CN1791604A

CN1791604A - Diaminopyrroloquinazolines compounds as protein tyrosine phosphatase inhibitors

Info

Publication number: CN1791604A
Application number: CN 200480013338
Authority: CN
Inventors: S·J·贝特尔; K·C·萨卡
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 2003-05-15
Filing date: 2004-05-10
Publication date: 2006-06-21
Anticipated expiration: 2024-05-10
Also published as: CN100334088C

Abstract

This Invention relates to diaminopyrroloquinazoline compounds of formula (I) wherein R1, R2, R3, Ra, Rb, Rc, Rd, Re, Rf and A are as defined in the description and Claims, which are useful for inhibiting protein tyrosine phosphatases, particularly PTP1B, and are useful for lowering blood glucose concentrations in mammals.

Description

Diaminopyrroloquinazcompounds compounds as protein tyrosine phosphatase inhibitors

The present invention relates to Diaminopyrroloquinazcompounds compounds, it is effective to arrestin matter tyrosine phosphatase, particularly PTP1B, and is used to reduce mammiferous blood sugar concentration.These compounds are characterized by formula (I) and pharmaceutical salts thereof:

Wherein

A is the unsaturated or saturated rings of 5-or 6-unit, or contains the unsaturated or saturated rings of at least one heteroatomic 5-that is selected from S, N and O or 6-unit,

R ₁Be selected from low alkyl group, ethanoyl, dimethylamino alkylsulfonyl, hydroxyalkyl, one or the low alkyl group that replaces of dihydroxyl, phenyl lower alkyl, benzyloxy-alkyl and phenyl lower alkoxy low alkyl group;

R ₂Be selected from hydrogen, low alkyl group, ethanoyl, hydroxyalkyl, one or the low alkyl group that replaces of dihydroxyl, phenyl lower alkyl and phenyl lower alkoxy low alkyl group;

R ₃Be hydrogen or methyl;

Ra is selected from hydrogen, low alkyl group, lower alkoxy

Hydroxyalkyl, one or the low alkyl group that replaces of dihydroxyl, phenyl lower alkyl, the benzyloxy alkyl, or

R ₁₀Be hydrogen, or

X and y are the integers of independent 0-4;

Rb and Rc are selected from hydrogen individually, low alkyl group, and perfluor-low alkyl group, the alkyl of replacement, alkoxyl group, phenoxy group, halogen, the phenyl lower alkyl that unsubstituted low alkyl group replaces, the phenyl lower alkoxy, or

R ₁₁Be hydrogen, phenyl or unsubstituted low alkyl group;

P is the integer of 0-1;

Rd is a hydrogen, the alkyl of replacement or perfluor-low alkyl group;

Re is a hydrogen, the alkyl of halogen or replacement and perfluor-low alkyl group;

Rf is hydrogen or low alkyl group.

Protein Tyrosine Phosphatases (PTPases) is the key enzyme of regulating in cell growth and the atomization.The inhibition of these enzymes can play a role in the adjusting of many signals pipeline, and wherein the tyrosine phosphorylation dephosphorylation plays a role.PTP1B is a kind of concrete Protein Tyrosine Phosphatases, and it is usually as this zymoid prototype.

The PTPase inhibitor thinks that a kind of potential is used for the treatment of the treatment of diabetes medicine.Referring to for example, Moeller etc., 3 (5): 527-40, Current Opinion in Drug Discovery andDevelopment, 2000; Or Zhang, Zhong-Yin, 5:416-23, Current Opinion inChemical Biology, 2001.The PTP enzyme inhibitors is the discussion theme of several pieces of survey articles as the effectiveness of therapeutical agent, and these articles comprise for example Expert Opin Investig Drugs 12 (2): 223-33, in February, 2003.

Except as otherwise noted, list following definition to explain and to define implication and the scope that is used to describe the used various terms of the present invention.

In this manual, term " rudimentary " is used to mean by 1-6, preferred 1-4 group that carbon atom is formed.

Term " halogen " or " halo " are meant fluorine, chlorine, bromine and iodine, preferred fluorine, chlorine and bromine.

Term " alkyl ", separately or with other moiety combinations, be meant 1-20 carbon atom, preferably 1-16 carbon atom, the more preferably side chain or the straight chain monovalence radical of saturated aliphatic alkyl of 1-10 carbon atom.Alkyl can followingly define low alkyl group and be substituted.As the low alkyl group of giving a definition is preferred alkyl.

As used in this specification sheets, term " low alkyl group " alone or in combination, is meant the straight or branched alkyl that contains maximum 6 carbon atoms, as methyl, and ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, n-hexyl etc.Low alkyl group can be unsubstituted or is independently selected from following group and replace by one or more: cycloalkyl; nitro, aryloxy, aryl; hydroxyl; halogen, cyano group, lower alkoxy; low-grade alkane acidyl; lower alkylthio, low alkyl group sulfinyl, the amino of low alkyl group alkylsulfonyl and replacement.The example of the low alkyl group that replaces comprises 2,3-dihydro propyl group and 3-hydroxypropyl.

Term " lower alkoxy " is meant the straight or branched alkoxyl group that contains 1-6 carbon atom, as methoxyl group, and oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy etc.

Term " perfluor low alkyl group " is meant that all hydrogen of any wherein low alkyl group are replaced by fluorine or the alternate low alkyl group.Wherein preferred perfluor low alkyl group is a trifluoromethyl, pentafluoroethyl group, seven fluoropropyls etc.

Term " heteroaryl " is meant and contains heteroatomic single, double or three cyclophane family groups, described heteroatoms such as nitrogen-atoms, Sauerstoffatom and sulphur atom.The example of " heteroaryl " can be a pyridyl, thienyl, benzofuryl, pyrimidyl, quinolyl, isoquinolyl is with isoxazolyl, indolinyl, furyl ， oxadiazole base, benzothiazolyl, pyrazinyl, diazosulfide base, thiazolidyl, Imidazothiazole base, piperidyl, piperazinyl and THP trtrahydropyranyl.

Term " aryl " is meant list or bicyclic aromatic group, and as phenyl or naphthyl, it is unsubstituted or is replaced by conventional substituting group.Preferred substituted has low alkyl group, lower alkoxy, hydroxyl low-grade alkyl, hydroxyl, hydroxy alkoxy base, halogen; lower alkylthio, low alkyl group sulfinyl, low alkyl group alkylsulfonyl, cyano group, nitro; perfluoroalkyl, alkyloyl, aroyl, aromatic yl polysulfide yl, low-grade alkynyl and low-grade alkane acidyl amino.Particularly preferred substituting group is a low alkyl group, lower alkoxy, hydroxyl, halogen, cyano group and perfluor low alkyl group.The example of aryl is a phenyl used according to the present invention, p-methoxyphenyl, rubigan, a hydroxy phenyl, a methyl thio-phenyl, benzyloxy ethyl etc.

Term " low-grade alkylaryl " is meant the low alkyl group that wherein one or more hydrogen atoms are replaced by aryl.Can use any conventional low-grade alkylaryl according to the present invention, as benzyl etc.

Term " lower alkoxy aryl " is meant the lower alkoxy that wherein one or more hydrogen atoms are replaced by aryl.Can use any conventional lower alkoxy aryl according to the present invention, as benzyloxy.

Term " pharmaceutical salts " refers to keep the conventional acid additive salt or the base addition salt of the biological effectiveness and the character of general formula I, I-A and I-B compound, and it is by suitable non-toxicity organic or inorganic acid, and perhaps organic or inorganic alkali forms.The example of acid salt comprises and derives from for example hydrochloric acid of mineral acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, thionamic acid, those salt of phosphoric acid and nitric acid, and derive from for example p-toluenesulphonic acids of organic acid, Whitfield's ointment, methylsulfonic acid, oxalic acid, succsinic acid, citric acid, oxysuccinic acid, lactic acid, those salt of fumaric acid etc.The example of base addition salt comprises and derives from ammonium, potassium, sodium and quaternary ammonium hydroxide, for example those salt of tetramethyl ammonium hydroxide.Medical compounds (being medicine) chemically modified salify is pharmacy worker's a routine techniques, so that obtain the improved physics of this compound, chemical stability, water absorbability, flowability and solvability.Referring to for example, H.Ansel etc., Pharmaceutical Dosage Formsand Drug Delivery Systems (6th Ed.1995) pp.196 and 1456-1457.

At length, the present invention relates to the compound and the pharmaceutical salts thereof of formula (I):

Wherein A is the unsaturated or saturated rings of 5-or 6-unit, or contains the unsaturated or saturated rings of at least one heteroatomic 5-that is selected from S, N and O or 6-unit,

R ₃Be hydrogen or methyl;

Ra is selected from hydrogen, low alkyl group, lower alkoxy

R ₁₀Be hydrogen, or

X and y are the integers of independent 0-4;

R ₁₁Be hydrogen, phenyl or unsubstituted low alkyl group;

P is the integer of 0-1;

Rd is a hydrogen, the alkyl of replacement or perfluor-low alkyl group;

Rf is hydrogen or low alkyl group.

An embodiment preferred relates to the compound and the pharmaceutical salts thereof of formula (I) as defined above,

Wherein

R ₁Be selected from low alkyl group, ethanoyl, hydroxyalkyl and benzyloxy-alkyl;

R ₂Be selected from hydrogen, low alkyl group, ethanoyl, hydroxyalkyl;

R ₃Be hydrogen or methyl;

Ra is selected from hydrogen, low alkyl group, lower alkoxy, hydroxyalkyl and benzyloxy alkyl;

Rb is selected from hydrogen, low alkyl group, perfluor-low alkyl group, the alkyl of replacement, alkoxyl group and phenoxy group;

Rc and Rd are the alkyl of hydrogen or replacement independently, perfluor-low alkyl group;

Rf is hydrogen or low alkyl group.

Another preferred embodiment relates to compound as defined above, wherein

R1 is selected from methyl, ethyl, benzyl, ethanoyl, 2,3-dihydroxypropyl, 3-hydroxypropyl and 2-benzyloxy ethyl;

R2 is selected from hydrogen, methyl, ethyl, benzyl, and ethanoyl;

Ra is selected from hydrogen, methyl, hydroxyethyl, 2-benzyloxy-ethyl and 2-[4-difluoro phosphono-methyl]-benzyloxy]-ethyl;

Rb is selected from hydrogen, methyl, methoxyl group, phenoxy group and trifluoromethyl;

Rc and Rd are selected from hydrogen and trifluoromethyl independently of one another;

Re is selected from hydrogen, chlorine and trifluoromethyl; With

Rf is selected from hydrogen and methyl.

Another embodiment of the invention relates to compound or pharmaceutically acceptable salt thereof as defined above, and wherein said compound has formula (I-B)

R wherein ₁' be low alkyl group, phenyl lower alkyl, one or the low alkyl group that replaces of dihydroxyl, or phenyl lower alkoxy low alkyl group;

R ₂' be hydrogen, low alkyl group, phenyl lower alkyl, one or the low alkyl group that replaces of dihydroxyl, or phenyl lower alkoxy low alkyl group;

Ra ' is a hydrogen, low alkyl group, and one or the low alkyl group that replaces of dihydroxyl, or

R ₁₀Be hydrogen or

Rb ' and Rc ' are selected from hydrogen individually, perfluor-low alkyl group, halogen, the phenyl lower alkyl that unsubstituted low alkyl group replaces, low alkyl group, the phenyl lower alkoxy or

R ₁₁Be hydrogen, phenyl or unsubstituted low alkyl group;

P is the integer of 0-1; With

X and y are the integer of 0-4 individually.

Another embodiment of the invention relates to compound as defined above, wherein

R ₁' be low alkyl group;

R ₂' be hydrogen or low alkyl group; With

Rb ' and Rc ' are perfluor low alkyl group or hydrogen,

Among Rb ' and the Rc ' at least one is the perfluor low alkyl group.

R ₁' be one or the dihydroxyl low alkyl group and the R that replace ₂' be hydrogen or one or the low alkyl group that replaces of dihydroxyl, and Rb ' and Rc ' be perfluor low alkyl group or hydrogen independently, at least one among described Rb ' and the Rc ' is the perfluor low alkyl group.

Ra ' is one or the low alkyl group that replaces of dihydroxyl.

Another embodiment of the invention relates to compound as defined above, and wherein Ra ' is

And R ₁₀, x and y are as defined above.

Another embodiment of the invention relates to compound as defined above, and wherein one of Rb ' and Rc ' are

Or lower alkoxy;

R ₁₁Be hydrogen, phenyl or unsubstituted low alkyl group; With

P is the integer of 0-1.

Another embodiment of the invention relates to compound as defined above, and wherein one of Rb ' and Rc ' are low alkyl groups.

Another embodiment of the invention relates to compound or pharmaceutically acceptable salt thereof as defined above, and wherein said compound has formula (I-A)

Wherein

Be to contain 1-2 the heteroatomic 5 or 6 yuan of hetero-aromatic rings that are selected from oxygen, sulphur or nitrogen;

R ₁' be low alkyl group, phenyl lower alkyl, one or the low alkyl group that replaces of dihydroxyl, or phenyl lower alkoxy low alkyl group;

Ra ' is selected from hydrogen, phenyl lower alkyl, and low alkyl group, lower alkoxy, one or the low alkyl group that replaces of dihydroxyl, or

R ₁₀Be hydrogen, or

Rb ' and Rc ' are independently selected from hydrogen, the perfluor low alkyl group, and halogen, the phenyl lower alkyl that low alkyl group replaces, low alkyl group, the phenyl lower alkoxy, or

R ₁₁Be hydrogen, low alkyl group and phenyl;

P is the integer of 0-1; And

X and y are the integer of 0-4 individually.

Another embodiment of the invention relates to compound as defined above, wherein Be 5 or 6 yuan of hetero-aromatic rings, this hetero-aromatic ring contains sulfur heteroatom as heteroatoms unique in the described ring.

Rb ' and Rc ' are hydrogen or low alkyl group;

R ₁' be low alkyl group or one or the low alkyl group that replaces of dihydroxyl; With

R ₂' be hydrogen, low alkyl group or one or the low alkyl group that replaces of dihydroxyl.

Rb ' and Rc ' are hydrogen or lower alkoxy or phenyl lower alkoxy independently, and at least one is not a hydrogen among Rb ' and the Rc ';

R ₂' be the low alkyl group of hydrogen or low alkyl group or one or two rudimentary hydroxyls replacements.

Be to contain Sauerstoffatom as unique heteroatomic 5 or 6 yuan of hetero-aromatic rings.

R ₁' be low alkyl group; With

R ₂' be hydrogen or low alkyl group.

Be to contain nitrogen-atoms as unique heteroatomic 5 or 6 yuan of hetero-aromatic rings.

One of Rb ' and Rc ' are that hydrogen and another are hydrogen, low alkyl group or

R wherein ₁₁Be phenyl or low alkyl group; With

R ₁' and R ₂' be low alkyl group.

Be to contain two heteroatomic 5 or 6 yuan of hetero-aromatic rings.

Rb ' and Rc ' are low alkyl groups, hydrogen or lower alkoxy.

Another embodiment of the invention relates to compound and pharmaceutical salts thereof as defined above, and wherein said compound has formula (II)

Wherein

R ₁Be selected from low alkyl group, ethanoyl, hydroxyalkyl, and benzyloxy-alkyl;

R ₂Be selected from hydrogen, low alkyl group, ethanoyl, hydroxyalkyl

R ₃Be hydrogen or methyl;

Ra is selected from hydrogen, low alkyl group, lower alkoxy

Hydroxyalkyl and benzyloxy alkyl;

Re is a hydrogen, the alkyl of halogen or replacement and perfluor-low alkyl group

Rf is hydrogen or low alkyl group.

R ¹Be selected from methyl, ethyl, allyl group, benzyl, ethanoyl, 2,3-dihydroxypropyl, 3-hydroxypropyl and 2-benzyloxy ethyl;

R ²Be selected from hydrogen, methyl, ethyl, allyl group, benzyl, and ethanoyl;

Rc and Rd are hydrogen or trifluoromethyl independently;

Re is a hydrogen, chlorine halogen or trifluoromethyl; With

Rf is hydrogen or methyl.

Another embodiment of the invention relates to compound and pharmaceutical salts thereof as defined above, and this compound has formula (III)

Wherein

R ¹Be selected from hydrogen, low alkyl group, ethanoyl, hydroxyalkyl

R ²Be hydrogen or methyl;

X is a sulphur, oxygen, nitrogen or N-tertbutyloxycarbonyl;

Rb is selected from hydrogen, low alkyl group, lower alkoxy

Hydroxyalkyl and benzyloxy alkyl;

R _d' and R _e' be independently selected from hydrogen, low alkyl group and alkoxyl group.

R ¹Be selected from methyl, ethyl, ethanoyl, 3-hydroxypropyl and dimethylamino alkylsulfonyl;

R ²And Rb ' is independently selected from hydrogen, methyl and ethyl; With

Rd ' and Re ' are independently selected from hydrogen, methyl or methoxy.

In the compound of preferred formula I-B, the preferred embodiment of several these compounds is arranged.According to first embodiment, R ₁' be hydrogen or unsubstituted low alkyl group, R ₂' be that unsubstituted low alkyl group and Rb ' and Rc ' they are the perfluor low alkyl groups, preferred trifluoromethyl, and at least one is the perfluor low alkyl group among Rb ' and the Rc '.According to this first embodiment of the compound of formula I-A, Ra ' can be a hydrogen, unsubstituted low alkyl group or one or the low alkyl group that replaces of dihydroxyl, and Rb ' and Rc ' they are perfluor low alkyl group such as trifluoromethyl, another is hydrogen or perfluor low alkyl group.

According to another embodiment of the compound of formula I-B, Ra ' can be

R wherein ₁₀, x and y are as mentioned above.According to this embodiment, R ₁' can be hydrogen or low alkyl group, R ₂' can be low alkyl group.In addition, in the special preferred classes of this embodiment, Rb ' and Rc ' can be perfluor low alkyl group or hydrogen, and at least one is the perfluor low alkyl group among Rb ' and the Rc '.

According to another embodiment that the compound of formula I-B also has, one of Rb ' and Rc ' are low alkyl groups, and preferred especially Rb ' and two of Rc ' are low alkyl groups.On the other hand in this embodiment, R ₈And R ₉Can all be that hydrogen or Rb ' and Rc ' can be that hydrogen and another are low alkyl group.In another embodiment that the compound according to formula I-B has again, one of Rb ' and Rc ' are the substituting groups of lower alkoxy or following formula:

R wherein ₁₁With p as mentioned above.In this embodiment, wherein one of Ra ' and Rb ' are that the compound of unsubstituted low alkyl group is particularly preferred.In addition, in this particularly preferred embodiment, wherein Ra ' is that the compound of unsubstituted low alkyl group is preferred.

About the compound of formula I-A, include many embodiments in the formula according to the present invention.Preferably in ring, contain 5 or 6 members according to hetero-aromatic ring of the present invention.The compound that formula I-A is arranged among these, wherein the hetero-aromatic ring that forms in this compound contains sulfur heteroatom as heteroaromatic atom unique in this ring (as thiphene ring).Have in containing the compound of thiphene ring wherein that Rb ' and Rc ' are hydrogen or low alkyl group, R ₁' be hydrogen, low alkyl group or one or the dihydroxyl low alkyl group and the R that replace ₆Be low alkyl group or one or those compounds of the low alkyl group that replaces of dihydroxyl.According to hetero-aromatic ring wherein is the embodiment of this compound of thiphene ring, and preferred compound has wherein that Rb ' and Rc ' are hydrogen independently, those of lower alkoxy or phenyl lower alkoxy, and wherein at least one is not a hydrogen among Rb ' and the Rc '.In this preferred embodiment, R ₁' be hydrogen or low alkyl group or one or the dihydroxyl low alkyl group and the R that replace ₂' be low alkyl group or one or the low alkyl group that replaces of dihydroxyl.

According to another embodiment of the compound of formula I-A, aromatic ring is to contain Sauerstoffatom as unique heteroatomic 5 or 6 yuan of hetero-aromatic rings, as furan nucleus.In this embodiment, the preferred compound of a class is R wherein ₁' be hydrogen or low alkyl group and R ₂' be those of low alkyl group.Another embodiment of the compound of formula I-A is that wherein hetero-aromatic ring is to contain nitrogen-atoms those compounds as 5 or 6 yuan of hetero-aromatic rings of unique hetero-aromatic ring.According to this embodiment, wherein one of Rb ' and Rc ' substituting group are that hydrogen and another are the substituent compounds of hydrogen, low alkyl group or following formula

R wherein ₁₁With p as mentioned above.According to this embodiment, wherein p is that 1 compound is an embodiment preferred, R ₁₁Be phenyl or low alkyl group, R ₁' and R ₂' be unsubstituted low alkyl group.

According to another embodiment of the compound of formula I-B, It can be the hetero-aromatic ring that contains 5 or 6 members and two heteroatomss such as nitrogen or oxygen or oxygen or sulphur.In this embodiment, R ₁' and R ₂' can be low alkyl group, hydrogen or alkoxyl group.

Preferred compound is those and the pharmaceutical salts thereof that is selected from by the following group of forming as defined above:

7, N1-dimethyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

7, N1, N1-trimethylammonium-6-(2-trifluoromethyl)-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

7, N1-dimethyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

N1-ethyl-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

6-(3,5-couple-trifluoromethyl-phenyl)-7, N1, N1, N3-tetramethyl--7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

7, N1-diethyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

7-ethyl-N1-methyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

7-ethyl-N1, N1-dimethyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

N1, N1-diethyl-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

7-methyl-N1, N1-dipropyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

7-methyl isophthalic acid-piperidines-1-base-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-3-base amine,

N1, N1-dibenzyl-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

7-methyl isophthalic acid-tetramethyleneimine-1-base-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-3-base amine,

6-(2-methoxyl group-phenyl)-7, N1-dimethyl-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

6-(2-methoxyl group-phenyl)-7, N1, N1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

N1, N1-diethyl-7-methyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

7, N1, N1-trimethylammonium-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

7, N1, N1, N3-tetramethyl--6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

6-iodo-7, N1-dimethyl-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

7, N1, N1-trimethylammonium-6-(5-methyl-thiophene-2-yl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

7, N1-dimethyl-6-(5-methyl-thiophene-2-yl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

6-(5-chloro-2-methoxyl group-phenyl)-7, N1, N1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

6-furans-2-base-7, N1, N1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

6-furans-2-base-7, N1-dimethyl-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

2-[3-amino-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1-base is amino]-ethanol,

2-(3-amino-7-methyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1-base is amino)-ethanol,

3-[3-amino-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1-base is amino]-third-1-alcohol,

3-(3-amino-7-methyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1-base is amino)-third-1-alcohol,

2-[3-amino-7-methyl-6-(5-methyl-thiophene-2-yl)-7H-pyrrolo-[3,2-f] quinazoline-1-base is amino]-ethanol,

6-furans-3-base-7, N1, N1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

7, N1, N1-trimethylammonium-6-(4-methyl-thiophene-2-yl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

2-(3-amino-1-dimethylamino-7-methyl-7H-pyrrolo-[3,2-f] quinazoline-6-yl)-pyrroles-1-carboxylic acid tert-butyl ester,

6-(3,5-dimethyl-isoxazole-4-bases)-7, N1-dimethyl-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

7, N1-dimethyl-6-(2-phenoxy group-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

2-[3-amino-7-(2-hydroxyl-ethyl)-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1-base is amino]-ethanol,

6-(4-methoxyl group-thiophene-2-yl)-7, N1, N1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

3-[3-amino-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1-base is amino]-the third-1, the 2-glycol,

2-[3-amino-1-dimethylamino-6-(2-trifluoromethyl-phenyl)-pyrrolo-[3,2-f] quinazoline-7-yl]-ethanol,

[(4-{2-[3-amino-1-dimethylamino-6-(2-trifluoromethyl-phenyl)-pyrrolo-[3,2-f] quinazoline-7-yl]-ethoxyl methyl }-phenyl)-two fluoro-methyl]-phosphonic acids,

6-(5-methoxyl group-thiophene-2-yl)-7, N1, N1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

6-(5-methoxyl group-thiophene-2-yl)-7, N1-dimethyl-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

6-(4-methoxyl group-thiophene-2-yl)-7, N1-dimethyl-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

6-(2,6-dimethyl-phenyl)-7, N1, N1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

6-(2,6-dimethyl-phenyl)-7, N1-dimethyl-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

7, N1, N1-trimethylammonium-6-(4-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

7, N1-pair-(2-benzyloxy-ethyl)-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

2-[[3-amino-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1-yl]-(2-hydroxyl-ethyl)-amino]-ethanol,

3-amino-7-methyl-6-thiophene-2-base-2,7-dihydro-pyrrolo-[3,2-f] quinazoline-1-ketone,

7, N1, N1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines and

6-(2,4-dimethoxy-pyrimidine-5-yl)-7, N1, N1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines.

Other as defined above preferred compound be those and the pharmaceutical salts thereof that is selected from by the following group of forming:

7, N1-dimethyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines, with the compound of trifluoroacetic acid,

N1-ethyl-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines, with the compound of trifluoroacetic acid,

7, N1-diethyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines, with the compound of trifluoroacetic acid,

7-ethyl-N1-methyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines, with the compound of trifluoroacetic acid,

7-ethyl-N1, N1-dimethyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines, with the compound of trifluoroacetic acid,

N1, N1-diethyl-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines, with the compound of trifluoroacetic acid,

7-methyl-N1, N1-dipropyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines, with the compound of trifluoroacetic acid,

7-methyl isophthalic acid-piperidines-1-base-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-3-base amine, with the compound of trifluoroacetic acid,

N1, N1-dibenzyl-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines, with the compound of trifluoroacetic acid,

7-methyl isophthalic acid-tetramethyleneimine-1-base-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-3-base amine, with the compound of trifluoroacetic acid,

6-(2-methoxyl group-phenyl)-7, N1-dimethyl-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines, with the compound of trifluoroacetic acid,

6-(2-methoxyl group-phenyl)-7, N1, N1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines, with the compound of trifluoroacetic acid,

N1, N1-diethyl-7-methyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines, with the compound of trifluoroacetic acid,

7, N1, N1-trimethylammonium-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines, with the compound of trifluoroacetic acid,

7, N1, N1, N3-tetramethyl--6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines, with the compound of trifluoroacetic acid,

6-iodo-7, N1-dimethyl-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

6-(5-chloro-2-methoxyl group-phenyl)-7, N1, N1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines, with the compound of trifluoroacetic acid,

6-furans-2-base-7, N1-dimethyl-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines, with the compound of trifluoroacetic acid,

2-[3-amino-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1-base is amino]-ethanol, with the compound of trifluoroacetic acid,

2-(3-amino-7-methyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1-base is amino)-ethanol, with the compound of trifluoroacetic acid,

3-[3-amino-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1-base is amino]-third-1-alcohol, with the compound of trifluoroacetic acid,

3-(3-amino-7-methyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1-base is amino)-third-1-alcohol, with the compound of trifluoroacetic acid,

2-[3-amino-7-methyl-6-(5-methyl-thiophene-2-yl)-7H-pyrrolo-[3,2-f] quinazoline-1-base is amino]-ethanol, with the compound of trifluoroacetic acid,

6-(3,5-dimethyl-isoxazole-4-bases)-7, N1-dimethyl-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines, with the compound of trifluoroacetic acid,

7, N1-dimethyl-6-(2-phenoxy group-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines, with the compound of trifluoroacetic acid,

2-[3-amino-7-(2-hydroxyl-ethyl)-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1-base is amino]-ethanol, with the compound of trifluoroacetic acid,

3-[3-amino-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1-base is amino]-the third-1, the 2-glycol, with the compound of trifluoroacetic acid,

2-[3-amino-1-dimethylamino-6-(2-trifluoromethyl-phenyl)-pyrrolo-[3,2-f] quinazoline-7-yl]-ethanol, with the compound of trifluoroacetic acid,

6-(2,6-dimethyl-phenyl)-7, N1, N1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines, with the compound of trifluoroacetic acid,

6-(2,6-dimethyl-phenyl)-7, N1-dimethyl-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines, with the compound of trifluoroacetic acid,

7, N1-pair-(2-benzyloxy-ethyl)-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines, with the compound of trifluoroacetic acid,

2-[[3-amino-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1-yl]-(2-hydroxyl-ethyl)-amino]-ethanol, with the compound of trifluoroacetic acid,

Particularly preferred compound as defined above is those and the pharmaceutical salts thereof that is selected from by the following group of forming:

6-(5-methoxyl group-thiophene-2-yl)-7, N1-dimethyl-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines and

6-furans-2-base-7, N1-dimethyl-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines.

Other particularly preferred compound as defined above is those and the pharmaceutical salts thereof that is selected from by the following group of forming:

7, N1-dimethyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines trifluoroacetate,

7, N1-dimethyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines trifluoroacetate,

6-(2,6-dimethyl-phenyl)-7, N1-dimethyl-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines trifluoroacetate,

7-ethyl-N1-methyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines trifluoroacetate,

6-furans-2-base-7, N1-dimethyl-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines trifluoroacetate.

The all cpds of below mentioning separately constitutes the preferred embodiments of the invention.The aforesaid compound of preferred non-pharmaceutical salts and/or medicinal ester.

The compound of formula (I) has one or more unsymmetrical carbons and can exist with the form of the mixture of optically pure enantiomorph, optically pure diastereomer or diastereomer.Optically pure form can be for example fractionation by racemoid obtain, this splits by asymmetric synthesis or asymmetric chromatography (with chiral sorbent or eluent chromatographic separation).The present invention includes all these forms.

Should be appreciated that the compound of formula of of the present invention (I) can be in functional group derivatize so that the derivative that can transform back parent compound in vivo to be provided.Can produce in the physiologically acceptable and metabolism of parent compound of general formula (I) unsettled derivative in vivo also within the scope of the invention.

The present invention prepares the preparation method of the compound of formula (I) as defined above, comprises the compound of formula (XII) and the compound reaction of formula (XIII)

R wherein ₁, R ₂, R ₃, Ra, Rb, Rc, Rd, Re, Rf and A have the above meaning that provides.

The reaction of the compound of the compound of described formula XII and formula XIII can be undertaken by well known to a person skilled in the art method, for example is similar to embodiment described below and reaction scheme.Pd (P (phenyl) can be for example used in reaction ₃) ₄In solvent such as DME or ETOH, carry out and use Na ₂CO ₃And H ₂O handles.

Another embodiment of the present invention relates to the compound as defined above by the preparation of method as defined above.

As mentioned above, compound of the present invention can be as the medicine that treats and/or prevents the disease of regulating by the PTP1B inhibitor.The example of this disease is based on the disease of hyperglycemia concentration, particularly diabetes.Compound vitro inhibition PTP1B of the present invention and shown and reduce glucose level in the body.Therefore, compound of the present invention is effective to treat diabetes.

Therefore the present invention also relates to pharmaceutical composition, and it comprises compound and pharmaceutical carrier and/or adjuvant as defined above.

In addition, the present invention relates to compound as defined above, it is as therapeutic active substance, in particular as treating and/or preventing the treatment of diseases active substance of regulating by the PTP1B inhibitor.The example of this disease is based on the disease of hyperglycemia concentration, particularly diabetes.

In another embodiment, the present invention relates to treat and/or prevent the method for the disease of regulating by the PTP1B inhibitor, this method comprises to the human or animal uses compound as defined above.The example of this disease is based on the disease of hyperglycemia concentration, particularly diabetes.

The present invention relates to the application of compound in treating and/or preventing the disease of regulating by the PTP1B inhibitor as defined above in addition.The preferred embodiment of this disease is based on the disease of hyperglycemia concentration, particularly diabetes.

In addition, the present invention relates to the application of compound in the preparation medicine as defined above, the disease that described medicine is used for the treatment of and/or prevents to regulate by the PTP1B inhibitor.The preferred embodiment of this disease is based on the disease of hyperglycemia concentration, particularly diabetes.This medicine comprises compound as defined above.

Compound of the present invention can be oral, rectum or parenterai administration, for example in intravenously, intramuscular, subcutaneous, the sheath or percutaneous dosing; Perhaps sublingual administration or as ophthalmic preparation.The example of form of administration is useful on capsule, tablet, suspensoid or the solution of oral administration, suppository, injection liquid, eye drop, ointment agent or spray solution.

Intravenously, intramuscular, oral or inhalation are preferred administering modes.The compounds of this invention is used effective dosage and is changed according to character, patient's age and requirement and the administering mode of given activity composition.Dosage can be determined for example clinical trial of dose limitation by any ordinary method.Usually, dosage preferred every day about 0.1, particularly preferred dosage was 1-25mg/kg every day to the 100mg/kg body weight.

The present invention further comprises the The compounds of this invention that contains medicine effective quantity and the pharmaceutical composition of pharmaceutical carrier.Said composition can be by any ordinary method preparation.Tablet or granule can contain a series of tackiness agents, weighting agent, carrier or thinner.Liquid composition can be, sterilized water-miscible solution form for example.Capsule can also contain weighting agent or thickening material except containing activeconstituents.In addition, can also have the additive that improves taste, usually as anticorrosion, stablize, preserve moisture and the emulsive material, and the salt, damping fluid and other additive that change osmotic pressure.

Above-mentioned solid support material and thinner can contain the medicinal organic or inorganic material of any routine, for example water, gelatin, lactose, starch, Magnesium Stearate, talcum powder, gum arabic, polyalkylene glycol etc.

Oral unit dosage form, for example tablet and capsule preferably contain 25mg to 1000mg compound of the present invention.Compound of the present invention can be synthetic by any ordinary method.

According to the present invention, compound herein and the effective control of their pharmaceutical salts or prevention and the concentration dependent disease of hyperglycemia.Preferably indication related to the present invention is those relevant with diabetes.

Dosage can change in wide region, must regulate according to indivedual the requirement in each particular condition certainly.In the oral administration situation, adult's dosage can extremely change in the pharmaceutical salts scope of the compound of about 1000mg/ days formula I or II or its respective amount at about 0.01mg.Per daily dose can be used as single dose or divided dose is used, and in addition, the upper limit also can surpass when finding indication.

The method that the compound of formula (I) can provide by the following method that provides, by embodiment or prepare by similar approach.Appropriate reaction condition for independent reactions steps is that those skilled in the art are known.Starting material are commercially available or method that can be by the following method that provides is provided, prepare by the reference quoted in the context or the method described in the embodiment or by methods known in the art.

The concrete grammar of preparation compound of the present invention is described in following reaction scheme.

Reaction scheme 1

Following reaction scheme 2 provides general synthesis step, and embodiment provides the detailed description of diagram method.

Compound I I: with 5-nitro-2,3-dihydro-1H-indoles I (48g, 0.29mol) handle silver sulfide (100g, 0.32mol) and iodine (82g, 0.32mol) at N, the mixture in dinethylformamide (700mL) and the ethanol (1400mL).The mixture that obtains was stirred 1.5 hours down at 25 ℃, filter and wash filter bed with ethyl acetate.Vacuum concentrated filtrate is to the volume of about 500mL.Handle this solution with 1.0N sodium thiosulfate solution (100mL) and saturated sodium-chloride water solution (400mL).Collect the precipitation that obtains by filtering, water and petroleum ether, vacuum-drying is to provide 7-iodo-5-nitro-2, and 3-dihydro-1H-indoles II (83.9g, 98.9%) is white solid. ¹H NMR (DMSO-d ₆, 300MHz) δ 8.18 (d, J=2.20Hz, 1H), 7.80 (d, J=1.46Hz, 1H), 7.03 (wide s, 1H), 3.65 (t, J=8.97Hz, 2H), 3.17 (t, J=8.60Hz, 2H).

Compound III: with 2,3-two chloro-5,6-dicyano-1, (13.6g 59.9mmol) handles 25 ℃ 7-iodo-5-nitro-2,3-dihydro-1H-indoles II (15g, 51.7mmol) solution in ethanol (1200mL) and Virahol (20mL) to the 4-benzoquinones.The solution that obtains was warming up to 65 ℃ and bubbling air 1 hour.Add other 0.57 normal 2,3-two chloro-5,6-dicyano-1, the 4-benzoquinones (6.8g, 29.9mmol) and will be reflected at 65 ℃ and stir other 2 hours, vacuum concentration afterwards.Flash chromatography (Merck silica gel 60,230-400 order, 90/10 toluene/ethyl acetate) provides 7-iodo-5-nitro-1H-indoles III (13.07g, 79%), is yellow solid. ¹H NMR (DMSO-d ₆, 300MHz) δ 11.82 (wide s, 1H), 8.59 (d, J=1.83Hz, 1H), 8.30 (d, J=1.83Hz, 1H), 7.61 (t, J=2.93Hz, 1H), 6.90 (dd, J ₁=1.83Hz, J ₂=3.30Hz, 1H).

Compound IV: (26.1g, 485.8mmol) (13.6g 242.9mmol) handles the 7-iodo-5-nitro in methyl alcohol (650mL)-1H-indoles III (20g, 69.4mmol) solution of 25 ℃ to the ammonium chloride in the water (550mL) for solution and iron powder.With mixture under nitrogen atmosphere, be heated to 100 ℃ 5 hours.The mixture filtration that obtains is washed with hot methanol by Celite pad and with Celite pad.Vacuum concentrated filtrate also distributes resistates and separates between methylene dichloride and water.With ammonium hydroxide with the pH regulator of water layer to pH=10 and use dichloromethane extraction.With the organic phase that dried over sodium sulfate merges, filtration and vacuum concentration are to the volume of 250mL.Handle this solution and descend stirring 2 hours with the 4.0M aqueous hydrochloric acid in the Zai diox at 25 ℃.Also use methylene dichloride and petroleum ether by filtering collecting precipitation, acquisition 7-iodo-1H-indoles-5-base amine hydrochlorate IV (24.7g quant.), is gray solid: ¹HNMR (DMSO-d ₆, 300MHz) δ 11.34 (wide s, 1H), 9.93 (wide s, 2H), 7.56 (d, J=1.46Hz, 1H), 7.48 (t, J=2.74Hz, 1H), 7.44 (d, J=1.83Hz, 1H), 6.68 (dd, J ₁=1.83Hz, J ₂=2.93Hz, 1H).

Compound V: with dicyanamide sodium (18.6g, 209mmol) handle 25 ℃ at N, the 7-iodo-1H-indoles in the dinethylformamide (400mL)-5-base amine hydrochlorate IV (24.6g, 83.7mmol) solution.With reaction mixture be warming up to 50 ℃ 2 hours, vacuum concentration, water (500mL) are handled resistates.The mixture that obtains was left standstill under 25 ℃ 2.5 hours, during form yellow mercury oxide.By filtering collecting precipitation and washing with water so that N to be provided " cyano group-N-(7-iodo-1H-indoles-5-yl) guanidine V (22.59g, 83%) is faint yellow solid: ¹H NMR (DMSO-d ₆, 300MHz) δ 11.02 (wide s, 1H), 8.89 (wide s, 1H), 7.46 (d, J=1.83Hz, 1H), 7.37 (d, J=1.83Hz, 1H), 7.35 (t, J=2.56Hz, 1H), 6.85 (wide s, 2H), 6.56 (dd, J ₁=1.83Hz, J ₂=3.10Hz, 1H).

Compound VI: with N " cyano group-N-(7-iodo-1H-indoles-5-yl) guanidine V (6.08g, 18.7mmol) solution in 2-methoxy ethyl ether (50mL) be heated to 175 ℃ 32.5 hours.Reaction mixture is cooled to 25 ℃, removes the solid that obtains and use methanol wash by filtering.Vacuum concentrated filtrate is to provide brown oil.Resistates is dissolved in is adsorbed onto Merck silica gel 60 in the methyl alcohol then, 230-400 order (25g).Flash chromatography (Merck silica gel 60,230-400 order, 90/10/1 methylene chloride/ammonium hydroxide) provides 6-iodo-7H-pyrrolo-[3,2-f] quinazoline-1, and 3-diamines VI (3.61g, 59%) is brown solid: ¹H NMR (DMSO-d ₆, 300MHz) δ 11.36 (wide s, 1H), 7.45 (wide s, 1H), 7.43 (t, J=2.93Hz, 1H), 7.20 (s, 1H), 6.74 (wide s, 2H), 5.78 (wide s, 2H).

Compound VI I: be used to carry out derivative VI and various halogenide (for example RaBr or RaI, wherein Ra as above defines) alkylating representative condition be in appropriate solvent such as ether or DME or tetrahydrofuran (THF) or DMF, use suitable alkali such as sodium hydroxide or potassium hydroxide or lithium hydroxide, temperature range is-78 ℃ to 25 ℃, so that 6-iodo-7-alkyl-7H-pyrrolo-[3 to be provided, 2-f] quinazoline-1,3-diamines VII.

Compound VIII: the 6-iodo-7-alkyl-7H-pyrrolo-[3 of acquisition, 2-f] quinazoline-1,3-diamines VII then further-50 ℃ to the room temperature in appropriate solvent such as ether or DME or tetrahydrofuran (THF) or DMF, use suitable alkali such as sodium hydride and various halogenide (R for example ₁Br, R ₂Br, R ₃Br or R ₁I, R ₂I, R ₃I, wherein R ₁, R ₂, R ₃As above definition) alkylation, generation one, two or trisubstituted 6-iodo-7-alkyl-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines VIII.

Compound I X: linked reaction can be undertaken by the aryl coupling method of routine, for example the Suzuki coupling method: (a) Suzuki etc., Synth.Commun.1981,513, (b) Suzuki, Pure and Appl.Chem.1985,57,1749-1758, (c) Suzuki etc., Chem.Rev.1995,95,2457-2483, (d) Shieh etc., J.Org.Chem.1992,57,379-381, (e) Martin etc., Acta ChemicaScandinavica.1993,47,513.

The Suzuki link coupled representative condition that is used to carry out VIII comprises and uses aryl or heteroaryl boric acid or ester (for example wherein Ar such as aryl define) as the coupling part, in the aqueous solution of alkali such as sodium bicarbonate or salt of wormwood or hydrated barta or triethylamine, palladium catalyst (2-20mol%) is as four (triphenyl phosphine)-palladiums (o) or [1,1 '-two (diphenyl phosphine)-ferrocene] two chloro-palladiums (II), in appropriate solvent such as ethanol or THF or DMF or aqueous glycol solution, temperature is 25 ℃ to 125 ℃, 2-18 hour, produce 7-alkyl-7H-pyrrolo-[3 that compound 6-aryl replaces, 2-f] quinazoline-1,3-diamines IX.

Alternatively, linked reaction can be undertaken by the aryl or the heteroaromatic coupling part of routine, utilizes the Stille coupling, Stille etc. for example, Angew.Chem.Int.Ed.Engl., 1986,25,508.The representative condition that is used to carry out the Stille reaction comprises and uses organic stannane as the coupling part, palladium catalyst (2-20mol%) is as four (triphenyl phosphine)-palladiums (o) or [1,1 '-two (diphenyl phosphine)-ferrocene] two chloro-palladiums (II), salt such as Potassium monofluoride or lithium chloride, in suitable anhydrous solvent such as THF or DMF or ethylene glycol, temperature is in 25 ℃ to 125 ℃ the temperature range 2-18 hour, produces 7-alkyl-7H-pyrrolo-[3 that the 6-aryl replaces, 2-f] quinazoline-1,3-diamines IX.

Following reaction scheme 3 provides alternative general synthesis step, and embodiment provides the detailed description of graphic technique.

Reaction scheme 3

Compound VI I: be used to carry out derivative VI and various halogenide (for example RaBr or RaI, wherein Ra as above defines) alkylating representative condition be in appropriate solvent such as tetrahydrofuran (THF) or DMF, use suitable alkali such as sodium hydroxide, temperature range is-78 ℃ to 25 ℃, so that 6-iodo-7-alkyl-7H-pyrrolo-[3 to be provided, 2-f] quinazoline-1,3-diamines VII.

Compounds X: linked reaction can be undertaken by the aryl coupling method of routine, for example the Suzuki coupling method: (a) Suzuki etc., Synth.Commun.1981,513, (b) Suzuki, Pure and Appl.Chem.1985,57,1749-1758, (c) Suzuki etc., Chem.Rev.1995,95,2457-2483, (d) Shieh etc., J.Org.Chem.1992,57,379-381, (e) Martin etc., Acta ChemicaScandinavica.1993,47,513.

The Suzuki link coupled representative condition that is used to carry out VII comprises and uses aryl or heteroaryl boric acid or ester (for example wherein Ar such as aryl define) as the coupling part, in the aqueous solution of alkali such as sodium bicarbonate or salt of wormwood or hydrated barta or triethylamine, palladium catalyst (2-20mol%) is as four (triphenyl phosphine)-palladiums (o) or [1,1 '-two (diphenyl phosphine)-ferrocene] two chloro-palladiums (II), in appropriate solvent such as ethanol or THF or DMF or aqueous glycol solution, temperature is 25 ℃ to 125 ℃, 2-18 hour, produce compounds X.Alternatively, linked reaction can utilize the Stille coupling to carry out by conventional aryl or heteroaromatic coupling part, Stille etc. for example, Angew.Chem.Int.Ed.Engl., 1986,25,508.

The representative condition that is used to carry out the Stille reaction comprises and uses organic stannane as the coupling part, palladium catalyst (2-20mol%) is as four (triphenyl phosphine)-palladiums (o) or [1,1 '-two (diphenyl phosphine)-ferrocene] two chloro-palladiums (II), salt such as Potassium monofluoride or lithium chloride, in suitable anhydrous solvent such as THF or DMF or ethylene glycol, temperature is in 25 ℃ to 125 ℃ the temperature range 2-18 hour, produces compounds X.

Compounds X I: compounds X then further-50 ℃ to the room temperature with suitable alkali such as sodium hydride and various halogenide (R for example ₁Br, R ₂Br, R ₃Br or R ₁I, R ₂I, R ₃I, wherein R ₁, R ₂, R ₃As above definition) alkylation, generation one, two or trisubstituted compounds X I.Can control alkylation by selecting used halid suitable equivalent.

The present invention illustrates by the following example.In these embodiments, embodiment 2-22 is undertaken by the method for embodiment 1, and embodiment 24-42 is undertaken by the method for embodiment 23.

Embodiment

Embodiment 1

(A) 2-(3-amino-7-methyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1-base is amino)-ethanol three fluoro-acetates

With powdered sodium hydroxide (0.66g, 16.5mmol), methyl iodide (0.62mL, 9.96mmol) and Tetrabutylammonium bromide (0.8g, 2.48mmol) processing 6-iodo-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines VI (2.68g, 8.24mmol) solution in tetrahydrofuran (THF) (100mL), the mixture that obtains was stirred 18 hours at 25 ℃.The mixture that vacuum concentration obtains.Resistates is distributed between methylene dichloride (70mL) and water (70mL), this mixture was stirred 30 minutes at 25 ℃.By the filtering separation precipitation, wash with water, vacuum-drying is to obtain 6-iodo-7-methyl-7H-pyrrolo-[3,2-f] quinazoline-1, and 3-diamines (2.67g, 95.5%) is yellow solid; ¹H NMR (DMSO-d ₆, 300MHz) δ 7.58 (s, 1H), 7.47 (d, J=2.93Hz, 1H), 6.99 (d, J=2.93Hz, 1H), 6.78 (wide s, 2H), 5.83 (wide s, 2H), 4.16 (s, 3H).

With 6-iodo-7-methyl-7H-pyrrolo-[3,2-f] quinazoline-1, and the 3-diamines (580mg, 1.71mmol) at tetrahydrofuran (THF) (20mL) and N, the solution in the dinethylformamide (10mL) is cooled to-50 ℃, and (270mg 6.84mmol) handles with 60% sodium hydride.Reaction mixture is warming up to-20 ℃, makes and stirred 20 minutes, be cooled to-50 ℃ afterwards again.(300mg 1.88mmol), removes cooling bath, makes the mixture that obtains stir 6 hours down at 25 ℃ to add 2-(2-bromine oxethyl) tetrahydrochysene-2-H-pyrans.Then reaction mixture is cooled to again-4 ℃, (270mg 6.84mmol) handles, and then (300mg 1.88mmol) handles with another part 2-(2-bromine oxethyl) tetrahydrochysene-2-H-pyrans with other a part of 60% sodium hydride.Make the mixture that obtains stir 2 days down, then vacuum concentration at 25 ℃.The HPLC purifying (moved 4 times on 21.2mm * 100mm Zorbax CombiHT post in 15 minutes, use 5: 95 to 95: 5 acetonitrile: water: the 0.75%TFA gradient) provide 2-(3-amino-6-iodo-7-methyl-7H-pyrrolo-[3,2-f] quinazoline-1-base amino)-ethanol trifluoroacetate (270mg, 32%), is pale solid; The LRMS C of free radical (freebase) ₁₃H ₁₄IN ₅O (M+H) ⁺M/z=384.

Use thiophene-2-boric acid (60mg down at 25 ℃, 0.47mmol), 2.0M sodium bicarbonate aqueous solution (2.0mL) and four (triphenyl phosphine)-palladiums (o) (5.0mg) are handled 2-(3-amino-6-iodo-7-methyl-7H-pyrrolo-[3,2-f] quinazoline-1-base amino)-ethanol trifluoroacetate (90mg, 0.23mmol) solution in ethylene glycol dimethyl ether (8.0mL) and ethanol (4.0mL).With the mixture heating up that obtains to refluxing 18 hours.The mixture that vacuum concentration obtains is suspended in acetonitrile and the water resistates and filtration.The HPLC purifying is (in 15 minutes on 21.2mm * 100mm Zorbax CombiHT post, use 5: 95 to 95: 5 acetonitrile: water: the 0.75%TFA gradient) provide 2-(3-amino-7-methyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1-base amino)-ethanol three fluoro-acetates, be faint yellow solid; LRMSC ₁₇H ₁₇N ₅O (M+H) ⁺M/z=340.

Embodiment 2

In a similar fashion, obtain by 2-(3-amino-6-iodo-7-methyl-7H-pyrrolo-[3,2-f] quinazoline-1-base is amino) ethanol trifluoroacetate and 5-thiotolene-2-boric acid

It is amino to produce 2-[3-amino-7-methyl-6-(5-methyl-thiophene-2-yl)-7H-pyrrolo-[3,2-f] quinazoline-1-base]-ethanol three fluoro-acetates, be pale solid; LRMS C ₁₈H ₁₉N ₅OS (M+H) ⁺M/z=354.

Embodiment 3

By 3-(3-amino-6-iodo-7-methyl-7H-pyrrolo-[3,2-f] quinazoline-1-base amino)-third-1-alcohol three fluoro-acetates and synthetic 3-(the 3-amino-7-methyl-6-thiophene-2-base-7H-pyrrolo-[3 of thiophene-2-boric acid, 2-f] quinazoline-1-base amino)-third-1-alcohol, three fluoro-acetates, be pale solid; LRMSC ₁₈H ₁₉N ₅OS (M+H) ⁺M/z=354.

Embodiment 4

By 6-iodo-7, N1, N1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines and 2-(trifluoromethyl) phenylo boric acid synthesizes 7, N1, N1-trimethylammonium-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines three fluoro-acetates are white solid; LRMS C ₂₀H ₁₈F ₃N ₅(M+H) ⁺M/z=386.

Embodiment 5

By N1-ethyl-6-iodo-7-methyl-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines three fluoro-acetates and 2-(trifluoromethyl) phenylo boric acid synthesize N1-ethyl-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines three fluoro-acetates are white solid; LRMSC ₂₀H ₁₃F ₃N ₅(M+H) ⁺M/z=386.

Embodiment 6

(embodiment 6) are by 3-(3-amino-6-iodo-7-methyl-7H-pyrrolo-[3,2-f] quinazoline-1-base amino)-third-1-alcohol three fluoro-acetates and the synthetic 3-[3-amino of 2-(trifluoromethyl) phenylo boric acid-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1-base amino]-third-1-alcohol, three fluoro-acetates, be pale solid; LRMS C ₂₁H ₂₀F ₃N ₅O (M+H) ⁺M/z=416.

Embodiment 7

By 2-(3-amino-1-dimethylamino-6-iodo-pyrrolo-[3,2-f] quinazoline-7-yl)-ethanol three fluoro-acetates and 2-(trifluoromethyl) phenylo boric acid Synthetic 2-[3-amino-1-dimethylamino-6-(2-trifluoromethyl-phenyl)-pyrrolo-[3,2-f] quinazoline-7-yl]-ethanol three fluoro-acetates, be pale solid; LRMSC ₂₁H ₂₀F ₃N ₅O (M+H) ⁺M/z=416.

Embodiment 8

By 2-[3-amino-7-(2-hydroxyl-ethyl)-6-iodo-7H-pyrrolo-[3,2-f] quinazoline-1-base amino]-ethanol three fluoro-acetates and 2-(trifluoromethyl) phenylo boric acid Synthetic 2-[3-amino-7-(2-hydroxyl-ethyl)-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1-base amino]-ethanol three fluoro-acetates, be pale solid; LRMS C ₂₁H ₂₀F ₃N ₅O ₂(M+H) ⁺M/z=432.

Embodiment 9

By 3-(3-amino-6-iodo-7-methyl-7H-pyrrolo-[3,2-f] quinazoline-1-base amino)-the third-1,2-glycol three fluoro-acetates and 2-(trifluoromethyl) phenylo boric acid synthesize 3-[3-amino-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1-base amino]-the third-1,2-glycol three fluoro-acetates are pale solid; LRMS C ₂₁H ₂₀F ₃N ₅O ₂(M+H) ⁺M/z=432.

Embodiment 10

By 2-[(3-amino-6-iodo-7-methyl-7H-pyrrolo-[3,2-f] quinazoline-1-yl)-(2-hydroxyl-ethyl)-amino]-ethanol three fluoro-acetates and 2-(trifluoromethyl) phenylo boric acid Synthetic 2-[[3-amino-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-quinazoline-1-yl]-(2-hydroxyl-ethyl)-amino]-ethanol three fluoro-acetates, be faint yellow solid; LRMS C ₂₂H ₂₂F ₃N ₅O ₂(M+H) ⁺M/z=446.

Embodiment 11

By 7, N1-pair-(2-benzyloxy-ethyl)-6-iodo-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines three fluoro-acetates and 2-(trifluoromethyl) phenylo boric acid synthetic 7, N1-pair-(2-benzyloxy-ethyl)-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines three fluoro-acetates are faint yellow solid; LRMS C ₃₅H ₃₂F ₃N ₅O ₂(M+H) ⁺M/z=612.

Embodiment 12

By ({ 4-[2-(3-amino-1-dimethylamino-6-iodo-pyrrolo-[3,2-f] quinazoline-7-yl)-ethoxyl methyl]-phenyl }-two fluoro-methyl)-phosphoric acid and synthetic [(the 4-{2-[3-amino-1-dimethylamino-6-(2-trifluoromethyl-phenyl)-pyrrolo-[3 of 2-(trifluoromethyl) phenylo boric acid, 2-f] quinazoline-7-yl]-ethoxyl methyl }-phenyl)-two fluoro-methyl]-phosphoric acid, be faint yellow solid; LRMS C ₂₉H ₂₇F ₅N ₅O ₄P (M+H) ⁺M/z=636.

Embodiment 13

By N1, N1-dibenzyl-6-iodo-7-methyl-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines three fluoro-acetates and 2-(trifluoromethyl) phenylo boric acid synthesize N1, N1-dibenzyl-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines three fluoro-acetates are white solid; LRMSC ₃₂H ₂₆F ₃N ₅(M+H) ⁺M/z=538.

Embodiment 14

By 2-(3-amino-6-iodo-7-methyl-7H-pyrrolo-[3,2-f] quinazoline-1-base amino)-ethanol three fluoro-acetates and 2-(trifluoromethyl) phenylo boric acid Synthetic 2-[3-amino-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1-base amino]-ethanol three fluoro-acetates, be pale solid; LRMS C ₂₀H ₁₈F ₃N ₅O (M+H)+m/z=402.

Embodiment 15

By N1, N1-diethyl-6-iodo-7-methyl-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines three fluoro-acetates and 2-(trifluoromethyl) phenylo boric acid synthesize N1, N1-diethyl-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines three fluoro-acetates are pale solid; (ES)+-HRMS m/e theoretical value C ₂₂H ₁₉N ₅F ₆(M+H) ⁺468.1617, experimental value 468.1618.

Embodiment 16

By 6-iodo-7-methyl-N1, N1-dipropyl-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines three fluoro-acetates and 2-(trifluoromethyl) phenylo boric acid synthesize 7-methyl-N1, N1-dipropyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines three fluoro-acetates are white solid; LRMSC ₂₄H ₂₆F ₃N ₅(M+H) ⁺M/z=442.

Embodiment 17

By 6-iodo-7, N1, N1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines and furans-3-boric acid synthesizes 6-furans-3-base-7, N1, N1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines; EI-HRMS m/e theoretical value C ₁₇H ₁₇N ₅O (M ⁺) 307-1433, experimental value 307.1427.

Embodiment 18

By 6-iodo-7, N1, N1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines and 4-thiotolene-2-boric acid synthesize 7, N1, N1-trimethylammonium-6-(4-methyl-thiophene-2-yl)-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines; (ES)+-HRMS m/e theoretical value C ₁₈H ₁₉N ₅S (M+) 337.1361, theoretical value 337.1357.

Embodiment 19

By 6-iodo-7, N1, N1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines and 1-(tertbutyloxycarbonyl) pyrroles-2-boric acid Synthetic 2-(3-amino-1-dimethylamino-7-methyl-7H-pyrrolo-[3,2-f] quinazoline-6-yl)-pyrroles-1-carboxylic acid tert-butyl ester; EI-HRMS m/e theoretical value C ₂₂H ₂₆N ₆O ₂(M+) 406.2117, experimental value 406.2115.

Embodiment 20

By 6-iodo-7, N1, N1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines and 5-methoxyl group-2-thienyl boric acid are synthesized 6-(5-methoxyl group-thiophene-2-yl)-7, N1, N1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines; EI-HRMS m/e theoretical value C ₁₈H ₁₉N ₅OS (M ⁺) 353.1310, experimental value 353.1306.

Embodiment 21

By 6-iodo-7, N1-dimethyl-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines and 2,6-dimethyl benzene ylboronic acid synthesizes 6-(2,6-dimethyl-phenyl)-7, N1-dimethyl-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines three fluoro-acetates are pale solid; EI-HRMS m/e theoretical value C ₂₀H ₂₁N ₅(M ⁺) 331.1797, experimental value 331.1786.

Embodiment 22

By 6-iodo-7, N1, N1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines and 2,4-dimethoxypyridin-5-boric acid synthesize 6-(2,4-dimethoxy-pyrimidine-5-yl)-7, N1, N1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines is white solid; EI-HRMS m/e theoretical value C ₁₉H ₂₁N ₇O ₂(M ⁺) 379.1757, experimental value 379.1763.

Embodiment 23

7, N1-dimethyl-6-(5-methyl-thiophene-2-yl)-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines

Use sodium hydroxide (98mg down at 25 ℃, 2.46mmol), methyl-iodide (0.09mL, 1.48mmol), and Tetrabutylammonium bromide (198mg, 0.62mmol) processing 6-iodo-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines is (as embodiment 1 preparation, 400mg, the 1.23mmol) solution in tetrahydrofuran (THF) (20mL), and under 25 ℃, stirred 18 hours.Use ethyl acetate, water and saturated sodium-chloride water solution are handled the mixture that obtains, and vibration also separates.Use the ethyl acetate extraction water layer, the organic layer by dried over sodium sulfate merges filters and vacuum concentration, and 6-iodo-7-methyl-7H-pyrrolo-[3,2-f] quinazoline-1 is provided, and 3-diamines (500mg) is yellow solid.Product is used for next reaction and is not further purified.

With 6-iodo-7-methyl-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines (600mg, 1.77mmol), 2-(thiophene) phenylo boric acid (321mg, 2.20mmol), four (triphenyl phosphine)-palladium (o) (231mg, 0.2mmol) at ethanol (6.0mL), the mixture in ethylene glycol dimethyl ether (6.0mL) and the saturated aqueous sodium carbonate (3.0mL) heated 18 hours under refluxing.The mixture that obtains is poured in the water into methylene chloride extraction with 9/1.Merge organic layer,, filter and vacuum-drying by dried over mgso.Biotage chromatography (FLASH 12M, Silica, 9: 1 methylene chloride) provides 7-methyl-6-(5-methyl-thiophene-2-yl)-7H-pyrrolo-[3,2-f] quinazoline-1, and 3-diamines (190mg, 34.8%) is solid; EI-HRMSm/e theoretical value C ₁₆H ₁₅N ₅S (M+H) ⁺310.1121, experimental value 310.1125.

Following at 25 ℃ with 60% sodium hydride (25mg, 0.62mmol) and methyl iodide (0.62mL, 0.35mmol) processing 7-methyl-6-(5-methyl-thiophene-2-yl)-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines (100mg, 0.32mmol) at N, the solution in the dinethylformamide (5.0mL) stirred 15 minutes down at 25 ℃.The mixture that obtains is poured in the water also with 9/1 methylene chloride solution extraction.Flash chromatography (Merck silica gel 60,230-400 order, 9: 1 methylene chloride) produces 7, N1-dimethyl-6-(5-methyl-thiophene-2-yl)-7H-pyrrolo-[3,2-f] quinazoline-1, and 3-diamines (12mg, 11.5%) is faint yellow solid; EI-HRMS m/e theoretical value C ₁₇H ₁₇N ₅S (M+H) ⁺324.1278, experimental value 324.1280; With 7, N1, N1-trimethylammonium-6-(5-methyl-thiophene-2-yl)-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines (18mg, 16.5%) is the burgundy solid; EI-HRMS m/e theoretical value C ₁₈H ₁₉N ₅S (M+H) ⁺338.1434, experimental value 338.1437.

Embodiment 24

By 6-(4-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines synthesizes 7, N1, N1-trimethylammonium-6-(4-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines; EI-HRMS m/e theoretical value C ₂₀H ₁₈F ₃N ₅(M ⁺) 385.1517, experimental value 385.1514.

Embodiment 25

By 6-furans-2-base-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines synthesizes 6-furans-2-base-7, N1-dimethyl-7H-pyrrolo-[3,2-f] quinazoline-1, and 3-diamines three fluoro-acetates are faint yellow solid; EI-HRMS m/e theoretical value C ₁₆H ₁₅N ₅O (M ⁺) 293.1277, experimental value 293.1280.

Embodiment 26

By 6-furans-2-base-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines: 6-furans-2-base-7, N1, N1-trimethylammonium-7H pyrrolo-[3,2-f] quinazoline-1, the 3-diamines is yellow solid; EI-HRMS m/e theoretical value C ₁₇H ₁₇N ₅O (M ⁺) 307.1433, experimental value 307.1434

Embodiment 27

By 6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines three fluoro-acetates synthesize 7, N1-dimethyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1, and 3-diamines three fluoro-acetates are faint yellow solid; LRMS C ₁₆H ₁₅N ₅S (M+H) ⁺M/z=310.

Embodiment 28

By 6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines synthesizes 7-ethyl-N1-methyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines three fluoro-acetates; (ES) ⁺-HRMSm/e theoretical value C ₁₇H ₁₇N ₅S (M+H) ⁺324.1277, experimental value 324.1281.

Embodiment 29

By 7-methyl-6-(5-methyl-thiophene-2-yl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines: 7, N1, N1-trimethylammonium-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines is yellow solid; EI-HRMS m/e theoretical value C ₁₇H ₁₇N ₅S (M ⁺) 323.1205, experimental value 323.1209

Embodiment 30

By 7-methyl-6-(5-methyl-thiophene-2-yl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines: 7, N1, N1-trimethylammonium-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines is yellow solid; EI-HRMS m/e theoretical value C ₁₇H ₁₇N ₅S (M ⁺) 323.1205, experimental value 323.

Embodiment 31

By 7-methyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines synthesizes 7, N1-dimethyl-6-(5-methyl-thiophene-2-yl)-7H-pyrrolo-[3,2-f] quinazoline-1, and the 3-diamines is yellow solid; (ES)+-HRMS m/e theoretical value C ₁₇H ₁₇N ₅S (M+H) ⁺324.1278, experimental value 324.1280.

Embodiment 32

By 7-methyl-6-(2-methoxyl group-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines synthesizes 6-(2-methoxyl group-phenyl)-7, N1-dimethyl-7H-pyrrolo-[3,2-f] quinazoline-1, and 3-diamines three fluoro-acetates are white solid; LCMS C ₁₉H ₁₉N ₅O (M ⁺)+m/z=333

Embodiment 33

By 7-ethyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines synthesizes 7, N1-diethyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines three fluoro-acetates; (ES) ⁺-HRMS m/e theoretical value C ₁₈H ₁₉N ₅S (M+H) ⁺338.1434, experimental value 338.1437.

Embodiment 34

By 7-ethyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines synthesizes 7-ethyl-N1, N1-dimethyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines three fluoro-acetates; (ES) ⁺-HRMS m/e theoretical value C ₁₈H ₁₉N ₅S (M+H) ⁺338.1434, experimental value 338.1437.

Embodiment 35

Synthesize 7 by 7-methyl-6-(5-methyl-thiophene-2-yl)-7H-pyrrolo-[3,2-f] quinazoline-1,3 diamines, N1, N1-trimethylammonium-6-(5-methyl-thiophene-2-yl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines is yellow solid; (ES) ⁺-HRMS m/e theoretical value C ₁₈H ₁₉N ₅S (M+H) ⁺338.1434, experimental value 338.1437.

Embodiment 36

By 6-(5-methoxyl group-thiophene-2-yl)-7-methyl-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines synthesizes 6-(5-methoxyl group-thiophene-2-yl)-7, N1-dimethyl-7H-pyrrolo-[3,2-f] quinazoline-1, and the 3-diamines is white solid; EI-HRMS m/e theoretical value C ₁₇H ₁₇N ₅OS (M ⁺) 339.1154, experimental value 339.1159.

Embodiment 37

By 6-(2,6-dimethyl-phenyl)-7-methyl-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines synthesizes 6-(2,6-dimethyl-phenyl)-7, N1, and N1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines three fluoro-acetates are pale solid; EI-HRMS m/e theoretical value C ₂₁H ₂₃N ₅(M ⁺) 345.1953, experimental value 345.1958.

Embodiment 38

By 6-(2-methoxyl group-phenyl)-7-methyl-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines synthesizes 6-(2-methoxyl group-phenyl)-7, N1, and N1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines three fluoro-acetates are white solid; EI-HRMS m/e theoretical value C ₂₀H ₂₁N ₅O (M ⁺) 347.1746, experimental value 347.1739.

Embodiment 39

By 7-methyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines synthesizes N1, N1-diethyl-7-methyl-6-thiophene-2-base-7H-pyrrolo-[3,2-f] quinazoline-1, and 3-diamines three fluoro-acetates are faint yellow solid; EI-HRMS m/e theoretical value C ₁₉H ₂₁N ₅S (M ⁺) 351.1518, experimental value 351.1517.

Embodiment 40

By 6-(4-methoxyl group-thiophene-2-yl)-7-methyl-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines synthesizes 6-(4-methoxyl group-thiophene-2-yl)-7, N1, and N1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines is yellow solid; EI-HRMS m/e theoretical value C ₁₈H ₁₉N ₅OS (M ⁺) 353.1310, experimental value 353.1307.

Embodiment 41

By 7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines synthesizes 7, N1-dimethyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines three fluoro-acetates; ¹H NMR (DMSO-d ₆, 400MHz) δ 12.36 (m, 1H), 8.09 (m, 1H), 7.98 (d, J=7.81Hz, 1H), 7.81 (m, 3H), 7.71 (d, J=2.93Hz, 1H), 7.61 (d, J=5.86Hz, 1H), 7.41 (d, J=3.91Hz, 1H), 7.04 (s, 1H), 3.21 (d, J=3.91Hz, 3H), 3.17 (s, 3H).

Embodiment 42

By 6-(4-methoxyl group-thiophene-2-yl)-7-methyl-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines synthesizes 6-(4-methoxyl group-thiophene-2-yl)-7, N1-dimethyl-7H-pyrrolo-[3,2-f] quinazoline-1, and the 3-diamines is faint yellow solid; EI-HRMS m/e theoretical value C ₁₇H ₁₇N ₅OS (M ⁺) 339.1154, experimental value 339.1148.

Embodiment 43

The vitro inhibition of PTP1B

Enzyme

With conventional molecular biology method from the human cDNA library PTP1B (1-321) that clones people.This cDNA sequence is identical with disclosed people PTP1B sequence (registration number M33689).Description according to J.Mol Biol (1994) 239,726-730 such as Barford D. is expressed and this protein of purifying from intestinal bacteria (E.coli).

PTPase detects

The active mensuration of PTPase is carried out with one of following two kinds of methods:

First method is used to measure PTP1B and suppresses active, uses tyrosine peptide based on the phosphorylation of the aminoacid sequence of insulin receptor tyrosine autophosphorylation site 1146 (TRDI (pY) E) as substrate.Reaction conditions is as follows:

Containing 37.5mM Bis-Tris pH of buffer 6.2,140mM NaCl is hatched 15min with PTP1B (0.5-2nM) with compound in the damping fluid of 0.05%BSA and 2mM DTT.Add 50 μ M substrate initial actions.After at room temperature (22-25 ℃) keeps 20min, use the KOH termination reaction, (1994 Biochem such as Harder J.298 according to former report; 395), utilize Victoria Green WPB (Malachite Green) to detect the amount of free phosphoric acid.

Second method is used for measuring general PTPase by the PTPase plate and suppresses active.The substrate of every kind of enzyme use (6,8-two fluoro-4-methyl umbelliferyl phosphoric acid (DiFMUP; Derive from MolecularProbes) at Km.Identical in buffer condition and the above-mentioned Victoria Green WPB detection method.Use the KOH termination reaction.In this method, the product of dephosphorylation sends fluorescence, and record fluorescence (excites: 360mM/ emission: 460nM).

For dynamic experiment, use identical buffer condition, except using the enzyme initial action, react termination after 10 minutes.

The PTP1B of the application's compound suppresses active IC ₅₀Value (μ M) is 0.1 μ M to 500 μ M, preferred 1 μ M to 100 μ M.The IC that most preferred shows ₅₀Value is lower than 30.0 μ M.

The corresponding IC of some compounds of embodiment ₅₀Be worth as follows:

Embodiment	IC ₅₀(μM)
Embodiment	IC ₅₀(μM)	2	7.10
4	9.47	2	7.10
4	9.47	6	10.22
8	11.35	6	10.22

Embodiment 44

The glucose uptake test

Measuring the day before yesterday, change the SKMC substratum into high glucose DMEM, 25mM Hepes, the FBS that pH7.0 and 2% charcoal/dextran is handled 19 hours.

Measuring morning on the same day, with cell at low dextrose (5.5mM glucose) DMEM, 25mMHepes, among pH7.0 and the 0.5%BSA hungry maximum 2 hours.Hungry substratum is removed, and (150mM NaCl, 25mM Hepes pH7.0) replace, and this test medium contains 1%DMSO or is diluted in test compound among the DMSO, or pork insulin, and final concentration is 1,0.1,0.05,0.01 and 0.01 μ M with test medium.Each measuring point carries out in triplicate.With cell 37 ℃ of incubations 45 minutes.Glucose transport (is GLUT 1﹠amp to stop initiatively to add 10 μ M Cytochalasin Bs (CB) in appropriate well; 4).In institute is porose, add 2-deoxidation-D (U-this moment ¹⁴C) (200uCi/ml), final concentration is 0.8 μ Ci/ml to glucose for Amersham, Code CFB195.With cell other 45 minutes of 37 ℃ of incubations in incubator.Then cell is very gently washed 3 times in PBS (RT).Add 20 minutes (RT) lysing cell of 0.05%NaOH solution then.Lysate is transferred to the scintillation vial that contains the 5ml scintillation solution and in Beckman LS6500 scintillometer, counts.Analytical results: from each value, deduct the counting that obtains with CB (passive glucose transport value) so that only assess initiatively glucose transport with PI (or compound) acquisition.Increase by using the value that exists under the PI (or compound) to calculate multiple divided by the value that exists DMSO (contrast) to obtain down.Will be under 0.05 μ M during the glucose uptake increase at least 25% of pork insulin reaction when them, think that compound is activated.

Suppress in the body of PTP1B: compound is to the influence of the glucose level of mouse model

In order to measure the anti-diabetic effect, test compounds in the rodent body inner model of confirming diabetes B and obesity.

Embodiment 45

The fat C57BL6/J mouse (DIO mouse) of diet induced

Mouse was fed 4-6 month with high fat diet, can be produced the diabetes B mouse.(Diabetes 37：1163-67 Sept 1988)。Male C57B16/J mouse (3-4 age in week) was fed 4-6 month with high fat diet.At this moment, these mouse performance hyperglycemia and hyperinsulinisms, body weight 40-50g.(n=10) weighs with the DIO mouse, and fasting was 2 hours before oral administration was handled.Be about to before the administration, obtain glucose readings before the dosage by cutting a part of tail and collecting blood from the tail vein.With the compound (acute) of single dose or once a day totally 5 days (inferior chronic) handle mouse.For acute study, glucose measurement in 2,4,6,8 hours after processing usually.If compare with the animal of vehicle treated, significant (p≤0.05) glucose of compound exhibits statistics reduces (＞15%), thinks that so they are activated.

For Asia chronic (5 days) research, as mentioned above with the mouse dosed administration once a day by gavage.At the 5th day, 2 hours measurement glucose behind (0 time) and the dosed administration before dosed administration.Behind dosed administration, measured Regular Insulin and tri-glyceride in 2 hours.If compound shows significantly (p≤0.05) reduction of glucose, Regular Insulin and tri-glyceride statistics with respect to the vehicle treated animal, think that then this compound has activity.

Embodiment A

Can produce the tablet that contains following component in a conventional manner:

Component Every

The compound 10.0-100.0mg of formula (I)

Lactose 125.0mg

W-Gum 75.0mg

Talcum 4.0mg

Magnesium Stearate 1.0mg

Embodiment B

Can produce the capsule that contains following component in a conventional manner:

Component Every capsules

The compound 25.0mg of formula (I)

Lactose 150.0mg

W-Gum 20.0mg

Talcum 5.0mg

Embodiment C

Can produce the injection liquid that contains following component in a conventional manner:

The compound 3.0mg of formula (I)

Gelatin 150.0mg

Phenol 4.7mg

It is 7 that yellow soda ash obtains final pH

Water for injection adds to 1.0ml

Claims

1. the compound and the pharmaceutical salts thereof of formula (I):

R ₃Be hydrogen or methyl;

Ra is selected from hydrogen, low alkyl group, lower alkoxy

Hydroxyalkyl, one or the low alkyl group that replaces of dihydroxyl, phenyl lower alkyl, the benzyloxy alkyl or

R ₁₀Be hydrogen or

X and y are the integers of independent 0-4;

R ₁₁Be hydrogen, phenyl or unsubstituted low alkyl group;

P is the integer of 0-1;

Rd is a hydrogen, the alkyl of replacement or perfluor-low alkyl group;

Rf is hydrogen or low alkyl group.

2. according to the compound and the pharmaceutical salts thereof of the formula (I) of claim 1,

R ₂Be selected from hydrogen, low alkyl group, ethanoyl, hydroxyalkyl;

R ₃Be hydrogen or methyl;

Rf is hydrogen or low alkyl group.

3. according to any one compound among the claim 1-2, wherein

R2 is selected from hydrogen, methyl, ethyl, benzyl, and ethanoyl;

Re is selected from hydrogen, chlorine and trifluoromethyl; With

Rf is selected from hydrogen and methyl.

4. according to the compound or pharmaceutically acceptable salt thereof of claim 1, wherein said compound has formula (I-B)

R ₁₀Be hydrogen, or

R ₁₁Be hydrogen, phenyl or unsubstituted low alkyl group;

P is the integer of 0-1; With

X and y are the integer of 0-4 individually.

5. according to the compound of claim 4, wherein

R ₁' be low alkyl group;

R ₂' be hydrogen or low alkyl group; With

Rb ' and Rc ' are perfluor low alkyl group or hydrogen,

Among Rb ' and the Rc ' at least one is the perfluor low alkyl group.

6. according to the compound of claim 4, R wherein ₁' be one or the dihydroxyl low alkyl group and the R that replace ₂' be hydrogen or one or the low alkyl group that replaces of dihydroxyl, and Rb ' and Rc ' be perfluor low alkyl group or hydrogen independently, at least one among described Rb ' and the Rc ' is the perfluor low alkyl group.

7. according to the compound of claim 5, wherein Ra ' is one or the low alkyl group that replaces of dihydroxyl.

8. according to the compound of claim 5, wherein Ra ' is

And R ₁₀, x and y are as defined in claim 5.

9. according to the compound of claim 4, wherein one of Rb ' and Rc ' are

Or lower alkoxy;

R ₁₁Be hydrogen, phenyl or unsubstituted low alkyl group; With

P is the integer of 0-1.

10. according to the compound of claim 4, wherein one of Rb ' and Rc ' are low alkyl groups.

11. according to the compound or pharmaceutically acceptable salt thereof of claim 1, wherein said compound has formula (I-A)

Wherein

R ₁₀Be hydrogen or

R ₁₁Be hydrogen, low alkyl group and phenyl;

P is the integer of 0-1; And

X and y are the integer of 0-4 individually.

12. according to the compound of claim 11, wherein Be 5 or 6 yuan of hetero-aromatic rings, this hetero-aromatic ring contains sulfur heteroatom as heteroatoms unique in the described ring.

13. according to the compound of claim 12, wherein

Rb ' and Rc ' are hydrogen or low alkyl group;

14. according to the compound of claim 12, wherein

Rb ' and Rc ' are hydrogen or lower alkoxy or phenyl lower alkoxy independently, and wherein at least one is not a hydrogen among Rb ' and the Rc ';

15. according to the compound of claim 11, wherein

16. according to the compound of claim 15, wherein R ₁' be low alkyl group; With

R ₂' be hydrogen or low alkyl group.

17. according to the compound of claim 11, wherein

18. according to the compound of claim 17, wherein

One of Rb ' and Rc ' they are that hydrogen and another are hydrogen, low alkyl group, or

R wherein ₁₁Be phenyl or low alkyl group; With

R ₁' and R ₂' be low alkyl group.

19. according to the compound of claim 11, wherein

Be to contain two heteroatomic 5 or 6 yuan of hetero-aromatic rings.

20. according to the compound of claim 19, wherein

Rb ' and Rc ' are low alkyl groups, hydrogen or lower alkoxy.

21. according to any one compound and pharmaceutical salts thereof among the claim 1-2, this compound has formula (II)

Wherein

R ₂Be selected from hydrogen, low alkyl group, ethanoyl, hydroxyalkyl

R ₃Be hydrogen or methyl;

Ra is selected from hydrogen, low alkyl group, lower alkoxy hydroxyalkyl and benzyloxy alkyl;

Rf is hydrogen or low alkyl group.

22. according to the compound of claim 21, wherein

Rc and Rd are hydrogen or trifluoromethyl independently;

Re is a hydrogen, chlorine halogen or trifluoromethyl; With

Rf is hydrogen or methyl.

23. according to any one compound and pharmaceutical salts thereof among the claim 1-2, this compound has formula (III)

Wherein

R ¹Be selected from hydrogen, low alkyl group, ethanoyl, hydroxyalkyl

R ²Be hydrogen or methyl;

X is a sulphur, oxygen, nitrogen or N-tertbutyloxycarbonyl;

Rb is selected from hydrogen, low alkyl group, lower alkoxy hydroxyalkyl and benzyloxy alkyl;

24. according to the compound of claim 23, wherein

R ²And Rb ' is independently selected from hydrogen, methyl and ethyl; With

Rd ' and Re ' are independently selected from hydrogen, methyl or methoxy.

25. according to any one compound and pharmaceutical salts thereof among the claim 1-24, described compound is selected from the group of being made up of and the following:

6-iodo-7, N1-dimethyl-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

6-furans-2-base-7, N1, N 1-trimethylammonium-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

7, N 1-dimethyl-6-(2-phenoxy group-phenyl)-7H-pyrrolo-[3,2-f] quinazoline-1, the 3-diamines,

26. according to any one compound and pharmaceutical salts thereof among the claim 1-25, described compound is selected from the group of being made up of following:

6-furans-2-base-7, N1-dimethyl-7H-pyrrolo-[3,2-f] quinazoline-1,3-diamines.

27. a method for preparing according to the compound of any one among the claim 1-26, it comprises the compound reaction with the compound of formula (XII) and formula (XIII)

R1 wherein, R2, R3, Ra, Rb, Rc, Rd, Re, Rf and A have in claim 1-26 the meaning that provides in any one.

28. by according to the preparation of the method for claim 27 according to any one compound among the claim 1-26.

29. pharmaceutical composition, it comprises according to any one compound and pharmaceutical carrier and/or adjuvant among the claim 1-26.

30. according to any one compound among the claim 1-26, it is as therapeutic active substance.

31. according to any one compound among the claim 1-26, it is as treating and/or preventing the treatment of diseases active substance of regulating by the PTP1B inhibitor.

32. a method that treats and/or prevents the disease of regulating by the PTP1B inhibitor, this method comprise in the human or animal uses according to claim 1-26 the compound of any one.

33. treating and/or preventing by the application in the disease of PTP1B inhibitor adjusting according to the compound of any one among the claim 1-26.

34. in the application of preparation in the medicine, described medicine is used for the treatment of and/or prevent disease by the adjusting of PTP1B inhibitor according to any one compound among the claim 1-26.

35. according to any one application or method among the claim 31-34, wherein said disease is diabetes.

36. aforesaid basically new compound, technology, method and this application of compound.