contained one or two hetero atoms that are independently selected from O, N and S and choose groups replacement that is independently selected from methyl, ethyl and halogen by one or two wantonly;
R 1eBe benzyl or 2-phenylethyl, wherein phenyl is optional is substituted
Figure S2006800349355D00051
Wherein q is 1 or 2, R 2, R 3And R 4Be H, F, Cl, Br, CH independently 3, 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 and
R 4Can also be nitro, acetylamino, amidino groups, cyanic acid, carbamoyl, methylamino formoxyl, formyl-dimethylamino, 1,3,4-
Figure 2006800349355_10
Diazole-2-base, 5-methyl isophthalic acid, 3,4-
Figure 2006800349355_11
Di azoly, 1,3,4-thiadiazolyl group, 5-methyl isophthalic acid, 3,4-thiadiazoles-1H-tetrazole radical, N-morpholinyl carbonyl amino, N-morpholinyl sulfonyl and N-pyrrolidinyl carbonylamino;
R 5And R 6Be H, F, Cl or methyl independently;
Ar 1For
Figure S2006800349355D00052
Wherein U and V are N, CR independently 2Perhaps CR 3R 2, R 3And R 4Be H, F, Cl, Br, CH independently 3, 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, and R 4Can also be nitro, acetylamino, amidino groups, cyanic acid, carbamoyl, methylamino formoxyl, formyl-dimethylamino, 1,3,4-
Figure 2006800349355_12
Diazole-2-base, 5-methyl isophthalic acid, 3,4-
Figure 2006800349355_13
Diazole, 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 5And R 6Be H, F, Cl or methyl independently;
Ar 2For
Wherein dotted line is represented two keys, and it can be in form between the carbon atom between V and U and the V, perhaps between the carbon atom between U and U and the V; Wherein U be-S-,-O-perhaps-N=and wherein when U for-O-perhaps-during S-, V is-CH=,-CCl=perhaps-N=; With as U be-during N=, V be CH=perhaps-NCH 3-; R 7And R 8Be H, methoxycarbonyl group, methylamino formoxyl, acetylamino, acetyl group, methyl, ethyl, trifluoromethyl or halogen independently,
Ar 3For
Wherein U be-NH-,-NCH 3-perhaps-O-; And R 7And R 8Be H, F, Cl or methyl independently.
Said chemical compound is mek inhibitor and can be used for cancer and the treatment of other hyperproliferation disease.
The invention still further relates to the pharmaceutical compositions of the formula I chemical compound that contains pharmacy effective dose or its pharmaceutically acceptable salt, ester, prodrug, solvate or hydrate and pharmaceutically acceptable carrier.Said compositions can contain reagent, filler, binding agent, adsorbent, buffer, disintegrating agent, solubilizing agent, other carrier and other inert fraction of auxiliary agent, excipient, antiseptic, delay absorption.The compound method of said compositions is known in the art.
The invention still further relates to the method for treatment hyper-proliferative disease in mammal (comprising the mankind), comprise formula I chemical compound or its pharmaceutically acceptable salt, salt, ester, prodrug or the hydrate of the said mammal treatment of administration effective dose.
The invention still further relates to the method for treatment inflammatory diseases, situation or disease in mammal (comprising the mankind), comprise formula I chemical compound or its pharmaceutically acceptable salt, salt, ester, prodrug or the hydrate of the said mammal treatment of administration effective dose.
The invention still further relates to and in mammal (comprising the mankind), treat, comprise formula I chemical compound or its pharmaceutically acceptable salt, salt, ester, prodrug or the hydrate of the said mammal treatment of administration effective dose through the disease of MEK cascade adjusting or the method for situation.
Suitable dosage for concrete patient can be confirmed by those skilled in the art according to known method.
In a kind of subclass embodiment, the present invention provides formula IA-1 chemical compound,
Figure S2006800349355D00071
R wherein 1aAs above define.
In another embodiment, the present invention provides formula IA-2 chemical compound, wherein R 1aAs above define and R wherein 0' be the R of above definition 0, but be not H.
Figure S2006800349355D00072
In another embodiment, the present invention provides formula IB-1 chemical compound,
Figure S2006800349355D00073
Wherein X and Y such as for formula I definition and R wherein 1bSuch as for formula I definition.
In another embodiment, the present invention provides formula IB-2 chemical compound,
Figure S2006800349355D00081
R wherein 1bSuch as as above for formula I definition and R wherein 0' be the R of above definition 0, but be not H.
In the 3rd embodiment, the present invention provides formula IC-1 chemical compound,
Figure S2006800349355D00082
R wherein 1cBe (CH 2) nO mR ', wherein m is 0 or 1, when m is 1 n be 2 or 3 and when m is 0 n be 1 or 2, and R ' is C 1-C 6Alkyl, optional by individual F, Cl, OH, the OCH of being independently selected from of 1-3 3, OCH 2CH 3And C 3-C 6The substituent group of cycloalkyl replaces.
In another embodiment, the present invention provides formula IC-2 chemical compound,
Figure S2006800349355D00083
R wherein 1cAs above define and R wherein 0' be the R of above definition 0, but be not H.
In another embodiment, the present invention provides formula ID-1 chemical compound,
Figure S2006800349355D00091
R wherein 1dFor C (A) (A ') (B)-, wherein B, A and A ' are H or optional by one or two OH groups or the substituted C of halogen atom independently 1-4Alkyl; Perhaps A forms 3-6 unit saturated rings altogether with the carbon atom that A ' is connected with them, and said ring is optional to be contained one or two hetero atoms that are independently selected from O, N and S and choose groups replacement that is independently selected from methyl, ethyl and halogen by one or two wantonly.
In another embodiment, the present invention provides formula ID-2 chemical compound,
R wherein 1dAs above define and R wherein 0' be the R of above definition 0, but be not H.
In another embodiment, the present invention provides formula IE-1 chemical compound,
Figure S2006800349355D00093
R wherein 1eAs above define.
In another embodiment, the present invention provides formula IE-2 chemical compound,
Figure S2006800349355D00101
R wherein 0' be the R of above definition 0, but be not H.
In another embodiment, the present invention provides formula II-A chemical compound, and wherein G is Ar 1,
Figure S2006800349355D00102
R wherein 2-6, U and V as above define.
In another embodiment, the present invention provides formula II-B chemical compound,
R wherein 0' be the R of above definition 0, but be not H.
In another embodiment, the present invention provides formula III-A chemical compound,
Figure S2006800349355D00111
In another embodiment, the present invention provides formula III-B chemical compound,
Figure S2006800349355D00112
R wherein 0, be the R of above definition 0, but be not H.
In other inferior embodiment, the present invention provides formula IA-1, IA-2, IB-1, IB-2, IC-1, IC-2, ID-1, ID-2, II-A, II-B, III-A and III-B chemical compound, and wherein X is F, Cl or CH 3Y is I, Br, Cl, CF 3Perhaps C 1-C 3Alkyl and Z are H or F.
In other inferior embodiment, the present invention provides formula IA-2, IB-2, IC-2, ID-2, II-B and III-B chemical compound, and wherein X is F, Cl or CH 3Y is I, Br, Cl, CF 3Perhaps C 1-C 3Alkyl and Z are H or F, and R 0Be halogen, C 1-C 6Alkyl, single halo C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, phenyl, monosubstituted phenyl, OR 3, O-C (=O) R 4Perhaps C (=O) OR 5
In other inferior embodiment, the present invention provides or expects formula IA-2, IB-2, IC-2, ID-2, II-B and III-B chemical compound, and wherein X is F, Cl or CH 3Y is I, Br, Cl, CF 3Perhaps C 1-C 3Alkyl, Z are H or F, and R 0For furyl, thienyl, thiazolyl, isothiazolyl,
Figure 2006800349355_14
Azoles base, different
Figure 2006800349355_15
Azoles base, pyrrole radicals or pyrazolyl.
In other inferior embodiment, the present invention provides formula IA-2, IB-2, IC-2, ID-2, II-B and III-B chemical compound, and wherein X is F, Cl or CH 3Y is I, Br, Cl, CF 3Perhaps C 1-C 3Alkyl, Z are H or F, and R 0Be F, Cl, C 1-C 4Alkyl, C 1-C 3Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl.
In inferior embodiment more specifically, the present invention provides formula IA-1 chemical compound, wherein R 1aBe methyl, single halogenated methyl, C 1-C 3Alkoxy methyl perhaps encircles the propoxyl group methyl.
In another inferior more specifically embodiment, the present invention provides formula IA-2 chemical compound, wherein R 1aBe methyl, single halogenated methyl, C 1-C 3Alkoxy methyl or encircle the propoxyl group methyl and R wherein 0' be F, Cl, C 1-C 3Alkyl, a chlorine C 1-C 3Alkyl, C 1-C 3Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl.
In the more specifically inferior embodiment of formula IB-1, the present invention provides formula IB-1 chemical compound, wherein R 1bBe isopropyl, 2-butyl, 2-amyl group, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl, all are all chosen wantonly by 1 or 2 and are independently selected from F, Cl, OH and OCH 3Substituent group replace; Y is Br, I, methyl or trifluoromethyl.
In the more specifically inferior embodiment of formula IB-2, the present invention provides formula IB-2 chemical compound, wherein R 1bBe isopropyl, 2-butyl, 2-amyl group, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl, choose wantonly and be independently selected from F, Cl, OH and OCH by 1 or 2 3Substituent group replace; Y is Br, I, methyl or trifluoromethyl; And R 0Be F, Cl, C 1-C 3Alkyl, a chlorine C 1-C 3Alkyl, C 1-C 3Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl.
In the more specifically inferior embodiment of formula IB-1, the present invention provides formula IB-1 chemical compound, wherein R 1bBe isopropyl, 2-butyl, 2-amyl group, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl, all are all chosen wantonly by 1 Cl or by 1 or 2 OH group and replace; With Y be Br, I, methyl or trifluoromethyl.
In the more specifically inferior embodiment of formula IB-2, the present invention provides formula IB-2 chemical compound, wherein R 1bBe isopropyl, 2-butyl, 2-amyl group, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl, optional by 1 Cl or by 1 or 2 OH group replacement; Y is Br, I, methyl or trifluoromethyl; And R 0' be F, Cl, C 1-C 3Alkyl, a chlorine C 1-C 3Alkyl, C 1-C 3Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl.
In another inferior more specifically embodiment, the present invention provides formula IC-1 or IC-2 chemical compound, and wherein m is zero, and n is 1 or 2, and R ' is optional substituted as stated C 1-C 4Alkyl.
In another inferior more specifically embodiment, the present invention provides formula IC-1 or IC-2 chemical compound, and wherein m is 1, and n is 2 or 3, and R ' is optional substituted as stated C 1-C 4Alkyl.
In inferior embodiment more specifically, the present invention provides IC-1 or IC-2 chemical compound, and wherein m is zero, and n is 1 or 2, and R ' is selected from OH, OCH for optional by 1-3 3, Cl and cyclopropyl the substituted C of group 1-C 4Alkyl.
In another inferior more specifically embodiment, the present invention provides formula ID-1 chemical compound, wherein R 1dBe cycloalkyl or 1-alkyl-cycloalkyl, wherein the 1-alkyl is optional replaces by one or two OH groups or by one or two halogen atoms.
In other more specifically inferior embodiment, the present invention provides formula ID-2 chemical compound, wherein R 0' be halogen, C 1-C 6Alkyl, single halo C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, phenyl, monosubstituted phenyl, OR 3, O-C (=O) R 4Perhaps C (=O) OR 5And R 1dBe cycloalkyl or 1-alkyl-cycloalkyl, wherein the 1-alkyl is optional replaces by one or two OH groups or by one or two halogen atoms.
In another inferior more specifically embodiment, the present invention provides formula ID-2 chemical compound, wherein R 0' be furyl, thienyl, thiazolyl, isothiazolyl,
Figure 2006800349355_16
Azoles base, different
Figure 2006800349355_17
Azoles base, pyrrole radicals or pyrazolyl; And R 1dBe cycloalkyl or 1-alkyl-cycloalkyl, wherein the 1-alkyl is optional replaces by one or two OH groups or by one or two halogen atoms.
In another inferior more specifically embodiment, the present invention provides formula ID-1 chemical compound, wherein R 1dBe cycloalkyl or 1-alkyl-cycloalkyl, wherein the 1-alkyl optional by one or two OH groups replace and wherein Y be Br, I, methyl or trifluoromethyl.
In another inferior more specifically embodiment, the present invention provides formula ID-1 chemical compound, wherein R 1dBe cycloalkyl or 1-alkyl-cycloalkyl, wherein the 1-alkyl optional by one or two fluorine or the chlorine atom replaces and wherein Y be Br, I, methyl or trifluoromethyl.
In another inferior more specifically embodiment, the present invention provides formula ID-2 chemical compound, wherein R 1dBe perhaps (1-alkyl)-cycloalkyl of cycloalkyl, wherein the 1-alkyl is optional is replaced and R wherein by one or two OH groups 0' be F, Cl, C 1-C 3Alkyl, a chlorine C 1-C 3Alkyl, C 1-C 3Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl.
In another inferior more specifically embodiment, the present invention provides formula ID-1 chemical compound, wherein R 1dBe tetrahydrofuran base, tetrahydro-thienyl, pyrrolidinyl, piperidyl, piperazinyl or morpholinyl, optional separately be substituted as stated and wherein Y be Br, I, methyl or trifluoromethyl.
In another inferior more specifically embodiment, the present invention provides formula ID-1 chemical compound, wherein R 1dFor
Figure 2006800349355_18
Oxazolidinyl, thiazolidinyl, different
Figure 2006800349355_19
Oxazolidinyl, isothiazole alkyl, tetrahydrofuran base, tetrahydro-thienyl, pyrrolidinyl, piperidyl, piperazinyl or morpholinyl, optional separately be substituted as stated and wherein Y be Br, I, methyl or trifluoromethyl.
In another inferior more specifically embodiment, the present invention provides formula ID-2 chemical compound, wherein R 1dBe perhaps (1-alkyl)-cyclopropyl of cyclopropyl, wherein the 1-alkyl is optional is replaced and R wherein by one or two OH groups 0' be F, Cl, methyl, ethyl, chloromethyl, C 1-C 2Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl.
In a more particular embodiment, the present invention provides formula ID-1 chemical compound, wherein R 1dBe 1-(monohydroxy alkyl) cycloalkyl.
In another more particular embodiment, the present invention provides formula ID-2 chemical compound, wherein R 1dBe (1-monohydroxy alkyl) cycloalkyl, wherein R 0' be F, Cl, methyl, ethyl, chloromethyl, C 1-C 2Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl.
In a more particular embodiment, the present invention provides formula ID-1 chemical compound, wherein R 1dBe 1-(dihydroxy alkyl) cycloalkyl.
In another more particular embodiment, the present invention provides formula ID-2 chemical compound, wherein R 1dBe (1-dihydroxy alkyl) cycloalkyl, wherein R 0' be F, Cl, methyl, ethyl, chloromethyl, C 1-C 2Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl.
In the more specifically inferior embodiment of formula IIA, the present invention is provided as the formula II-A1 chemical compound of formula II-A chemical compound, and wherein U is CR 2With V be N.
In another inferior more specifically embodiment, the present invention is provided as the formula IIB-1 chemical compound of formula II-B chemical compound, and wherein U and V are N.
Figure S2006800349355D00151
In inferior embodiment more specifically, the present invention is provided as the formula IIA-3 chemical compound of formula IIA chemical compound, and wherein U is CR 2With V be CR 3
In inferior embodiment more specifically, the present invention provides formula I chemical compound, and wherein G is Ar 1And Ar 1Be phenyl or monosubstituted phenyl, R 0Be F, methyl, ethyl, C 1-C 3Alkoxyl, trifluoromethoxy or 2-methoxyl group-ethyoxyl; X is F, Cl or CH 3Y is I; With Z be F.
In another inferior embodiment, the present invention provides formula I chemical compound, and wherein G is Ar 1, Ar wherein 1Be phenyl or mono-substituted phenyl, R 0Be halogen, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, all said alkyl, cycloalkyl, thiazolinyl and alkynyl are optional to be replaced by 1-3 substituent group that is independently selected from halogen, OH, CN, cyanogen methyl, nitro, phenyl and trifluoromethyl; Perhaps R 0Be phenyl, OR 3, furyl, thienyl, thiazolyl, isothiazolyl, Azoles base, different
Figure 2006800349355_21
Azoles base, pyrrole radicals or pyrazolyl.
In inferior embodiment more specifically, the present invention provides formula I chemical compound, and wherein A is Ar 1, Ar wherein 1Be phenyl or monosubstituted phenyl, R 0Be F, Cl, C 1-C 3Alkyl, C 1-C 3Alkoxyl, 2-methoxy ethoxy, C 2-C 3Thiazolinyl, C 2-C 3Alkynyl, trifluoromethyl, phenyl, furyl or thienyl, thiazolyl, isothiazolyl, Azoles base, different
Figure 2006800349355_23
Azoles base, pyrrole radicals or pyrazolyl; X is F, Cl or methyl; Y is I, Br, Cl, CF 3Perhaps C 1-C 3Alkyl; With Z be F.
In another inferior more specifically embodiment, the present invention provides the G chemical compound of formula I, and wherein G is Ar 1, Ar wherein 1Be phenyl or monosubstituted phenyl, R 0Be H; X is F, Cl or CH 3Y is Br or I; With Z be F.
In another inferior embodiment, the present invention provides the G chemical compound of formula I, and wherein G is Ar 2, Ar wherein 2Be 2-thienyl, 2-furyl, 3-thienyl, 3-furyl, 2-pyrrole radicals or 3-pyrrole radicals, all are optional by methoxy carbonyl, methylamino formoxyl, acetylamino, acetyl group, methyl, ethyl, trifluoromethyl or halogen replacement.
In inferior embodiment more specifically, the present invention provides the G chemical compound of formula I, and wherein G is Ar 2, Ar wherein 2Be 2-thienyl, 2-furyl, 3-thienyl, 3-furyl, 2-pyrrole radicals or 3-pyrrole radicals, all are optional by methoxy carbonyl, methylamino formoxyl, acetylamino, acetyl group, methyl, ethyl, trifluoromethyl or halogen replacement; R 0Not H; X is F, Cl or CH 3Y is I, Br, Cl, CF 3Perhaps C 1-C 3Alkyl and Z are H or F.
In another inferior embodiment, the present invention provides the G chemical compound of formula I, and wherein G is Ar 2, Ar wherein 2Be 2-thienyl, 2-furyl, 3-thienyl, 3-furyl, 2-pyrrole radicals or 3-pyrrole radicals, all are optional by methoxy carbonyl, methylamino formoxyl, acetylamino, acetyl group, methyl, ethyl, trifluoromethyl or halogen replacement; R 0Be F, Cl, C 1-C 3Alkyl, a chlorine C 1-C 3Alkyl, C 1-C 3Alkoxyl, trifluoromethoxy, methoxyl group-methoxyl group or 2-methoxyl group-ethyoxyl; X is F, Cl or CH 3Y is I, Br, Cl, CF 3Perhaps C 1-C 3Alkyl and Z are H or F.
In another inferior embodiment, the present invention provides the G chemical compound of formula I, and wherein G is Ar 2, Ar wherein 2Be 2-thienyl, 2-furyl, 3-thienyl, 3-furyl, 2-pyrrole radicals or 3-pyrrole radicals, all are optional by methoxy carbonyl, methylamino formoxyl, acetylamino, acetyl group, methyl, ethyl, trifluoromethyl or halogen replacement; R 0Be H; X is F, Cl or CH 3Y is I, Br, Cl, CF 3Perhaps C 1-C 3Alkyl and Z are H or F.
In another inferior embodiment, the present invention provides the G chemical compound of formula I, and wherein G is Ar 2, Ar wherein 2For thiazolyl, isothiazolyl, Azoles base, different
Figure 2006800349355_25
Azoles base, pyrrole radicals or pyrazolyl, all are optional by methoxy carbonyl, methylamino formoxyl, acetylamino, acetyl group, methyl, ethyl, trifluoromethyl or halogen replacement; R 0Be H or methoxyl group; X is F, Cl or CH 3Y is I, Br, Cl, CF 3Perhaps C 1-C 3Alkyl and Z are H or F.
Detailed Description Of The Invention
Comprise the biological effectiveness of the free bronsted lowry acids and bases bronsted lowry that keeps appointed compound and the salt of not expecting at " pharmaceutically acceptable salt " of this use in biology or others.The compounds of this invention can have acid or basic group, and thus can with any one reaction in multiple inorganic or organic base and inorganic and the organic acid, thereby form pharmaceutically acceptable salt.The instance of pharmaceutically acceptable salt comprises The compounds of this invention and those salt inorganic or organic acid or inorganic base prepared in reaction; Said salt comprises sulfate, pyrosulfate, disulfate, sulphite, bisulfites, phosphate, hydrophosphate, dihydric phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprate, caprylate, acrylates, formates, isobutyrate, caproate, enanthate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butine-1; 4-diacid salt, hexin-1,6-diacid salt, benzoate, chloro-benzoate, ar-Toluic acid salt, dinitro-benzoate, hydroxy benzoate, methoxybenzoic acid salt, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenpropionate, benzenebutanoic acid salt, citrate, lactate, gamma hydroxybutyrate, glycollate, tartrate, mesylate, propane sulfonic acid salt, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt and mandelate.
" prodrug " in this use is under physiological condition or through solvolysis, to be converted into the chemical compound that appointed compound perhaps is converted into the pharmaceutically acceptable salt of said chemical compound.Prodrug comprise amino acid residue wherein, or the polypeptide chain of two or more a plurality of amino acid residues through the chemical compound on amide or the covalently bound free amine group of ester bond, hydroxyl or the carboxyl at formula I chemical compound.The amino acid residue of expection includes but not limited to naturally occurring 20 seed amino acids.Other suitable aminoacid comprises 4-hydroxyproline, oxylysine, demosine, isodemosine, 3-Methyl histidine, norvaline, Beta-alanine, GABA, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Other prodrug type is known in the art.
Following table has shown each chemical compound that the present invention provides or expects.
Table I has shown and has been the embodiment of the present invention of formula IA-1 chemical compound.
Table 1: according to the embodiment of formula IA-1
Figure S2006800349355D00181
R 1a X Y Z
CH 2Cl F I F
CH 2Cl Cl I F
CH 2Cl F Br F
CH 2Cl Cl Br F
CH 2Cl F CH 3 F
CH 2Cl Cl CH 3 F
CH 2Cl F CF 3 F
CH 2Cl Cl CF 3 F
CHCl 2 F I F
CHCl 2 Cl I F
CHCl 2 F Br F
CHCl 2 Cl Br F
CHCl 2 F CH 3 F
CHCl 2 Cl CH 3 F
CHCl 2 F CF 3 F
CHCl 2 Cl CF 3 F
CCl 3 F I F
CCl 3 Cl I F
CCl 3 F Br F
CCl 3 Cl Br F
CCl 3 F CH 3 F
CCl 3 Cl CH 3 F
CCl 3 F CF 3 F
CCl 3 Cl CF 3 F
CH 2OH F I F
CH 2OH Cl I F
CH 2OH F Br F
CH 2OH Cl Br F
CH 2OH F CH 3 F
CH 2OH Cl CH 3 F
CH 2OH F CF 3 F
CH 2OH Cl CF 3 F
CH 2OMe F I F
CH 2OMe Cl I F
CH 2OMe F Br F
CH 2OMe Cl Br F
CH 2OMe F CH 3 F
CH 2OMe Cl CH 3 F
CH 2OMe F CF 3 F
CH 2OMe Cl CF 3 F
CH 2OMe F C≡CH F
CH 2OMe Cl SCH 3 F
Figure S2006800349355D00211
Table 2: according to the embodiment of formula IB
Figure S2006800349355D00221
Figure S2006800349355D00231
Figure S2006800349355D00241
Table 3 has shown the embodiment according to formula IC
Table 3 is according to the embodiment of formula IC
R 1c X Y Z
CH 2CH 3 F I F
CH 2CH 3 Cl I F
CH 2CH 3 F Br F
CH 2CH 3 Cl Br F
CH 2CH 3 F CH 3 F
CH 2CH 3 Cl CH 3 F
Figure S2006800349355D00251
R 1c X Y Z
CH 2CH 2F F I F
CH 2CH 2F Cl I F
CH 2CH 2F F Br F
CH 2CH 2F Cl Br F
CH 2CH 2F F CH 3 F
CH 2CH 2F Cl CH 3 F
CH 2CH 2F F CF 3 F
CH 2CH 2F Cl CF 3 F
CH 2CH 2Cl F I F
CH 2CH 2Cl Cl I F
CH 2CH 2Cl F Br F
CH 2CH 2Cl Cl Br F
CH 2CH 2Cl F CH 3 F
CH 2CH 2Cl Cl CH 3 F
CH 2CH 2Cl F CF 3 F
CH 2CH 2Cl Cl CF 3 F
CH 2CH 2CH 2Cl F I F
CH 2CH 2CH 2Cl Cl I F
CH 2CH 2CH 2Cl F Br F
CH 2CH 2CH 2Cl Cl Br F
CH 2CH 2CH 2Cl F CH 3 F
CH 2CH 2CH 2Cl Cl CH 3 F
CH 2CH 2CH 2Cl F CF 3 F
CH 2CH 2CH 2Cl Cl CF 3 F
CH 2CH 2OH F I F
CH 2CH 2OH Cl I F
CH 2CH 2OH F Br F
CH 2CH 2OH Cl Br F
CH 2CH 2OH F CH 3 F
CH 2CH 2OH Cl CH 3 F
CH 2CH 2OH F CF 3 F
CH 2CH 2OH Cl CF 3 F
CH 2CH 2CH 2OH F I F
CH 2CH 2CH 2OH Cl I F
CH 2CH 2CH 2OH F Br F
CH 2CH 2CH 2OH Cl Br F
CH 2CH 2CH 2OH F CH 3 F
CH 2CH 2CH 2OH Cl CH 3 F
CH 2CH 2CH 2OH F CF 3 F
CH 2CH 2CH 2OH Cl CF 3 F
Figure S2006800349355D00281
Figure S2006800349355D00291
Figure S2006800349355D00311
Figure S2006800349355D00321
Table 4a and 4b have shown the material according to formula I, wherein A=R 1d, but R wherein 1dBe heterocycle; The chemical compound of the type is present in the table 5.Each row of this table is corresponding to different five kinds of materials on the Y position only.
Table 4a
Corresponding to A=R 1dMaterial
Figure S2006800349355D00322
Y a＝CH 3；Y b＝Br；Y c＝I；Y d＝Cl；
CMPD# A，A′ B R 0
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
5(a-d) H，H H CN
6(a-d) H，H H CF 3
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
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
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
19(a-d) -(CH 2) 2- CH 3 OCH 3
20(a-d) -(CH 2) 2- -CH 2CH 2OH OCH 3
21(a-d) -(CH 2) 2- -(CH 2) 2CH(OH)CH 2OH OCH 3
CMPD# A，A′ B R 0
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
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
Table 2B
CMPD# A，A′ B R 0
1(a-d) H，H H The 2-furyl
2(a-d) H，H H 1,2,3 triazolyls-4-base
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 triazolyls-4-base
6(a-d) H，H H The 4-imidazole radicals
7(a-d) H，H -CH 2CH(OH)CH 2OH The 2-furyl
8(a-d) H，H -CH 2CH(OH)CH 2OH 1,2,3 triazolyls-4-base
9(a-d) H，H -CH 2CH(OH)CH 2OH The 4-imidazole radicals
10(a-d) -(CH 2) 2- -CH 2(C 3H 5) The 2-furyl
11(a-d) -(CH 2) 2- -CH 2(C 3H 5) 1,2,3 triazolyls-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
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 2-
Figure 2006800349355_26
The azoles base
18(a-d) -(CH 2) 2- -CH 2CH 2OH 2- The azoles base
19(a-d) -(CH 2) 2- -(CH 2) 2CH(OH)CH 2OH 2-
Figure 2006800349355_28
The azoles base
20(a-d) CH 3，H -(CH 2) 2CH(OH)CH 2OH 2- The azoles base
Table 5 has shown the material of formula II-A and III-A and the material of general formula I D-1, wherein R 1dBe the saturated heterocyclic group.Each row of this table is corresponding to different five kinds of materials on the Y position only.In table, representational material shows through structural formula, and numbers labelling with the respective compound in this table.Chemical compound 1a-74d, 85a-86d and 93a-94d are that wherein G is the illustration of the chemical compound of phenyl; Chemical compound 37a-38d, 77a-82d, 87a-92d, 95a-112d and 115a-116d are the illustrations of formula IA; Chemical compound 127a-130d and 137a-142d are the illustrations of formula II; Chemical compound 113a-114d and 131a-136d are the illustrations of formula III; Chemical compound 117a-124d is the illustration of formula IV; With chemical compound 125a-126d be the illustration of formula V.
The material of table 5 general formula I D-1, II-A and III-A
Figure S2006800349355D00341
Y a＝SCH 3；Y b＝Br；Y c＝I；Y d＝Cl；Y e＝CH 3
Chemical compound # A＝R 1d，Ar 1, or Ar 2 X
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
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
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
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
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
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
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
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
Chemical compound # A＝R 1d，Ar 1, or Ar 2 X
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
36(a-e) The 2-F-5-Cl-phenyl F
37(a-e) 3-cyanic acid-4-F-phenyl Cl
38(a-e) 3-cyanic acid-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
42(a-e) The 3-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
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
51(a-e) 3,5-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
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
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
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
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
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
74(a-e) 4-CHF 2The O-phenyl F
75(a-e) 2-methyl-5 nitros-phenyl Cl
76(a-e) 2-methyl-5-nitro-phenyl F
77(a-e) 2-cyanic acid-phenyl Cl
Chemical compound # A＝R 1d，Ar 1, or Ar 2 X
78(a-e) 2-cyanic acid-phenyl F
79(a-e) 3-cyanic acid-phenyl Cl
80(a-e) 3-cyanic acid-phenyl F
81(a-e) 4-cyanic acid-phenyl Cl
82(a-e) 4-cyanic acid-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
87(a-e) 3-carbamoyl-phenyl Cl
88(a-e) 3-carbamoyl-phenyl F
89(a-e) 3-carboxyl-phenyl Cl
90(a-e) 3-carboxyl-phenyl F
91(a-e) 3-(N, N-formyl-dimethylamino) phenyl Cl
92(a-e) 3-(N, N-formyl-dimethylamino) phenyl F
93(a-e) 4-methyl sulphonyl-phenyl Cl
94(a-e) 4-methyl sulphonyl-phenyl F
95(a-e) 3-(1，3，4
Figure 2006800349355_30
Diazole-2-yl) phenyl 		Cl
96(a-e) 3-(1，3，4
Figure 2006800349355_31
Diazole-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-
Figure 2006800349355_32
Diazole) phenyl 		Cl
100(a-e) 3-(5-methyl isophthalic acid, 3,4-
Figure 2006800349355_33
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-amidine-phenyl Cl
104(a-e) 3-amidine-phenyl F
105(a-e) 3-(1H-tetrazole radical) phenyl Cl
106(a-e) 3-(1H-tetrazole radical) phenyl F
107(a-e) The 4-tetrazolyl-phenyl Cl
108(a-e) The 4-tetrazolyl-phenyl F
109(a-e) 3-Cl-4-[(N-morpholinyl carbonyl) amino] phenyl Cl
110(a-e) 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, the 5-dimethyl is different
Figure 2006800349355_34
The azoles base 		Cl
114(a-e) 3, the 5-dimethyl is different
Figure 2006800349355_35
The azoles 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
118(a-e) The 3-F-benzyl F
119(a-e) The 4-F-benzyl Cl
Chemical compound # A＝R 1d，Ar 1, or Ar 2 X
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
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
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
131(a-e) 1,3,5 trimethyls-1H-pyrazolyl Cl
132(a-e) 1,3,5 trimethyls-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-CF3-1H-pyrazoles-4-base Cl
136(a-e) 1-methyl-3-CF3-1H-pyrazoles-4-base F
137(a-e) 2-acetamido-4-methyl-thiazole-5-Ji Cl
138(a-e) 2-acetamido-4-methyl-thiazole-5-Ji 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-imidazol-4 yl Cl
142(a-e) 1,2-dimethyl-1H-imidazol-4 yl F
Synthetic method and embodiment
The compounds of this invention can be through the several different methods preparation.Following those methods of method meant for illustration and the embodiment intention that provides are used to explain scope of the present invention.Not will be understood that said method or embodiment are with any method restriction the present invention.
I. the preparation of formula VI chemical compound is as follows
Above scheme I illustrates the preparation of the sulfamide derivative of formula VI.1,2 diamine derivative (formula IV) can be easily by nitro-derivative (formula I) preparation of expecting in two-step reaction.Formula IV chemical compound can react with sulfonyl chloride derivatives (formula V is referring to next scheme), thereby forms the sulfonamide of expectation.Additionally, can protect 1,2 diamine derivative IV before with corresponding sulfonic acid chloride reaction, thereby form imidazolone (formula VII).Under alkali condition, make 1,2 diamidogen VIII go protection, the material VI of expectation is provided.
II. the general route of synthetic general formula V chemical compound is as follows
Figure S2006800349355D00382
Above scheme II has shown a kind of embodiment for preparing complicated sulfonic acid chloride.Compounds X X can be synthetic by IX, carries out alkylation and change into potassium salt XII.Use SOCl 2Perhaps POCl 3Handle said salt, desired compounds is provided.Other method for preparing single sulfonyl chloride derivatives more specifically is reported in test portion.
Following examples are provided, so that can understand more fully to the present invention.These embodiment are illustrations scope of the present invention only, should it be regarded as limiting by any way the present invention.
The conventional method of synthetic sulfonamide:
Method A: in anhydrous methylene chloride (3 milliliters/mM) solution of amine (1 equivalent), add anhydrous triethylamine (5 equivalent).In this solution, add sulfonic acid chloride (1 equivalent), and at room temperature with gained solution stirring 16 hours.Through flash chromatography the gained residue is carried out purification with solvent evaporation and on silicon dioxide.
Method B: in anhydrous pyridine (5 milliliters/mM) solution of the amine (1 equivalent) that stirs, add sulfonic acid chloride (1-5 equivalent).Under 40 ℃, above-mentioned reactant mixture was stirred 48 hours.Above-mentioned reactant mixture is distributed between water and the EtOAc.The gained organic layer with brine wash, carry out drying (MgSO 4) and under reduced pressure concentrate.The gained residue carries out purification through flash chromatography on silicon dioxide.
Embodiment 1
N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl) Methanesulfomide:
Steps A: 2,3-two fluoro-N-(2-fluoro-4-iodophenyl)-6-nitroaniline:
(11.40g drips the THF solution (47mmol) that adds 47ml 1M LHMDS in 100ml anhydrous THF solution 47mmol) to 0 ℃ 2-fluoro-4-Iodoaniline.The color of solution becomes mulberry.Through sleeve pipe solution is changed in the Dropping funnel, and with solution (containing the amine free alkali) divide aliquot join 0 ℃ 2,3, (8.321g is in anhydrous THF (50ml) solution 47.0mmol) for the 4-trifluoronitrobenzene.Add after the completion, in argon, at room temperature mixture was stirred 15 hours.Reduce the volume of solvent, utilize ethyl acetate and saline to extract subsequently.The gained organic layer is used dried over sodium sulfate, and solvent is removed and through flash chromatography (EtOAc/ hexane 1: 5, R f=0.58) dark oil that obtains is carried out purification, thereby obtain thick product, it becomes brown solid (yield: 6.23g, 33.6%) through carrying out drying in a vacuum.m/z＝393[M-1] -。
Step B:5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen
To nitro-diaryl amine (6.23g, add in 300ml alcoholic solution 15.8mmol) iron powder (13.74g, 246mmol) and ammonium chloride (13.59g, 254mmol), and under 100 ℃ oil bath temperature, with mixture heated with stirred 14 hours.To its filter and the gained residue with twice of washing with alcohol.In a vacuum ethanol is removed and the gained residue extracts with ethyl acetate/1M NaOH solution.During milking, form more depositions, with its filtration with remove.The organic layer that merges carries out drying with brine wash and with sodium sulfate.With solvent remove and the thick product of gained at CHCl 3/ hexane carries out recrystallization in (1: 50).Obtain to be the product of brown spicule (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 is amino) phenyl) Methanesulfomide:
According to conventional method A, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and mesyl chloride reaction, thereby the product of acquisition expectation.
1H?NMR：(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
N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl) cyclopropane sulfonamide:
Figure S2006800349355D00411
According to conventional method A, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and the reaction of cyclopropane sulfonic acid chloride, thereby the product of acquisition expectation.
1H?NMR：(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] -.
Embodiment 3
N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl) propane-2-sulfonamide:
Figure S2006800349355D00412
According to conventional method A, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and the reaction of isopropyl sulfonic acid chloride, thereby the product of acquisition expectation.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-1] -.
Embodiment 4
N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl) butane-1-sulfonamide:
Figure S2006800349355D00421
According to conventional method A, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and the reaction of normal-butyl sulfonic acid chloride, thereby the product of acquisition expectation.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)，5.65(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 is amino) phenyl)-2,2,2-trifluoro ethyl sulfonamide:
According to conventional method A, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 1,1, the reaction of 1-trifluoro ethyl sulfonic chloride, thereby the product of acquisition expectation.Yield: 28%.m/z＝509[M-1] -.
Embodiment 6
N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl) butane-2-sulfonamide:
Figure S2006800349355D00431
According to conventional method A, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and the reaction of sec-butyl sulfonic acid chloride, thereby the product of acquisition expectation.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 is amino) phenyl)-N-methyl cyclopropane sulfonamide:
Figure S2006800349355D00432
Under-78 ℃; (283.9mg adds 1M LHMDS solution (0.6ml to cyclopropane-sulfonamide (referring to embodiment 2) in 3ml anhydrous THF solution 0.61mmol) to N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl); 0.6mol), and under this temperature with solution stirring 10 minutes.Then, (0.8ml, 1.824g 12.9mmol) add wherein, make mixture be warming up to room temperature and stir 7 hours with iodomethane.Solvent is removed and gained residue use EtAc and saline water extraction.The gained organic component uses Na 2SO 4Dry and solvent removed.The thick product utilization flash column chromatography (Si, EtAc/ hexane 1: 2, the R that obtain f=0.45) carries out purification.
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 is amino) phenyl) Methanesulfomide:
Figure S2006800349355D00441
According to conventional method A, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and the reaction of chloromethanes sulfonic acid chloride, thereby the product of acquisition expectation.m/z＝475[M-1] -。
Embodiment 9
N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl)-2-methylpropane-2-sulfonamide:
According to conventional method B, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 2-methylpropane-2-sulfonic acid chloride (synthetic) reaction, thereby the product of acquisition expectation according to literature method.
1H NMR (300MHz, CDCl 3): δ 7.50 (m, 1H), 7.43 (dd, J=1.8 & 10.5Hz, 1H), 7.28 (br s, 1H), 7.10 (dd, J=9.0 & 17.7Hz, 1H), 6.48 (br s, D 2O is tradable, 1H), 6.19 (t, J=7.8 & 9.6Hz, 1H), 5.58 (br s, D 2O is tradable, 1H), 1.39 (s, 9H); M/z=383 [M-1] -.
Embodiment 10
N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl) Pentamethylene. sulfonamide:
Figure S2006800349355D00451
According to conventional method B, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and the reaction of Pentamethylene. sulfonic acid chloride, thereby the product of acquisition expectation.
1HNMR (300MHz, CDCl 3): δ 7.42 (dd, J=2.1 & 10.5Hz, 1H), 7.36 (ddd, J=2.4,4.8, & 9.3Hz, 1H), 7.25 (m, 2H), 7.10 (dd, J=9.6 & 17.7Hz, 1H), 6.67 (br s, D 2O is tradable, 1H), 6.20 (dt, J=1.5,8.4 & 17.4Hz, 1H), 3.53 (p, 1H), 1.80 (m, 8H); M/z=495 [M-1] -.
Embodiment 11
N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl) cyclohexane extraction sulfonamide:
Figure S2006800349355D00452
According to conventional method B, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and the reaction of cyclohexane extraction sulfonic acid chloride, thereby the product of acquisition expectation.
1H NMR (300MHz, CDCl 3): δ 7.43 (dd, J=1.5 & 10.2Hz, 1H), 7.37 (ddd, J=2.4,4.8 & 9.6Hz; 1H), 7.27 (m, 1H), 7.11 (dd, J=9.3 & 18.0Hz, 1H); 6.64 (br s, 1H), 6.18 (dt, J=1.5,9.0 & 17.4Hz, 1H); 5.63 (br s, 1H), 2.95 (three 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 is amino) phenyl)-1-methyl cyclopropane-1-sulfonamide:
Steps A: the positive butyl ester of 3-chloro-1-propane sulfonic acid:
Figure S2006800349355D00461
At CH 2Cl 2(28ml, (36.6g is 200mmol) with 1-butanols (18.4g, CH 240mmol) 200mmol) slowly to join ice-cooled 3-chloro-1-third sulfonic acid chloride for triethylamine (50ml) 2Cl 2(250ml) in the solution, and continue to stir 16 hours.The gained mixture is used CH 2Cl 2(200ml) dilute, wash (HCl aqueous solution) and dry (MgSO 4), and with solvent evaporation, thereby obtaining title product 1 (40.85g, 95%) for the thick form of slight yellow oil, it need not be further purified and promptly can be used in next reaction.
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:
Figure S2006800349355D00462
Under-78 ℃, in nitrogen atmosphere, (1.6M, solution THF) join among the THF (150ml) simultaneously for 14.7ml, 23.53mmol with 3-chloro-1-propane sulfonic acid 1-butyl ester (4.6g, the 25ml THF solution of 21.39mmol) and butyl lithium.Make solution be warming up to 0 ℃ and water (2ml) quencher then.Volatile matter vapourisation under reduced pressure and gained residue are used CH 2Cl 2(150ml) extract.Extract obtained with water washing with carry out drying (MgSO 4) with evaporation, thereby be given the thick expected product (3.23g, 78.22%) of the almost pure form of light yellow oil, it need not be further purified and promptly can be used in next reaction.
1HNMR (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 (septet, 1H), 4.23 (t, J=6.6Hz, 2H).
Step C:1-methyl-cyclopropane sulfonic acid butyl ester
Under-78 ℃, in nitrogen atmosphere, to cyclopropane sulfonic acid 1-butyl ester (1g, slowly add in THF 5.58mmol) (15ml) solution butyl lithium solution (3.84ml, 6,14mmol, 1.6M, THF).After 15 minutes, (0.72ml 11.16mmol) adds wherein, and makes solution be warming up to 0 ℃ and water (1ml) quencher with MeI.Volatile matter vapourisation under reduced pressure and gained residue are used CH 2Cl 2(100ml) extract.Extract obtained with water washing, carry out drying (MgSO 4) and evaporation.The gained residue is through silica gel chromatography (eluent: hexane/CH 2Cl 2) carry out purification, thus obtain to be the title product of water white oil (0.59g, 55.0%).
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 sulfonic acid 1-potassium:
Figure S2006800349355D00472
Make 1-methyl-cyclopropane sulfonic acid 1-butyl ester (0.386g, 2mmol) and potassium thiocyanate (0.194g, the mixture of DME 2mmol) (5ml) and water (5ml) refluxed 16 hours.With volatile matter evaporation, 50 ℃ of following vacuum dryings 16 hours, thereby obtain thick sulfonate (0.348g, quantitatively).This thick product need not be further purified and promptly can be used in next reaction.
1H?NMR(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:
Figure S2006800349355D00481
Make 1-methyl-cyclopropane sulfonic acid 1-potassium (0.348g, 2mmol), the solution of thionyl chloride (5ml) and DMF (5) is 60 ℃ of refluxed 16 hours.Volatile matter vapourisation under reduced pressure and gained residue are used CH 2Cl 2(50ml) extract.Extract obtained with water washing, carry out drying (MgSO 4) and evaporation, thereby obtaining thick product into yellow gummy oil, it need not be further purified and promptly can be used in next reaction.
Step F: N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl)-1-methyl cyclopropane-1-sulfonamide:
According to conventional method B, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 1-methyl-cyclopropane sulfonic acid chloride reaction, thereby the product of acquisition expectation.
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 is amino) phenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide:
Steps A: cyclopropane sulfonic acid butyl ester:
Figure S2006800349355D00491
Cyclopropane sulfonic acid chloride (5g, 35 mMs, 1 equivalent) is dissolved among the excessive BuOH (20ml), under-10 ℃, reactant mixture is cooled off, and pyridine (5.8mL, 70 mMs, 2 equivalents) slowly is added dropwise to wherein.Make said mixture slowly be warming up to room temperature and with its stirred overnight.Decompression is removed solvent down and the gained white solid is dissolved in CHCl 3In.Gained organic facies water and brine wash are carried out drying (MgSO 4) and concentrate, thereby give fuel-displaced (4.8g, 24.9 mMs, 71%).
1HNMR(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:
Under nitrogen atmosphere, in the THF solution of-78 ℃ cyclopropane sulfonic acid 1-butyl esters (4.8g, 24.9 mMs), add simultaneously butyl lithium solution (15.6ml, 24.9mmol, 1.6M, THF) and allyl iodide (24.9 mM).Under-78 ℃, above-mentioned reactant mixture was stirred 2 hours and at room temperature stirred 3 hours.Under reduced pressure CH is used in volatile matter evaporation and gained residue 2Cl 2(100ml) extract.Extract obtained with water washing, carry out drying (MgSO 4) and evaporation.The gained residue is through silica gel chromatography (eluent: hexane/CH 2Cl 2) carry out purification, thus obtain to be the title product of water white oil (3.75g, 69.0%).
1HNMR(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:
Figure S2006800349355D00501
Make 1-methyl-cyclopropane sulfonic acid 1-butyl ester (3.75g, 17.2mmol) and potassium thiocyanate (1.7g, the mixture of DME 17.2mmol) (20ml) and water (20ml) refluxed 16 hours.With volatile matter evaporation, 50 ℃ of following vacuum dryings 16 hours, thereby obtain thick sulfonate (3.44g, quantitatively).This thick product need not be further purified and promptly can be used in next reaction.
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:
Figure S2006800349355D00502
Make 1-pi-allyl cyclopropane-1-potassium sulfonate (3.44g, 17.2mmol), the solution of thionyl chloride (10ml) and DMF (5) is 60 ℃ of refluxed 16 hours.Volatile matter vapourisation under reduced pressure and gained residue are used CH 2Cl 2(50ml) extract.Extract obtained with water washing, carry out drying (MgSO 4) and evaporation, to use hexane wash, thereby obtain thick product (2.7g, 15 mMs, 87%) into yellow gummy oil, it need not be further purified and promptly can be used in next reaction.
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 is amino) phenyl) cyclopropane-1-sulfonamide:
Figure S2006800349355D00503
According to conventional method B, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 1-pi-allyl cyclopropane-1-sulfonic acid chloride reaction, thereby the product of acquisition expectation.m/z＝507[M-1] -.
Step F: N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide:
Figure S2006800349355D00511
1-pi-allyl-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl) cyclopropane-1-sulfonamide (0,77g, 1.52 mMs) and 4-methyl morpholine N-oxide (0,18g, 1.52 mMs) are dissolved among the THF (50mL).At room temperature with Osmic acid. (0.152 mM, 0.965mL, 4%H 2O solution) add wherein, and at room temperature reactant mixture was stirred 16 hours.EtOAc is added wherein, the gained organic facies with water washing, carry out drying (MgSO 4) and under reduced pressure concentrate.The gained residue is through silica gel chromatography (eluent: EtOAc/MeOH) carry out purification, thereby obtain title product (0.65g, 79%).
1HNMR(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 is amino) phenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide:
Figure S2006800349355D00521
Pure S isomer obtains through 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 is amino) phenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide:
Pure R isomer obtains through 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?&?9.3H2，1H)，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 is amino) phenyl)-1-(2-ethoxy) cyclopropane-1-sulfonamide:
Steps A: 2-(1-bromine cyclopropyl) ethanol:
Under 0 ℃, to pure diethyl zinc (3.3ml, 3.977g, drip to add very lentamente in the anhydrous DCM solution of 100ml 30mmol) trifluoroacetic acid (2.31ml, 3.4188g, 30mmol).(careful: gas fiercely is overflowed, heat release! ).After TFA add to accomplish, under uniform temp, suspension was stirred 20 minutes, add subsequently diiodomethane (2.45ml, 8.134g, 30.4mmol).Under 0 ℃, it was further stirred 20 minutes, (10ml DCM solution 10.1mmol) adds wherein for 1ml, 1.523g with 3-bromine fourth-3-alkene-1-alcohol under uniform temp then.After adding fully, mixture is warming up to room temperature and stirred 4 hours.Said mixture is with 100mlMeOH and the quencher of 40ml saline and further it was stirred 30 minutes.Reduce solvent and gained residue and use CHCl 3/ NH 4The Cl extraction with aqueous solution.Collected organic layer is removed with saline and water washing with solvent, thereby provides 2-(1-bromine the cyclopropyl)-ethanol (1.6564g, 100%) of abundant purity.
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).
2-(the 1-bromine cyclopropyl) ethanol of step B:TBS protection:
Figure S2006800349355D00532
To ring propanol (steps A) (1.303g, add in the anhydrous DCM solution of 30ml 7.95mmol) anhydrous pyridine (1.2ml, 1,1736g, 14.8mmol) and TBSOTf (2.7ml, 3.1077g, 11.76mol), and at room temperature with solution stirring 16 hours.Use CHCl 3/ saline water extraction and gained organic component are used MgSO 4Dry.Reduce solvent and gained thick product utilization flash column chromatography (Si, CHCl 3/ hexane 1: 10, R f=0.4) carries out purification.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，11H)，0.15-0.05(s，6H).
2-(the 1-chlorosulfonyl cyclopropyl) ethanol of step C:TBS protection:
Figure S2006800349355D00541
Under-78 ℃, the Cyclopropyl Bromide that in step B, prepares (1.1227g, and the pentane solution of adding 1.7M t-BuLi in 15ml anhydrous ether solution 4.04mmol) (4.8ml, 8.16mmol).With solution stirring 30 minutes, (0.65ml, 1.029g was in 8ml diethyl ether solution 8.1mmol) under-78 ℃, to change it over to distillatory recently sulfonic acid chloride through pipet then under this temperature.This yellow suspension is warming up to room temperature.Solvent is removed and in a vacuum the gained residue carried out drying, thereby remove excessive sulfonic acid chloride.Then, the gained residue with twice of hexane extraction with after filtering in a vacuum with solvent evaporation, thereby be given the sulfonic acid chloride of the abundant purity of water white oil.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).
The N-of step D:TBS-protection (3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl)-1-(2-ethoxy) cyclopropane-1-sulfonamide:
Figure S2006800349355D00542
According to conventional method B, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1, the cyclopropyl sulfonic acid chloride for preparing among 2-diamidogen and step C reaction, thereby the product of acquisition expectation.
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 is amino) phenyl)-1-(2-ethoxy) cyclopropane-1-sulfonamide:
Figure S2006800349355D00551
Under 0 ℃, the sulfonamide of the TBS-that in step D, prepares protection (21mg adds 0.1ml 1.2N HCl aqueous solution in 1ml THF solution 0.033mmol), and with gained solution stirring 2 hours.Reduce solvent and gained residue and use NaHCO 3Aqueous solution and EtAc extract.The gained organic fraction is used MgSO 4Drying, and volatile matter removed.Use flash column chromatography (Si, CHCl 3/ MeOH 10: 1, R f=0.45) the thick product of gained is carried out purification, thereby provide net 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 is amino) phenyl)-3-hydroxy propane-1-sulfonamide:
Figure S2006800349355D00552
(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl)-(4-two for 69.4mg, 8ml 1 0.138mmol) for propane-1-sulfonamide to 3-chloro-N-
Figure 2006800349355_36
Alkane and 2ml H 2(0.674g 12.0mmol), and heats mixture 3 days under reflux temperature to add the KOH powder in the solution of O mixture.Use the EtAc/ saline water extraction, the gained organic component is used Na 2SO 4Dry and volatile matter removed.The gained residue uses flash column chromatography (Si, DCM/MeOH 5: 1, R f=0.3) carries out purification.Output: 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 is amino) phenyl)-2-methyl-5-(trifluoromethyl) furan-3-sulfonamide:
Figure S2006800349355D00561
According to conventional method; Make 5; 6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1; 2-diamidogen (0.182 mM) and 2-methyl-5-(trifluoromethyl) furan-3-sulfonic acid chloride (0.5 mM) reaction, thus N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl)-2-methyl-5-(trifluoromethyl) furan-3-sulfonamide formed.
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 is amino) phenyl sulfamoyl base)-methylthiazol-2-yl) acetamide:
Figure S2006800349355D00571
According to conventional method; Make 5; 6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1; 2-diamidogen (0.182 mM) and 2-acetylaminohydroxyphenylarsonic acid 4-methylthiazol-5-sulfonic acid chloride (0.5 mM) reaction, thus N-(5-(N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl) sulfamoyl)-4-methylthiazol-2-yl) acetamide obtained.
1HNMR(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 is amino) phenyl) thiophene-2-sulfonamide:
Figure S2006800349355D00572
According to conventional method, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1; 2-diamidogen (0.182 mM) and the reaction of 5-(5-chloro-1,2,4-thiadiazoles-3-yl) thiophene-2-sulfonic acid chloride (0.5 mM); Thereby obtain 5-(5-chloro-1; 2,4-thiadiazoles-3-yl)-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is 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 is amino) phenyl)-3,5-dimethyl different
Figure 2006800349355_37
azoles-4-sulfonamide:
Figure S2006800349355D00581
According to conventional method; Make 5; 6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1; 2-diamidogen (0.182 mM) and 3; Different azoles-4-sulfonic acid chloride of 5-dimethyl (0.5 mM) reaction; Thereby obtain N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl)-3,5-dimethyl different
Figure 2006800349355_39
azoles-4-sulfonamide.
1H?NMR(300MHz，CDCl 3))δ2.2(s，3(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 is amino) phenyl)-1,3-dimethyl-1H-pyrazoles-4-sulfonamide:
Figure S2006800349355D00582
According to conventional method; Make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen (0.182 mM) and 5-chloro-1; 3-dimethyl-1H-pyrazoles-4-sulfonic acid chloride (0.5 mM) reaction; Thereby obtain 5-chloro-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is 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 is amino) phenyl)-2,5-dimethyl furan-3-sulfonamide:
According to conventional method, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1; 2-diamidogen (0.182 mM) and 2,5-dimethyl furan-3-sulfonic acid chloride (0.5 mM) reaction, thus obtain N-(3; 4-two fluoro-2-(2-fluoro-4-iodophenyl is 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 is amino) phenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazoles-4-sulfonamide:
Figure S2006800349355D00601
According to conventional method; Make 5; 6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1; 2-diamidogen (0.182 mM) and 1-methyl-3-(trifluoromethyl)-1H-pyrazoles-4-sulfonic acid chloride (0.5 mM) reaction, thus N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazoles-4-sulfonamide obtained.
1HNMR(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 is amino) phenyl)-2,4-dimethylthiazole-5-sulfonamide:
Figure S2006800349355D00602
According to conventional method, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1; 2-diamidogen (0.182 mM) and 2,4-dimethylthiazole-5-sulfonic acid chloride (0.5 mM) reaction, thus obtain N-(3; 4-two fluoro-2-(2-fluoro-4-iodophenyl is 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，1H)，7.4(d，1H)，7.4(s，1H).
Embodiment 26
N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl)-1,2-dimethyl-1H-imidazoles-4-sulfonamide:
Figure S2006800349355D00611
According to conventional method B, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 1,2-dimethyl-1H-imidazoles-4-sulfonic acid chloride reaction, thus obtain 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 is amino) phenyl) thiophene-3-sulfonamide:
Figure S2006800349355D00612
According to conventional method B, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and thiophene-3-sulfonic acid chloride reaction, thus obtain title compound.
1H NMR (300MHz, CDCl 3): δ 8.00 (dd, J=1.2 & 3.3Hz, 1H), 7.45 (dd, J=0.9& 5.1Hz, 1H); 7.35 (m, 2H), 7.27 (m, 2H), 6.91 (dd, J=9.3 & 17.1Hz; 1H), 6.64 (ddd, J=2.1,4.8 & 8.7Hz, 1H), 6.34 (dt; J=5.4,8.7 & 14.1Hz, 1H), 5.98 (br d, J=2.1Hz, D 2O is tradable, 1H).
Embodiment 28
N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl) furan-2-sulfonamide:
Figure S2006800349355D00621
According to conventional method B, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and furan-2-sulfonic acid chloride reaction, thus obtain title compound.
1H NMR (300MHz, CDCl 3): δ 7.53 (br s, D 2O is tradable, 1H), 7.38 (dd, J=1.8 & 10.5Hz, 1H), 7.30 (d, J=8.4Hz; 1H), 7.21 (d, J=3.0Hz, 1H), 6.96 (dd, J=8.7 &16.5Hz, 1H); 6.87 (ddd, J=1.8,5.1 & 9.0Hz, 1H), 6.53 (dd, J=1.8 & 3.6Hz, 1H); 6.44 (dt, J=5.1,8.7 & 13.8Hz, 1H), 6.22 (br s, D 2O is tradable, 1H).
Embodiment 29
N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl)-5-methylthiophene-2-sulfonamide:
Figure S2006800349355D00622
According to conventional method B, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 5-methylthiophene-2--sulfonic acid chloride reaction, thus obtain title compound.
1H NMR (300MHz, CDCl 3): δ 7.34 (dd, J=0.9 & 10.2Hz, 1H), 7.30 (ddd, J=2.1,4.8 & 9.0Hz, 1H); 7.25 (d, J=3.9Hz, 1H), 7.07 (m, 2H), 6.65 (dd, J=1.2 & 3.9Hz; 1H), 5.89 (dt, J=2.4,8.7 & 17.4Hz, 1H), 5.54 (br s, D 2O is tradable, 1H), 2.46 (s, 3H).
Embodiment 30
5-chloro-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl) thiophene-2-sulfonamide:
According to conventional method B, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 5-chlorothiophene-2--sulfonic acid chloride reaction, thus obtain title compound.
1H NMR (300MHz, CDCl 3): δ 7.38 (dd, J=1.5 & 10.2Hz, 1H), 7.32 (ddd, J=2.1,5.1 & 9.3Hz, 1H), 7.25 (d; J=3.9Hz, 1H), 7.10 (dd, J=9.0 & 18.6Hz, 3H), 6.84 (d, J=4.2Hz; 1H), 5.86 (dt, J=1.8,8.7 & 17.4Hz, 1H), 5.49 (br s, D 2O is tradable, 1H).
Embodiment 31
5-bromo-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl) thiophene-2-sulfonamide:
Figure S2006800349355D00632
According to conventional method B, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 5-bromothiophene-2-sulfonic acid chloride reaction, thus obtain 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 is amino) phenyl) thiophene-3-sulfonamide:
According to conventional method B, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 4-bromothiophene-3-sulfonic acid chloride reaction, thus obtain title compound.
1H?NMR(300MHz，CDCl 3)：δ7.48(brm，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 is amino) phenyl) thiophene-2-sulfonamide:
Figure S2006800349355D00642
According to conventional method B, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 4-bromo-5-chlorothiophene-2-sulfonic acid chloride reaction, thus obtain 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 is amino) phenyl) thiophene-2-sulfonamide:
Figure S2006800349355D00651
According to conventional method B, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 3-bromo-5-chlorothiophene-2-sulfonic acid chloride reaction, thus obtain 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 is amino) phenyl)-2,5-thioxene-3-sulfonamide:
Figure S2006800349355D00652
According to conventional method B, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 2,5-thioxene-3-sulfonic acid chloride reaction, thus obtain 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 is amino) phenyl) thiophene-3-sulfonamide:
Figure S2006800349355D00661
According to conventional method B, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 2,5-dichloro-thiophene-3-sulfonic acid chloride reaction, thus obtain 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 is amino) phenyl) sulfonamides) thiophene-2-carboxylic acid methyl ester:
Figure S2006800349355D00662
According to conventional method B, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1, the reaction of 2-diamidogen and 3-(chlorosulfonyl) thiophene-2-carboxylic acid methyl ester, thus obtain 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 is amino) phenyl) sulfonamides)-1-methyl isophthalic acid H-pyrroles-2-carboxylate methyl ester:
According to conventional method B, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 5-(chlorosulfonyl)-1-methyl isophthalic acid H-pyrroles-2-carboxylate methyl ester reaction, thus obtain title compound.
1H?NMR(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(br?s，1H)，3.65(s，3H)，3.75(s，3H).
Embodiment 39
N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl)-5-methyl different azoles-4-sulfonamide:
Figure S2006800349355D00672
According to conventional method A, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and corresponding sulfonic acid chloride reaction, thus obtain title compound.Yield: 22%.m/z＝508[M-1] -.
Embodiment 40
3-chloro-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl) propane-1-sulfonamide:
Figure S2006800349355D00673
According to conventional method A, make 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl) benzene-1,2-diamidogen and 3-chloropropane-1-sulfonic acid chloride reaction, thereby the product of acquisition expectation.
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).
Synthesizing of conventional method C:N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl)-2-(alkyl amino) ethyl sulfonamide:
(0.1ml 1mmol) joins 5,6-two fluoro-N with 2-chloro-ethyl sulfonic chloride 1-(2-fluoro-4-iodophenyl) benzene-1, and the 2-diamidogen (0.364g, 1mmol) and triethylamine (0.28ml, CH 2mmol) 2Cl 2(5ml) in the solution, and at room temperature reactant mixture was stirred 16 hours.Use excess amine (10 equivalent) that it is handled then as solution or neat liquid.Reactant mixture was at room temperature stirred 6 hours in addition.Reactant mixture is used CH 2Cl 2(10ml) and water (10ml) dilute.The gained organic layer is used rare HCl in proper order, and (2 * 20ml is 2N) with saturated NaHCO 3(2 * 10ml) solution washings.Then to CH 2Cl 2Layer carries out drying (MgSO 4) and evaporation, thereby obtain thick product.Gained not net product carries out purification under preparation HPLC condition, thereby obtains net product with the 50-60% yield.
Embodiment 41
N-(2-(4-chloro-2-fluorophenyl is amino)-3,4-difluorophenyl) cyclopropane sulfonamide:
Figure S2006800349355D00681
Referring to embodiment 1.
1H?NMR(300MHz，CDCl 3)δ0.85-0.95(m，2H)，1.05-1.15(m，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 is amino) phenyl) cyclopropane sulfonamide:
Figure S2006800349355D00691
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 is amino)-3,4-difluorophenyl) cyclopropane sulfonamide:
Figure S2006800349355D00692
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, the 4-Dichlorobenzene base is amino)-3,4-difluorophenyl) cyclopropane sulfonamide:
Figure S2006800349355D00701
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:
Figure S2006800349355D00702
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 & 17.7Hz, 1H), 6.78 (br s, D 2O is tradable, 1H), 6.50 (t, J=8.1Hz, 1H), 6.00 (br d, D 2O is tradable, J=1.5Hz, 1H), 3.63 (t, J=6.0 & 6.3Hz, 2H), 3.29 (t, J=7.2 &7.8Hz, 2H), 2.26 (quintet, 2H); M/z=445 [M-1] -.
Embodiment 46
N-(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 & 17.4Hz, 1H), 6.90 (br s, D 2O is tradable, 1H), 6.45 (dd, J=1.5 & 8.4Hz, 1H), 6.39 (br s, D 2O is tradable, 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:
Figure S2006800349355D00712
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 & 17.4Hz, 1H), 6.91 (br s, D 2O is tradable, 1H), 6.50 (dd, J=8.4 & 1.5Hz, 1H), 6.37 (s, D 2O is tradable, 1H), 3.62 (t, J=6.0Hz, 2H), 3.29 (t, J=7.5 & 7.8Hz, 2H), 2.27 (quintet, 2H); M/z=462 [M-1] -.
Embodiment 48
3-chloro-N-(3,4-two fluoro-2-(2-bromo-4-trifluoromethyl) phenyl amino) phenyl) propane-1-sulfonamide:
Figure S2006800349355D00721
Referring to embodiment 1.
1H NMR (300MHz, CDCl 3): δ 7.82 (s, 1H), 7.38 (m, 2H), 7.20 (dd, J=9.0 & 17.7Hz, 1H), 6.62 (br s, D 2O is tradable, 1H), 6.43 (d, J=8.4Hz, 1H), 6.23 (s, D 2O is tradable, 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)-amide:
Steps A (2-fluoro-4-iodo-phenyl)-(2,3,5-three fluoro-6-nitro-phenyl)-amine:
Figure S2006800349355D00722
Under nitrogen, (3.64gm, anhydrous THF (100ml) solution 15.37mmol) is cooled to-78 ℃, and with 1.0M hexamethyl two silica-based amido lithium (LiN (SiMe with the 2-fluoro-4-Iodoaniline that stirs 3) 2), " LHMDS ", 15.37ml 15.37mmol) slowly adds wherein.
Under-78 ℃, this reactant mixture is kept stirring other 1 hour, then with 2,3,4,6-tetrafluoro Nitrobenzol adds wherein.Making above-mentioned reactant mixture be warming up to room temperature and continue stirs them 16 hours.Ethyl acetate (200ml) is joined in the reactant mixture and uses water washing.The gained organic layer is with dried over sodium sulfate and further carry out purification through column chromatography, thereby yellow solid (3.75gm, yield: 59.24%) are provided.
M-H +：410.9. 1HNMR(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-diamidogen:
Figure S2006800349355D00731
To (2-fluoro-4-iodo-phenyl)-(2,3,5-three fluoro-6-nitro-phenyl)-amine 3 that stirs (5.2gm, add in EtOH 12.62mmol) (200ml) solution ammonium chloride (10.12gm, 189.3mmol) and iron powder (10.57gm, 189.3mmol).Above-mentioned reactant mixture was kept refluxing and stirring 16 hours.Make reactant mixture cooling and with its filtration over celite be concentrated into drying.The residue that obtains is absorbed among the EtOAc and uses water washing.Gained EtOAc layer is with dried over sodium sulfate and further carry out purification through crystallization in EtOH, thereby pale solid (3.2gm, yield: 66.39%) are provided.
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:
Figure S2006800349355D00732
To 3,4 of stirring, 6-three fluoro-N 2-(2-fluoro-4-iodo-phenyl)-benzene-1,2-diamidogen 3 (0.285gm, CH 0.74mmol) 2Cl 2(2ml) add 1,1 in the solution '-N,N'-carbonyldiimidazole (0.125gm, 0.75mmol).When the product deposition is separated out, at room temperature above-mentioned reactant mixture is kept stirring 16 hours.Filter this white solid, can use without any need for being further purified.(0.2gm, yield: 65.85%); M/z=407 [M-1] -
Step D/E: cyclopropane sulfonic acid (3,4,6-three fluoro-2-(2-fluoro-4-iodo-phenyl amino)-phenyl)-amide:
Under nitrogen, with 4,6 of stirring; 7-three fluoro-1-(2-fluoro-4-iodo-phenyl)-1, and 3-dihydrobenzo imidazoles-2-ketone (0.2gm, anhydrous THF (4ml) solution 0.41mmol) is cooled to-78 ℃; And (0.41ml 0.41mmol) slowly adds wherein with 1.0M LiHMDS solution.(2ml) add subsequently the cyclopropane sulfonic acid chloride (0.050ml, 0.49mmol).At room temperature this reactant mixture is kept stirring 16 hours, be concentrated into drying and it is absorbed among the EtOAc.EtOAc is with water washing, be concentrated into drying with dried over sodium sulfate and with it.With the residue 1-cyclopropane sulfonyl-4 that obtains; 5; 7-three fluoro-3-(2-fluoro-4-iodo-phenyl)-1; 3-dihydro-benzimidazolyl-2 radicals-ketone 5 be absorbed into two
Figure 2006800349355_41
in the alkane (2ml); And, keep down stirring 16 hours at 50 ℃ indoor to wherein adding 1.0N NaOH (0.5ml).TLC shows reaction not exclusively, and product carries out purification through HPLC, thereby pale solid (4.4mg) is provided
M+H +：484.7，M-H +：486.7. 1H?NMR(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 is amino)-6-ethoxyphenyl) cyclopropane sulfonamide:
Steps A: (2,3-two fluoro-5-methoxyl group-6-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine:
Figure S2006800349355D00742
Under nitrogen, (1.23gm, anhydrous THF (25ml) solution 3mmol) is cooled to-78 ℃, and (0.68ml 0.3mmol) slowly adds wherein with 25%NaOMe solution with (2-fluoro-4-iodo-phenyl)-(2,3,5-three fluoro-6-nitro-phenyl)-amine that stirs.Making above-mentioned reactant mixture be warming up to room temperature and continue stirred 16 hours.TLC shows that reaction not exclusively.Ethyl acetate (100ml) is joined in the reactant mixture and uses water washing.The gained organic layer is with dried over sodium sulfate and further carry out purification through column chromatography, thereby yellow solid (0.6gm, yield: 47.6%) are provided.m/z＝424[M＝H]+.
Step B:5,6-two fluoro-N1-(4-fluoro-2-iodophenyl)-3-methoxybenzene-1, the 2-diamidogen:
Figure S2006800349355D00751
To (2,3-two fluoro-5-methoxyl group-6-nitro-phenyl)-(2-fluoro-4-iodo-the phenyl)-amine that stirs (0.57gm, add in EtOH 1.34mmol) (20ml) solution ammonium chloride (1.18gm, 20.16mmol) and iron powder (1.15gm, 21.44mmol).Above-mentioned reactant mixture was kept refluxing and stirring 16 hours.Make reactant mixture cooling and with its filtration over celite be concentrated into drying.The residue that obtains is absorbed among the EtOAc and uses water washing.Gained EtOAc layer is with dried over sodium sulfate and further carry out purification through crystallization in EtOH, thereby pale solid (0.47gm, yield: 90.3%) are provided.
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 of stirring, 6-two fluoro-N1-(4-fluoro-2-iodophenyl)-3-methoxybenzene-1,2-diamidogen (0.17gm, CH 0.43mmol) 2Cl 2(2ml) add 1 in the solution, and 1 '-N,N'-carbonyldiimidazole (0.085gm, 0.53mmol).When the product deposition is separated out, at room temperature above-mentioned reactant mixture is kept stirring 16 hours.Filter this white solid and can use without any need for being further purified.(0.089gm)；m/z＝419[M-1] -。
Step D/F:N-(3,4-two fluoro-2-(4-fluoro-2-iodophenyl is amino)-6-methoxyphenyl) cyclopropane sulfonamide:
Figure S2006800349355D00761
Under nitrogen; With the 1-(cyclopropyl sulfonyl)-4 that stirs; 5-two fluoro-3-(2-fluoro-4-iodophenyl)-7-methoxyl group-1H-benzo [d] imidazoles-2 (3H)-ketone (0.89gm; 0.17mmol) anhydrous THF (4ml) solution be cooled to-78 ℃, and (0.17ml 0.17mmol) slowly adds wherein with 1.0M LiHMDS solution.(2ml) add subsequently the cyclopropane sulfonic acid chloride (0.021ml, 0.21mmol).At room temperature this reactant mixture is kept stirring 16 hours, be concentrated into drying and it is absorbed among the EtOAc.The EtOAc layer is with water washing, be concentrated into drying with dried over sodium sulfate and with it.With gained 1-(cyclopropyl sulfonyl)-4; 5-two fluoro-3-(2-fluoro-4-iodophenyl)-7-methoxyl group-1H-benzo [d] imidazoles-2 (3H)-ketone be absorbed into two
Figure 2006800349355_42
in the alkane (2ml), and to wherein adding 1.0N NaOH (0.5ml) and keeping down stirring 16 hours at indoor 50 ℃.TLC shows reaction not exclusively, and product carries out purification through HPLC, thereby pale solid (2.5mg) is provided
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 N-(3,4-two fluoro-2-(2-fluoro-4-iodo-phenyl amino)-6-methoxyl group-phenyl)-amide:
Figure S2006800349355D00762
To 5 of stirring, 6-two fluoro-N 1-(4-fluoro-2-iodophenyl)-3-methoxybenzene-1,2-diamidogen (0.150gm, anhydrous CH 0.38mmol) 2Cl 2(4ml) slowly add in the solution TEA (0.264ml, 1.9mmol) and mesyl chloride.At room temperature this reactant mixture is kept stirring 16 hours, TLC shows that reaction is incomplete, observes two kinds of products with raw material.The gained reactant mixture is used water washing, and organic layer is with dried over sodium sulfate and be concentrated into drying, and products obtained therefrom carries out purification through column chromatography.Find that accessory 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]-amide:
Steps A: 1-pi-allyl-cyclopropane sulfonic acid [3,4,6-three fluoro-2-(2-fluoro-4-iodo-phenyl amino)-phenyl]-amide:
Figure S2006800349355D00771
According to conventional method B, make 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, thus obtain the 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 is amino) phenyl) cyclopropane-1-sulfonamide:
1-pi-allyl-cyclopropane sulfonic acid [3,4,6-three fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl]-amide (110mg, 0.21 mM) and 4-methyl morpholine N-oxide (24.6mg, 0.21 mM) are dissolved among the THF (8mL).At room temperature with Osmic acid. (0.021 mM, 0.153mL, 4%H 2O solution) add wherein, and at room temperature reactant mixture was stirred 16 hours.EtOAc is added wherein, the gained organic facies with water washing, carry out drying (MgSO 4) and under reduced pressure concentrate.The gained residue is through silica gel chromatography (eluent: EtOAc/MeOH) carry out purification, thereby obtain title product (0.89g, 75%).
1HNMR(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 53
(S)-1-(2, the 3-dihydroxypropyl)-N-(3,4,6-three fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl) cyclopropane-1-sulfonamide:
Figure S2006800349355D00782
Pure S isomer obtains through chirality HPLC separation of racemic mixture (embodiment 56).
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 54
(R)-1-(2, the 3-dihydroxypropyl)-N-(3,4,6-three fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl) cyclopropane-1-sulfonamide:
Figure S2006800349355D00791
Pure R isomer obtains through chirality HPLC separation of racemic mixture (embodiment 53).
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 is 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 is amino)-6-methoxyphenyl) cyclopropane-1-sulfonamide;
Figure S2006800349355D00792
According to conventional method B, make 1-pi-allyl-cyclopropane sulfonic acid chloride and 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl)-3-methoxybenzene-1, the 2-diamine reactant, thus obtain the 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 is amino) phenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide:
Figure S2006800349355D00801
1-pi-allyl-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino)-6-methoxyphenyl) cyclopropane-1-sulfonamide (97mg, 0.18 mM) and 4-methyl morpholine N-oxide (21mg, 0.18 mM) are dissolved among the THF (8mL).At room temperature with Osmic acid. (0.018 mM, 0.13mL, 4%H 2O solution) add wherein, and at room temperature reactant mixture was stirred 16 hours.EtOAc is added wherein, the gained organic facies with water washing, carry out drying (MgSO 4) and under reduced pressure concentrate.The gained residue is through silica gel chromatography (eluent: EtOAc/MeOH) carry out purification, thereby obtain title product (0.80g, 78%).
1HNMR(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 is amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide:
Pure S isomer obtains through chirality HPLC separation of racemic mixture (embodiment 59).
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 is amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide:
Figure S2006800349355D00812
Pure R isomer obtains through chirality HPLC separation of racemic mixture (embodiment 59).
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-ethoxy)-N-(3,4,6-three fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl) cyclopropane-1-sulfonamide:
1-(2-the ethoxy)-N-of steps A: TBS-protection (3,4,6-three fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl) cyclopropane-1-sulfonamide:
Figure S2006800349355D00821
According to conventional method B, make the sulfonic acid chloride and 5 for preparing among the embodiment 16 step C, 6-two fluoro-N1-(2-fluoro-4-iodophenyl)-3-fluorobenzene-1, the 2-diamine reactant, thus obtain the 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-ethoxy)-N-(3,4,6-three fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl) cyclopropane-1-sulfonamide:
Figure S2006800349355D00822
Identical with the method for embodiment 16 step e.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 is amino)-6-methoxyphenyl)-1-(2-ethoxy) cyclopropane-1-sulfonamide:
The N-of steps A: TBS-protection (3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino)-6-methoxyphenyl)-1-(2-ethoxy) cyclopropane-1-sulfonamide:
Figure S2006800349355D00831
According to conventional method B, make the sulfonic acid chloride and 5 for preparing among the embodiment 16 step C, 6-two fluoro-N1-(2-fluoro-4-iodophenyl)-3-methoxyl group-benzene-1, the 2-diamine reactant, thus obtain the 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 is amino)-6-methoxyphenyl)-1-(2-ethoxy) cyclopropane-1-sulfonamide:
Figure S2006800349355D00841
Identical with the method for embodiment 16 step e.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 is amino)-6-methoxyphenyl)-1-(3-hydroxyl-2-(methylol) propyl group) cyclopropane-1-sulfonamide:
Steps A: 2-(2-bromine pi-allyl) dimethyl maleate:
Figure S2006800349355D00842
Under 0 ℃, in argon, (5.0g adds dimethyl malenate (11.7ml, HMPA 100mmol) (5ml) solution in the suspension of HMPA 125mmol) (50ml distills) from calcium hydride to sodium hydride.Said mixture is heated to 50 ℃ and it was stirred 1 hour.After this, this solution is cooled to 0 ℃ and with 2 once more, (12.2ml, HMPA 100mmol) (5ml) solution joins in the reactant mixture 3-propylene bromide.Subsequently, solution is warming up to 40 ℃ and it was stirred 1 hour.Reactant mixture with the HCl aqueous solution (10%, 88ml) quencher and with ether (3 * 45ml) extract.Collect organic component, use MgSO 4Dry and in a vacuum solvent is removed.The thick oil of gained is through silica gel chromatography (eluent: chloroform/hexane) carry out purification, thereby obtain to be the title product of water white oil (16.3g, 65%).
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) propane-1, the 3-glycol:
Figure S2006800349355D00851
(1.9g 7.65mmol) processes serosity, and in dry ice/acetone batch, it is cooled to-78 ℃ with lithium aluminium hydride reduction in absolute ether (50ml).Then, (0.639g, absolute ether 16.84mmol) (26ml) solution drip and add wherein with the product that is obtained from steps A.After adding malonate wherein, make solution be warming up to room temperature and continue and stirred 3 hours.(50mL) will react quencher with saline, and (3 * 25mL) extract and use MgSO with ethyl acetate 4Carry out drying.In a vacuum solvent is removed, thereby provided the product (1.3g, 86%) of expectation, it need not be further purified and can use.
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: 2-(the 2-bromine pi-allyl) propane-1 of two-t-butyldimethylsilyl protection, the 3-glycol:
Figure S2006800349355D00852
(2.8g 14.20mmol) is dissolved among the anhydrous THF (140ml) with the product that is obtained from step B.(2.5ml 31.24mmol) adds wherein, and solution is cooled to 0 ℃ with anhydrous pyridine.(7.2ml 31.24mmol) drips adding wherein, and after accomplishing above-mentioned dropping, reaction solution is heated to 35 ℃ with the t-butyldimethylsilyl triflate.After stirring 6 days, reaction is with the quencher of 100ml saline, (3 * 50ml) extract and use MgSO with ethyl acetate 4Dry.The organic facies that merges is evaporated, thereby obtains to be the thick product of yellow oil (5.5g, 91%), and it need not be further purified promptly and can be used in the next step.
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: propane-1 2-(the 1-bromine cyclopropyl) methyl of two-t-butyldimethylsilyl protection), the 3-glycol:
Figure S2006800349355D00861
Under 0 ℃, in reaction flask, charge into anhydrous CH 2Cl 2(10ml) and diethyl zinc (the 1.0M hexane solution, 4.65ml, 4.65mmol).(0.358ml 4.65mmol) drip to add wherein, and with solution stirring 20 minutes with trifluoroacetic acid.Then, (0.375ml 4.65mmol) adds wherein, and solution stirred 20 minutes in addition with diiodomethane.At last, (0.492g, 1.16mmol adds wherein and makes solution be warming up to ambient temperature, stirs 16 hours with the product that is obtained from step C.Saturated NH is used in reaction 4The quencher of Cl aqueous solution.To each layer distribute and the gained water (3 * 5ml) extract with chloroform.MgSO is washed, used to the organic facies that merges with saline (10mL) 4Dry with in a vacuum volatile matter is removed.The thick product of gained is through silica gel chromatography (eluent: chloroform/hexane) carry out purification, thereby be provided as the product (0.280g, 64%) of clean oil.
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-sulfonic acid chloride of two-t-butyldimethylsilyl protection:
Figure S2006800349355D00862
(0.507g 1.16mmol) is dissolved in the absolute ether (6ml), and reaction solution is cooled to-78 ℃ with the product that is obtained from step D.After this, (1.7M pentane solution, 1.50ml 2.55mmol) dripped adding wherein with tert-butyl lithium in the clock time at 5 minutes.After stirring 0.5 hour, (0.206ml is in absolute ether 2.55mmol) (6ml) solution lithiated product to be changed over to the sulfonic acid chloride of-78 ℃ stirring through sleeve pipe.Accomplish in case shift, make solution be warming up to room temperature, the gained white solid is processed serosity with solvent evaporation with in anhydrous hexane.Immediately with this serosity filtration over celite, and in a vacuum all volatile matters are removed.The thick product of gained (0.376g, 71%) is separated into yellow oil, need not be further purified promptly to can be used in the following steps.
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 two-t-butyldimethylsilyl protection (3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino)-6-methoxyphenyl)-1-(3-hydroxyl-2-(methylol) propyl group) cyclopropane-1-sulfonamide:
Figure S2006800349355D00871
Under argon gas atmosphere, 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-diamidogen.To be dissolved in the product that is obtained from step e in the anhydrous pyridine (0.5ml) (20.5mg 0.045mmol) joins in the reaction flask, and under 80 ℃ with mixture heated 21 hours.In a vacuum organic solvent is removed and the thick product of gained through silica gel chromatography (eluent: ethyl acetate/hexane) carry out purification, thereby title compound (2.75mg, 15%) is provided.m/z?813.5(M-1).
Step G:N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino)-6-methoxyphenyl)-1-(3-hydroxyl-2-(methylol) propyl group) cyclopropane-1-sulfonamide:
Figure S2006800349355D00881
(27.9mg 0.0342mmo1) is dissolved among the THF (1ml), and under 0 ℃, (1.2N 0.2ml) handles with the HCl aqueous solution with the product that is obtained from step F.With gained solution stirring 4 hours.After this, use saturated NaHCO 3Aqueous solution will react quencher, with ethyl acetate extraction, use MgSO 4Dry and in a vacuum volatile matter is removed.The thick product of gained is through silica gel chromatography (eluent: methanol/chloroform) carry out purification, carry out the LC-MS purification subsequently, thereby title compound (11.8mg, 59%) is provided.
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/z?585.3(M-1).
Embodiment 61
N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino)-6-methoxyphenyl) Tetramethylene. sulfonamide:
Steps A: Tetramethylene. sulfonic acid chloride:
Figure S2006800349355D00882
Under vigorous stirring, (0.790g divides aliquot to add cyclobutyl bromine (1.8ml, 2.5722g, 20ml diethyl ether solution 19.1mmol) in 20ml absolute ether suspension 32.5mmol) to Mg smear metal (turning).After initial exothermic reaction stops, further with mixture heated to reflux temperature 30 minutes.Above-mentioned suspension is cooled to room temperature, and (4.6ml, 7.728g is in the ice-cold solution of the anhydrous DCM of 30ml 57.2mmol) to divide aliquot to join sulfonic acid chloride supernatant.After add accomplishing, above-mentioned suspension is warming up to room temperature and in a vacuum volatile matter is removed.In the oil pump vacuum,, use hexane (150ml) that it is extracted then with dry 15 minutes of gained residue.The hexane suspension is filtered and in a vacuum hexane removed, thereby be given the oily thick product of mulberry, it need not be further purified promptly and can be used in the next step.Wherein still there are some unreacted Cyclopropyl Bromides.Thick yield: 1.1g (38%).
Step B:N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino)-6-methoxyphenyl) Tetramethylene. sulfonamide
Figure S2006800349355D00891
According to conventional method B, make the cyclobutyl sulfonic acid chloride and 5 for preparing in the above step, 6-two fluoro-N1-(2-fluoro-4-iodophenyl)-3-methoxyl group-benzene-1, the 2-diamine reactant, thus obtain the 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 is amino)-6-aminomethyl phenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide:
Steps A: (3,4, the 5-trifluorophenyl) methanol:
In 30 fens clock times, to refrigerative (5 ℃) 3,4, (7.0g, portioning slowly adds NaBH to the 5-trifluro benzaldehyde in the solution of THF 43.75mmol) and aqueous mixtures (50ml, 9: 1) 4(1.662g, 43.75mmol).In 2 hours time, make reactant mixture reach room temperature and with its pour into carefully ice-cold HCl (200ml, 1N) in.The gained oil reservoir is extracted into CH 2Cl 2(250ml) and gained organic layer water (200ml) wash, carry out drying (MgSO 4) and evaporation.(7.08g quantitatively) need not be further purified and can use the thick product that obtains.
Step B:5-(bromomethyl)-1,2, the 3-trifluoro-benzene:
Figure S2006800349355D00901
CH to (3,4, the 5-trifluorophenyl) methanol (40mmol) 2Cl 2(150ml) slowly add thionyl bromide (6.16ml, CH 80mmol) in the solution 2Cl 2(50ml) solution.This reactant mixture is at room temperature stirred 16h, and pour in the frozen water (200mL).Organic layer is separated and uses saturated NaHCO 3(2 * 200ml) washings, water (200ml) wash, carry out drying (MgSO 4) and evaporation, thereby be the corresponding bromine compounds of light yellow oil with the quantitative yield acquisition.This thick product need not be further purified and promptly can be used in next reaction.
Step C:1,2,3-three fluoro-5-methylbenzene:
Above-mentioned bromine compounds (40mmol) is mixed with triethyl silicane (48mmol) and uses solid PdCl 2(4mmol) divide aliquot that the gained reactant mixture is handled.After a few minutes, violent exothermic reaction taking place, notes through placing the material in the reflux condenser backflow flask.At room temperature reactant mixture was stirred 6 hours in addition and made wherein species precipitate 16 hours.Then, carefully thick fluid product decant is not gone out with not being further purified promptly to can be used in next reaction.Can think to react and carry out with quantitative yield.
Step D:1,2,3-three fluoro-5-methyl-4-Nitrobenzol:
Under 0-5 ℃, with 1,2,3-three fluoro-5-methylbenzene (40mmol) join dense H 2SO 4(50ml).Use dense HNO then 3(3.39ml, 48.44mmol, 90%) is slowly handled reactant mixture, keeps internal temperature below 20 ℃ simultaneously.At room temperature reactant mixture was stirred 16 hours, be poured on the ice (300g) it and the gained oil reservoir is used CH 2Cl 2(2 * 125ml) extract.(2 * 200ml) wash, wash with saline (200ml) gained organic layer water, and carry out drying (MgSO 4) and evaporation, thereby obtain thick product, carry out purification through the fast silica gel chromatogram method and obtain title product (6.5g, 85%).
1HNMR (300MHz, CDCl 3): δ 6.96 (septet, 1H), 2.39 (s, 3H). 19F NMR (CDCl 3): δ-128.18 ,-141.50 ,-159.05.
Step e: 2,3-two fluoro-N-(2-fluoro-4-iodophenyl)-5-methyl-6-nitroaniline:
Figure S2006800349355D00911
Utilize the condition of describing among the embodiment 1 (steps A), make 2-fluoro-4-Iodoaniline and 1,2,3-three fluoro-5-methyl-4-Nitrobenzol reaction, thus form title compound.M-H +：4079
Step F: 5,6-two fluoro-N 1-(2-fluoro-4-iodophenyl)-3-methylbenzene-1, the 2-diamidogen:
Figure S2006800349355D00912
Use the described condition of embodiment 1 (step B), to 2,3-two fluoro-N-(2-fluoro-4-iodophenyl)-5-methyl-6-nitroaniline reduces, thereby forms title compound.M-H +：377.4
Step G:1-pi-allyl-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino)-6-aminomethyl phenyl) cyclopropane-1-sulfonamide:
Figure S2006800349355D00921
According to conventional method B, make 1-pi-allyl-cyclopropane sulfonic acid chloride (142mg, 142mg) with 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl)-3-methylbenzene-1,2-diamidogen (150mg, 0.4 mM) reaction, thereby obtain title product (100mg, 47%); M/z=521 [M-1] -
Step H:N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino)-6-aminomethyl phenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide:
Figure S2006800349355D00922
1-pi-allyl-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino)-6-aminomethyl phenyl) cyclopropane-1-sulfonamide (150mg, 0.29 mM) and 4-methyl morpholine N-oxide (33mg, 0.29 mM) are dissolved among the THF (5mL).At room temperature with Osmic acid. (0.029 mM, 0.18mL, 4%H 2O solution) add wherein, and at room temperature reactant mixture was stirred 16 hours.EtOAc is added wherein, the gained organic facies with water washing, carry out drying (MgSO 4) and under reduced pressure concentrate.The gained residue is through silica gel chromatography (eluent: EtOAc/MeOH) carry out purification, thereby obtain title product (0.110g, 68%).
1HNMR(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 is amino) phenyl) cyclopropane-1-sulfonamide:
Steps A: 1-(3,4, the 5-trifluorophenyl) ethanol:
Figure S2006800349355D00931
Under-78 ℃, (17.41ml, 52.24mmol 3M) slowly join 3,4, and (6.96g is in THF 43.53mmol) (125ml) solution for the 5-trifluro benzaldehyde with the ethereal solution of MeMgBr.At room temperature reactant mixture is stirred 16h, with its cooling (0 ℃) with in proper order with excessive acetic acid ethyl ester (10ml) and water (5ml) quencher.With excessive anhydrous MgSO 4(5g) adding wherein and was at room temperature stirred 30 minutes.(2 * 25ml) wash with ethyl acetate with gained suspension filtration over celite and the solid that obtains.The filtrating that is combined is evaporated, thereby obtains product (7.65g) with quantitative yield.
Step B:5-(1-bromoethyl)-1,2, the 3-trifluoro-benzene:
Figure S2006800349355D00932
To 1-(3,4, the 5-trifluorophenyl) ethanol (7.65g, CH 43.5mmol) 2Cl 2(250ml) slowly add thionyl bromide (18.1g, CH 87mmol) in the solution 2Cl 2(50ml) solution.This reactant mixture is at room temperature stirred 16h, and pour in the frozen water (200mL).Organic layer is separated, use saturated NaHCO 3(2 * 200ml) and water (200ml) washing, carry out drying (MgSO 4) and evaporation, thereby be the corresponding bromine compounds (10.4g) of light yellow oil with the quantitative yield acquisition.This thick product need not be further purified and promptly can be used in next reaction.
Step C:5-ethyl-1,2, the 3-trifluoro-benzene:
Figure S2006800349355D00933
(9.65g 40.4mmol) mixes with triethyl silicane (41mmol), and uses solid PdCl with above-mentioned bromine compounds 2(177mg 4mmol) divides aliquot that above-mentioned reactant mixture is handled.After a few minutes, violent exothermic reaction taking place, notes through placing the material in the reflux condenser backflow flask.At room temperature reactant mixture is stirred 6h in addition and made wherein species precipitate 16 hours.Then, with thick fluid product carefully decant do not go out with need not be further purified promptly be used for next the reaction.Can think to react and carry out with quantitative yield.
Step D:1-ethyl-3,4,5-three fluoro-2-Nitrobenzol:
Under 0-5 ℃, with 1,2, (6.46g 40.4mmol) joins dense H to 3-three fluoro-5-toluene 2SO 4(50ml).Then, use dense HNO 3(3.39ml, 48.44mmol, 90%) is slowly handled reactant mixture, keeps internal temperature below 20 ℃ simultaneously.At room temperature reactant mixture was stirred 16 hours and was poured on the ice (300g), the gained oil reservoir is used CH 2Cl 2(2 * 125ml) extract.Gained organic layer water (2 * 200ml), saline (200ml) washing, carry out drying (MgSO 4) and evaporation, thereby obtain thick product, through the fast silica gel chromatogram method it is carried out purification, obtain title product (6.6g, 79%).
1HNMR (CDCl 3): δ 6.98 (septet, 1H), 2.68 (q, 2H), 1.26 (t, J=7.8 7.2Hz, 3H).
Step e: 3-ethyl-5,6-two fluoro-N-(2-fluoro-4-iodophenyl)-2-nitroaniline:
Figure S2006800349355D00942
Use the condition described in the embodiment 1 (steps A), make 2-fluoro-4-Iodoaniline (2.05g, 10 mMs) and 1-ethyl-3,4,5-three fluoro-2-Nitrobenzol (2.37g, 10 mMs) reaction, thus form 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, the 2-diamidogen:
Figure S2006800349355D00951
Use the condition described in the embodiment 1 (step B), to 1,2,3-three fluoro-5-methyl-4-Nitrobenzol (2.47g, 5.85 mMs) reduce, thereby form title compound.M-H +：393
Step G:1-pi-allyl-N-(6-ethyl-3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl) cyclopropane-1-sulfonamide:
Figure S2006800349355D00952
According to conventional method B, make 1-pi-allyl-cyclopropane sulfonic acid chloride (230mg, 1.27 mMs) and 5,6-two fluoro-N1-(2-fluoro-4-iodophenyl)-3-methylbenzene-1,2-diamidogen (100mg, 0.255 mM) reaction, thus obtain 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 is amino) phenyl) cyclopropane-1-sulfonamide:
Figure S2006800349355D00953
1-pi-allyl-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino)-6-aminomethyl phenyl) cyclopropane-1-sulfonamide (70mg, 0.13 mM) and 4-methyl morpholine N-oxide (15mg, 0.13 mM) are dissolved among the THF (2mL).At room temperature with Osmic acid. (0.013 mM, 0.075mL, 4%H 2O solution) add wherein, and at room temperature reactant mixture was stirred 16 hours.EtOAc is added wherein, the gained organic facies with water washing, carry out drying (MgSO 4) and under reduced pressure concentrate.The gained residue is through silica gel chromatography (eluent: EtOAc/MeOH) carry out purification, thereby obtain the title product.
1H?NMR(300MHz，CDCl 3)：δ7.38(dd，J＝2.1?&?10.8Hz，1H)，7.27(m，2H)，7.12(brs，1H)，6.91(dd，J＝8.1?&?10.8Hz，1H)，6.69(brs，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 is 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-Nitrobenzol:
Figure S2006800349355D00961
Under 0 ℃, to 3,4,5-three fluoro-2-nitrophenols (1.93g, 10mmol), Ph 3P (3.93g; 15mmol) with 2-methoxyl group-ethanol (1.18ml; Add diisopropyl azo-2-carboxylic acid (2.91ml, THF 15mmol) (5ml) solution, and at room temperature above-mentioned reactant mixture being stirred 16 hours in anhydrous THF (25ml) mixture 15mmol).Be dissolved in CH with the volatile matter evaporation with the gained residue 2Cl 2(100ml), organic layer water (100ml) washs, washs, carries out drying (MgSO with saline (100ml) 4) and evaporation.The residue that obtains carries out purification through the fast silica gel chromatogram method, thereby obtains title product (1.70g) with 68% yield.
1HNMR(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:
Figure S2006800349355D00971
Use the condition described in the embodiment 1 (steps A) to make 2-fluoro-4-Iodoaniline (1.6g, 6.8 mMs) and 1,2,3-three fluoro-5-(2-methoxy ethoxy)-4-Nitrobenzol (1.7g, 6.8 mMs) reaction, thus form title compound (1.02g, 32%); M/z=467 [M-1] -
Step C:5,6-two fluoro-N 1-(2-fluoro-4-iodophenyl)-3-(2-methoxy ethoxy) benzene-1, the 2-diamidogen:
Figure S2006800349355D00972
Use the condition described in the embodiment 1 (step B), to 2,3-two fluoro-N-(2-fluoro-4-iodophenyl)-5-(2-methoxy ethoxy)-6-nitroaniline (1.017g, 2.17 mMs) reduces, thereby forms title compound; M/z=337 [M-1] -
Step D:1-pi-allyl-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino)-6-(2-methoxy ethoxy) phenyl) cyclopropane-1-sulfonamide:
Figure S2006800349355D00973
According to conventional method B, make 1-pi-allyl-cyclopropane sulfonic acid chloride (450mg, 2.5 mMs) and 5; 6-two fluoro-N1-(2-fluoro-4-iodophenyl)-3-(2-methoxy ethoxy) benzene-1,2-diamidogen (219mg, 2.5 mMs) reaction; Thereby obtain title product (230mg, 78%); M/z=581 [M-1] -
Step e: N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino)-6-(2-methoxy ethoxy) phenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide:
Figure S2006800349355D00981
1-pi-allyl-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino)-6-(2-methoxy ethoxy) phenyl) cyclopropane-1-sulfonamide (230mg, 0.395 mM) and 4-methyl morpholine N-oxide (46mg, 0.395 mM) are dissolved among the THF (2mL).At room temperature with Osmic acid. (0.039 mM, 0.25mL, 4%H 2O solution) add wherein, and at room temperature reactant mixture was stirred 16 hours.EtOAc is added wherein, the gained organic facies with water washing, carry out drying (MgSO 4) and under reduced pressure concentrate.The gained residue is through silica gel chromatography (eluent: EtOAc/MeOH) carry out purification, thereby obtain the title product.
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 is amino) phenyl) benzsulfamide:
Figure S2006800349355D00982
Use suitable sulfonic acid chloride synthetic, m/z=571 [M-1] through method A -
Embodiment 66
2-chloro-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl)-4-(trifluoromethyl) benzsulfamide:
Figure S2006800349355D00991
Use suitable sulfonic acid chloride synthetic, m/z=605 [M-1] through method A -
Embodiment 67
N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl)-2-(trifluoromethoxy) benzsulfamide:
Use suitable sulfonic acid chloride synthetic, m/z=587 [M-1] through method A -
Embodiment 68
4-(N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl) sulfamoyl) benzoic acid:
Figure S2006800349355D00993
Use suitable sulfonic acid chloride synthetic, m/z=584 [M-1] through method A -
Embodiment 69
N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl) benzsulfamide:
Figure S2006800349355D01001
Use suitable sulfonic acid chloride synthetic, m/z=503 [M-1] through method A -
Embodiment 70
N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino) phenyl)-2-fluorobenzene sulfonamide:
Figure S2006800349355D01002
Use suitable sulfonic acid chloride synthetic, m/z=521 [M-1] through method A -
Conventional method D: the replacement of iodine atom:
Will be two
Figure 2006800349355_43
Contain 1 equivalent aryl iodide, 1.5 equivalent boric acid or borate, 0.25 equivalent PdCl in the deoxidation mixture of alkane and water (3: 1) 2(dppf) x DCM and 10 equivalent anhydrous K 2CO 3The suspension of powder heated 60 minutes down at 115 ℃ in microwave reactor.
Use NH 4It is extracted Cl aqueous solution/THF and organic component is used Na 2SO 4Dry.The gained crude reaction product is with flash column chromatography (Si, EtAc/ hexane, perhaps CHCl 3/ MeOH) carry out purification.Yield: 20-40%.
Embodiment 71
N-(3,4-two fluoro-2-(2-fluoro-4-aminomethyl phenyl is amino) phenyl) cyclopropane sulfonamide:
Figure S2006800349355D01011
Conventional method D:
1H-NMR(500MHz，CDCl 3)：δ＝7.38-7.36(m，1H)，7.06-7.03(q，1H)，6.92-6.90(1H)，6.73-6.72(d，1H)，6.63(s，1H，br)，6.37-6.33(t，1H)，5.54(s，1H，br)，2.42-2.39(m，1H)，2.25(s，3H)，1.14-1.11(m，2H)，0.94-0.90(m，2H)；m/z＝355[M-1] -.
Wherein the racemic mixture of chipal compounds has been split into independent enantiomer, " is substantially free of " epimer in the word of this use and is meant optical siomerism excessive at least 90%.
Biological activity
IC 50The generation of data
The preparation of material and reagent: human GST-MEK1 and the active allele GST-MEK1 of formation CA(hide mutant Ser218Asp and Ser222Asp) all sub-clone go into to be obtained from the human MEK1cDNA of wild type Yeast expression carrier pGEM4Z (Promega, Madison, WI) in.GST-MEK1 CA(Amersham Pharmacia Biotech, Piscataway NJ) carry out partial purification to be expressed in the escherichia coli and to use glutathione agarose gel 4B affinity resin.ERK2 allele is from pUSEamp (Upstate Biotechnology; Inc., MAPK2/Erk2cDNA (wild type) sub-clone Waltham MA) is gone into carrier pET21a (Novagen, Madison; WI) in, cause the Mus ERK2 allele of the terminal histidine-labelling of N-.Make the ERK2 expression and carry out purification, thereby obtain homogeneity [Zhang, 1993#33].MBP (MBP) available from Gibco BRL (Rockville, MD).EasyTides adenosine 5 '-triphosphoric acid (ATP) ([γ- 33P]) (NEN Perkin Elmer, Wellesley MA) are the radioactive label source of all kinase reactions.Activatory Raf-1 (blocking) and activatory MAPKinase 2/ERK2 be available from Upstate, and Inc. (Lake Placid, NY).4-20%Criterion Precast gel available from Bio-Rad (Hercules, CA).
The mensuration of enzymatic activity: chemical compound dilutes from dimethyl sulfoxine (DMSO) raw material goes into 1xHMNDE (20mM HEPES pH 7.2,1mM MgCl 2, 100mM NaCl, 1.25mMDTT, 0.2mM EDTA) in.General 25-microlitre is measured and is contained 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.Screening test consists essentially of four addings.The chemical compound of 5 μ l dilution is distributed in the assay plate of 96-hole.Then, with 10 μ l 2.5x enzyme cocktails (MEK1 only CAAnd ERK2) joins in each hole, cultivated in advance at ambient temperature 30 minutes subsequently.Then, 10 μ l 2.5x substrate mixture (labelling and unlabelled ATP add MBP) are added wherein, cultivated at ambient temperature subsequently 60 minutes.At last, 100 μ l, 10% trichloroacetic acids (TCA) are added wherein, and at room temperature cultivate 30 minutes, thus stopped reaction and the radiolabeled protein product of deposition.Reactor product is captured on the fibre glass 96 hole filter plates of water and 1% pyrophosphate pre-wetted.Then, this filter plate is with water washing 5 times.Water is replaced and at room temperature makes air-dry 30 minutes of plate with absolute ethanol.Manual work applies sealing backside, and 40 μ l flicker mixture is distributed in each hole.Apply top seal, and plate is counted, every hole timing two seconds at TopCount.
For some test, use needs the MEK through the clipped form of Raf kinase activation.
The generation of EC50 data
The effect of chemical compound in cell confirmed through the Western blotting of phosphorylation ERK.The MDA-MB-231 breast cancer cell is placed 48 orifice plates and makes them under 37 ℃ with 20,000 cells/plate, at moistening CO 2Grow in the incubator.Second day, hungry medium (DMEM+0.1% hyclone) replacement is removed and used to growth medium (DMEM+10% hyclone).Cell was cultivated 16 hours in the medium of hunger, used the compound treatment 30 minutes of multiple concentration then.After cultivating, with 100ng/ml EGF irritation cell five minutes with chemical compound.Then, make cytolysis and analyze, use to promote (raise) monoclonal antibody to phosphorylation ERK through the Western trace.The secondary antibody that use is conjugated to vicinity-IR dyestuff is amplified signal and on Licor Odyssey scanning device, is detected.Signal intensity is carried out quantitatively, and these data are used to form dose response curve and carry out EC50 calculating.
Note: 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
Figure S2006800349355D01021
Figure S2006800349355D01031
Figure S2006800349355D01041
Figure S2006800349355D01051
Figure S2006800349355D01071

Claims (45)

1. the chemical compound of formula I
Wherein G is R 1a, R 1b, R 1c, R 1dOr R 1e
R 0Be H, F, C 1-C 4Alkoxyl;
X is F, Cl or methyl;
Y is I, Br, Cl, CF 3, C 1-C 3Alkyl, C 2-C 3Thiazolinyl, C 2-C 3Alkynyl, cyclopropyl, phenyl, pyridine radicals, pyrazolyl, OMe, OEt or SMe, wherein all said methyl, ethyl, the C of X and Y 1-C 3Alkyl and cyclopropyl are optional to be replaced by OH, and wherein all said phenyl of Y, pyridine radicals, pyrazolyl are optional is replaced and wherein all said methyl of X and Y are optional by one, two or three F atoms replacements by halogen, acetyl group, methyl and trifluoromethyl; With
Z is H or F;
R wherein 1aBe methyl, optional by 1-3 fluorine atom or 1-3 chlorine atom replacement, perhaps by OH, ring propoxyl group or C 1-C 4Alkoxyl replaces, wherein said ring propoxyl group or said C 1-C 3The C of alkoxyl 1-C 3Moieties is optional to be replaced and wherein said C by a hydroxyl or methoxyl group 1-C 4All C in the alkoxyl 3-alkyl is optional further to be replaced by second OH group;
R 1bBe CH (CH 3)-C 1-3Alkyl or C 3-C 6Cycloalkyl, said alkyl and cycloalkyl are optional to be independently selected from F, Cl, Br, I, OH, OCH by 1-3 3Replace with the substituent group of CN;
R 1cBe (CH 2) nO mR ', wherein m is 0 or 1; Wherein, when m was 1, n was 2 or 3 and when m is 0, and n is 1 or 2; Wherein R ' is C 1-C 6Alkyl, optional by individual F, Cl, OH, the OCH of being independently selected from of 1-3 3, OCH 2CH 3And C 3-C 6The substituent group of cycloalkyl replaces;
R 1dFor C (A) (A ') (B)-, wherein B, A and A ' are H or C independently 1-4Alkyl, optional by one or two OH groups replacements, perhaps A forms 3-6 unit saturated rings altogether with the carbon atom that A ' is connected together with them; With
R 1eBe benzyl or 2-phenylethyl, wherein phenyl is optional is substituted, as follows:
Figure FSB00000449518100021
Wherein q is 1 or 2, R 2, R 3And R 4Be H, F, Cl, Br, CH independently 3, 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, and R 4Can also be nitro, acetylamino, amidino groups, cyanic acid, carbamoyl, methylamino formoxyl, formyl-dimethylamino, 1,3,4- Diazole-2-base, 5-methyl isophthalic acid, 3,4-
Figure FSB00000449518100023
Diazole, 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 5And R 6Be H, F, Cl or methyl independently.
2. the chemical compound of claim 1, wherein X is F, Cl or CH 3Y is I, Br, Cl, CF 3Perhaps C 1-C 3Alkyl; With Z be H or F.
3. the chemical compound of claim 1, wherein R 0Be F, Cl, C 1-C 4Alkyl or C 1-C 4Alkoxyl, said C 1-C 4Alkyl and said C 1-C 4The C of alkoxyl 1-C 4Moieties is optional by F, Cl, OCH 3Perhaps OCH 2CH 3Replace.
4. the chemical compound of claim 2, wherein R 0Be H, F, Cl, C 1-C 4Alkyl, methoxyl group, ethyoxyl or 2-methoxyl group-ethyoxyl.
5. the chemical compound of claim 4, wherein G is R 1aWith Z be F.
6. the chemical compound of claim 5, wherein G is CH 3R 0Be H; With Y be Br, I, CF 3Perhaps CH 3
7. each chemical compound among the claim 1-4, wherein G is R 1b
8. the chemical compound of claim 4, wherein G is R 1bWith Z be F.
9. the chemical compound of claim 8, wherein R 0Be H, F or OCH 3, X is F or CH 3And Y is Br, I or CH 3
10. the chemical compound of claim 9, wherein G is unsubstituted C 3-C 6Cycloalkyl.
11. the chemical compound of claim 10, wherein R 0Be H.
12. the chemical compound of claim 9, wherein G is isopropyl or cyclopropyl.
13. each chemical compound among the claim 1-4, wherein G is R 1c
14. the chemical compound of claim 4, wherein G is R 1c, Y is I, Br, CH 3Perhaps CF 3With Z be F.
15. the chemical compound of claim 14, wherein m is zero.
16. each chemical compound among the claim 1-4, wherein G is R 1d
17. the chemical compound of claim 16, wherein R 0Be fluorine, chlorine, methyl, ethyl, propyl group, isopropyl, sec-butyl, isobutyl group, the tert-butyl group, cyclopropyl, cyclobutyl, fluoro methyl, methoxyl group, fluoro methoxyl group, methylamino or dimethylamino; X is F, Cl, CH 3Perhaps single, two or trifluoromethyl; Y is a perhaps trifluoromethyl of I, Br, Cl or list, two; With Z be H or F.
18. the chemical compound of claim 16, wherein R 0Be F, Cl, methyl, ethyl, methoxyl group, ethyoxyl or 2-methoxyl group-ethyoxyl; X is F, Cl or CH 3Y is a perhaps trifluoromethyl of I, Br, Cl or list, two; With Z be H or F.
19. the chemical compound of claim 16, wherein R 0Be H; X is F, Cl, CH 3Perhaps single, two or trifluoromethyl; Y is a perhaps trifluoromethyl of I, Br, Cl or list, two; With Z be H or F.
20. each chemical compound of claim 17-19, wherein A forms 3-6 unit saturated rings altogether with the carbon atom that A ' is connected together with them.
21. the chemical compound of claim 20, wherein B is H.
22. the chemical compound of claim 21, wherein C (A) (A ') is a cyclopropyl.
23. the chemical compound of claim 20, wherein B is a methyl, and is optional by the replacement of OH group, perhaps a C 2-C 4Alkyl, optional by one or two OH groups replacements.
24. the chemical compound of claim 23, wherein C (A) (A ') is a cyclopropyl.
25. the chemical compound of claim 24; Wherein B is methyl, ethyl, 2-ethoxy, n-pro-pyl, 3-hydroxypropyl, 2; 3-dihydroxypropyl, 3,4-dihydroxy butyl, isopropyl, 1-methyl-2-hydroxyethyl, normal-butyl, sec-butyl, isobutyl group or 2-methylol-3-hydroxypropyl.
26. the chemical compound of claim 25, wherein B is 2,3-dihydroxypropyl or 3,4-dihydroxy butyl.
27. the chemical compound of claim 26, wherein the chiral carbon among the B is the R configuration.
28. a compound compositions that comprises according to claim 27, it does not contain the S isomer.
29. each chemical compound among the claim 1-4, wherein G is R 1e
30. the chemical compound of claim 29, wherein q is 1.
31. the chemical compound of claim 30, wherein R 0Be H, R 4-6Be H; R 2And R 3Be H, F, Cl, Br, CH independently 3, 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.
32. a chemical compound is selected from following chemical compound:
Figure FSB00000449518100041
Figure FSB00000449518100051
33. a chemical compound is selected from following chemical compound:
Figure FSB00000449518100061
Wherein 2-OH carbon is the R configuration.
34. one kind comprise following shown in compound compositions, wherein 2-OH carbon is the R configuration, does not contain the S-isomer
Figure FSB00000449518100062
35. a chemical compound, be selected from following shown in chemical compound:
Figure FSB00000449518100063
Wherein this chemical compound is the dextrorotation configuration, does not contain laevoisomer.
36. (S)-N-(3,4-two fluoro-2-(2-fluoro-4-iodophenyl is amino)-6-methoxyphenyl)-1-(2, the 3-dihydroxypropyl) cyclopropane-1-sulfonamide.
37. a pharmaceutical compositions, its comprise effective dose pharmaceutically according to each formula I chemical compound or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier among the claim 1-36.
38. a pharmaceutical compositions, what it comprised effective dose pharmaceutically is selected from following chemical compound or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier
Figure FSB00000449518100071
39. the compositions of claim 38, wherein this chemical compound is R or S configuration.
40. be used for treating the purposes aspect the medicine of mammal hyper-proliferative disease in preparation according to each formula I chemical compound or its pharmaceutically acceptable salt among the claim 1-36, said mammal comprises the mankind.
41. be used to treat the purposes aspect the medicine of the disease of regulating or situation in preparation according to each formula I chemical compound or its pharmaceutically acceptable salt among the claim 1-36 through the MEK cascade.
42. be selected from following chemical compound:
Figure FSB00000449518100072
Wherein this 2-OH carbon is the S configuration.
43. show compound compositions under comprising, wherein this 2-OH carbon is the S configuration, does not contain the R-isomer
Figure FSB00000449518100081
44. be selected from those chemical compound as follows:
Figure FSB00000449518100082
Wherein this chemical compound is a laevo-configuration, does not contain dextroisomer.
45. the compositions of claim 38, wherein this chemical compound is the S configuration.
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