CN101014596A

CN101014596A - Imidazoquinolinyl, imidazopyridinyl, and imidazonaphthyridinyl sulfonamides

Info

Publication number: CN101014596A
Application number: CN 200480042087
Authority: CN
Inventors: 亚松·D·邦克; 小约瑟夫·F·德拉里亚
Original assignee: 3M Innovative Properties Co
Current assignee: 3M Innovative Properties Co
Priority date: 2003-12-30
Filing date: 2004-12-23
Publication date: 2007-08-08

Abstract

Imidazoquinolinyl, imidazopyridinyl, and imidazonaphthyridinyl sulfonamide compounds, pharmaceutical compositions containing the compounds, intermediates, and methods of making and methods of use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases are disclosed.

Description

Imidazoquinoline base sulphonamide, imidazopyridyl sulphonamide and imidazo-naphthyridine base sulphonamide

Related application

The present invention requires the United States Patent (USP) provisional application 60/533465 of submission on December 30th, 2003; The United States Patent (USP) provisional application 60/555936 that on March 24th, 2004 submitted to; With the right of priority of the United States Patent (USP) provisional application of submitting on June 18th, 2,004 60/581335, described application all is merged in this paper as a reference.

Technical field

The present invention relates to the derivative of imidazoquinoline, imidazopyridine and imidazo-naphthyridine compound, relate to the pharmaceutical composition that comprises this compound.The other aspect of the present invention relates to these compounds and is used for the biosynthesizing of induced animal cytokine as immunomodulator and is used for the treatment of application in each disease that comprises virus disease and tumorigenesis disease.

Background technology

In the 1950's, developed 1H-imidazo [4,5-c] quinoline loop systems, and synthesized 1-(6-methoxyl group-8-quinolyl)-2-methyl isophthalic acid H-imidazo [4,5-c] quinoline and be used for possible application as antimalarial drug.Subsequently, reported 1H-imidazo [4,5-c] quinolines synthetic of various replacements.For example, synthesized 1-[2-(4-piperidyl) ethyl]-1H-imidazo [4,5-c] quinoline, as possible anticonvulsive drug and cardiovascular drug.In addition, reported also [4,5-c] quinolines of several 2-oxo-imidazoles.

Found afterwards that the derivative that some 1H-imidazo [4,5-c] quinoline-4-amine and 1-thereof and 2-position replace can be used as antiviral drug, bronchodilator and immunomodulator.Subsequently, the 1H-imidazo [4 that has synthesized some replacement, 5-c] pyridine-4-amine, quinoline-4-amine, tetrahydroquinoline-4-amine, 1,5-naphthyridine-4-amine and tetrahydrochysene 1,5-naphthyridine-4-amine compound and some similar thiazole and and  azoles and compound, and find to can be used as immune response modifier, make them can be used for the treatment of various disease conditions.

Still interested and needs are arranged for regulating the compound of immunne response by the biosynthesizing of the inducing cell factor or other mechanism.

Summary of the invention

The invention provides a class new be used in the biosynthetic compound of the inducing cell factor in the animal.This compound is represented by following formula I:

More specifically, be the compound of representing by following formula 1a, Ib, II, IIa, III, IV, V, VI, VII, VIII, IX, X and XI:

Wherein: R ₁, R ", R ₂, R ₁', R _A, R _B, R _A', R _B', R _a, R _b, R _c,, X ', n and m be as to give a definition;

And pharmacologically acceptable salt.

Because when giving the compound of the formula of using I, 1a, Ib, II, IIa, III, IV, V, VI, VII, VIII, IX, X and XI to animal, these compounds can regulate the cytokine biosynthesizing (as, induce the biosynthesizing or the generation of one or more cytokines) or regulate immunne response, so the compound of formula I, 1a, Ib, II, IIa, III, IV, V, VI, VII, VIII, IX, X and XI can be used as for example immune response modifier (IRM).Compound can be by for example testing in the test method described in the embodiment part.Can be by in culture being that Interferon, rabbit (α) or the tumour necrosis factor (α) that the compound of 30 to 0.014 μ M is cultivated and analyzed in the culture supernatants checked biosynthetic the inducing of the compound pair cell factor with human PBMC and concentration range.Compound can be used for treating the multiple situation that this immunne response variation is responded as described in the biosynthesizing of adjusting cytokine made as the biosynthetic ability of inducing one or more cytokines, as virus disease and tumorigenesis disease.

In one aspect of the method, the invention provides the pharmaceutical composition that comprises the immune response modifier compound, with the method for tumorigenesis disease in the virus disease and treatment animal is provided in cytokine biosynthesizing in the induced animal, the treatment animal, described method comprises compound and/or its pharmacologically acceptable salt to one or more formulas I, Ia, Ib, II, IIa, III, IV, V, VI, VII, VIII, IX, X and the XI of animals administer significant quantity.

In one aspect of the method, the invention provides the compound of synthesis type I, Ia, Ib, II, IIa, III, IV, V, VI, VII, VIII, IX, X and XI and be used for the method for the intermediate of synthetic these compounds.

As used in this article, " one ", " one ", " being somebody's turn to do ", " at least one " and " one or more " are used interchangeably.

Term " comprises " and variant does not have restrictive sense when these terms appear in specification sheets and the claim.

The above-mentioned summary of the invention of the present invention is not intended to each disclosed embodiment or all schemes of the present invention described.Following description more specifically illustrates exemplary embodiment.This paper also provides guidance by enumerating embodiment, and what they can be different is used in combination.In each case, the example of enumerating is representational, and it is exclusive it should not being interpreted as.

The detailed description of exemplary of the present invention

The invention provides the compound of representing by following formula I:

More specifically, provide the compound of representing by following formula I, Ia, Ib, II, IIa, III, IV, V, VI, VII, VIII, IX, X and XI:

With

And the intermediate of representing by following formula XII, XIII, XIV, XV, XVI and XVII:

Wherein: R ₁, R ", R ₂, R1 ', R _A, R _B, R _A', R _B', R _a, R _b, R _c, X ', n and m be as to give a definition;

And pharmacologically acceptable salt.

In one embodiment, the invention provides the compound of representing by following formula (I):

Wherein: X ' is selected from-CH (R ₉)-,-CH (R ₉)-alkylidene group and-CH (R ₉)-alkenylene-; Wherein alkylidene group and alkenylene are optional is interrupted by one or more-O-group;

R ₁And R ₁' be independently selected from:

Hydrogen,

Alkyl,

Thiazolinyl,

Aryl,

Aryl alkylene,

Heteroaryl,

The heteroaryl alkylidene group,

Heterocyclic radical,

The heterocyclic radical alkylidene group and

Be independently selected from alkyl, thiazolinyl, aryl, aryl alkylene, heteroaryl, heteroaryl alkylidene group, heterocyclic radical or the heterocyclic radical alkylidene groups that following substituting group replaces by one or more:

Hydroxyl,

Alkyl,

Haloalkyl,

Hydroxyalkyl,

Alkoxyl group,

Halogenated alkoxy,

Halogen,

Cyano group,

Nitro,

Aryl sulfonyl,

Alkyl sulphonyl and

-N(R ₉) ₂，

Or R ₁And R ₁' can be combined together to form the ring shown in the following formula:

A ' is selected from-O ,-C (O)-,-CH ₂-,-S (O) _0-2-,-N (R ₄)-and-N (Q-R ₄)-;

A and b are 1 to 6 integer independently, and condition is a+b≤7;

Q be selected from key ,-C (R ₆)-,-C (R ₆)-C (R ₆)-,-S (O) ₂-,-C (R ₆)-N (R ₈)-W-, S (O) ₂-N (R ₈) ,-C (R ₆)-O-and C (R ₆)-N (OR ₉)-;

W be selected from key ,-C (O)-and-S (O) _2-

R ₄Be selected from hydrogen, alkyl, thiazolinyl, alkynyl, aryl, aryl alkylene, the aryloxy alkylidene group, alkyl arylene, heteroaryl, the heteroaryl alkylidene group, heteroaryl oxygen base alkylidene group, alkyl inferior heteroaryl and heterocyclic radical, alkyl wherein, thiazolinyl, alkynyl, aryl, aryl alkylene, the aryloxy alkylidene group, alkyl arylene, heteroaryl, the heteroaryl alkylidene group, heteroaryl oxygen base alkylidene group, alkyl inferior heteroaryl and heterocyclic radical can be unsubstituted or are independently selected from following substituting group and replace by one or more: alkyl, alkoxyl group, hydroxyalkyl, haloalkyl, halogenated alkoxy, halogen, nitro, hydroxyl, sulfydryl, cyano group, aryl, aryloxy, aryl alkylene oxygen base, heteroaryl, heteroaryl oxygen base, heteroaryl alkylidene group oxygen base, heterocyclic radical, amino, alkylamino, dialkyl amido, (dialkyl amido) alkylidene group oxygen base and at alkyl, thiazolinyl, replaced by oxo in the situation of alkynyl and heterocyclic radical;

R ₆Be selected from=O and=S;

R ₈Be selected from hydrogen, alkyl, alkoxyl group alkylidene group and aryl alkylene;

R ₉Be selected from hydrogen and alkyl;

R " be hydrogen or non-interfering substituting group;

R _AAnd R _BBe independently selected from:

Hydrogen,

Halogen,

Alkyl,

Thiazolinyl,

Alkoxyl group,

The alkyl sulfenyl and

-N(R ₉) ₂；

Or R _AAnd R _BForm fused aromatic rings unsubstituted or that replaced by one or more Ra groups altogether, or form unsubstituted or by one or more R _c5 to 7 yuan of saturated rings of condensed that group replaces;

Or R _AAnd R _BForm altogether and comprise heteroatomic condensed heteroaryl ring or 5 to the 7 yuan of saturated rings that are selected from N and S, wherein heteroaryl ring is unsubstituted or by one or more R _bGroup replaces, and 5 to 7 yuan of saturated rings are unsubstituted or by one or more R _cGroup replaces;

R _aBe selected from:

Fluorine,

Alkyl,

Haloalkyl,

Alkoxyl group and

-N(R ₉) ₂；

R _bBe selected from:

Halogen,

Hydroxyl,

Alkyl,

Thiazolinyl,

Haloalkyl,

Alkoxyl group and

-N (R ₉) ₂With

R _cBe selected from:

Halogen,

Hydroxyl,

Alkyl,

Thiazolinyl,

Haloalkyl,

Alkoxyl group,

The alkyl sulfenyl and

-N(R ₉) ₂；

Or its pharmacologically acceptable salt.

In one embodiment, the present invention also provides the compound by following formula (Ia) expression:

Wherein:

X ' is selected from-CH (R ₉)-,-CH (R ₉)-alkylidene group and-CH (R ₉)-alkenylene-; Wherein alkylidene group and alkenylene are optional is interrupted by one or more-O-group;

R ₁And R ₁' be independently selected from:

Hydrogen,

Alkyl,

Thiazolinyl,

Aryl,

Aryl alkylene,

Heteroaryl,

The heteroaryl alkylidene group,

Heterocyclic radical,

The heterocyclic radical alkylidene group and

Hydroxyl,

Alkyl,

Haloalkyl,

Hydroxyalkyl,

Alkoxyl group,

Halogenated alkoxy,

Halogen,

Cyano group,

Nitro,

Aryl sulfonyl,

Alkyl sulphonyl and

-N(R ₉) ₂，

R ₂Be selected from:

-R ₄、

-X-R ₄、

-X-Y-R ₄, and

-X-R ₅；

X is selected from alkylidene group, alkenylene, alkynylene, arylidene, inferior heteroaryl and inferior heterocyclic radical, wherein alkylidene group, alkenylene and alkynylene are optional is interrupted or end-blocking by arylidene, inferior heteroaryl or inferior heterocyclic radical, and optional by one or more-O-group interruption;

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

With

R ₅Be selected from:

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH _2-,-S (O) _0-2-With-N (R ₄)-;

A ' is selected from-O-,-C (O)-,-CH _2-,-S (O) _0-2-,-N (R ₄)-and-N (Q-R ₄)-;

Q be selected from key ,-C (R ₆)-,-C (R ₆)-C (R ₆)-,-S (O) _2-,-C (R ₆)-N (R ₈)-W-,-S (O) _2-N (R ₈)-,-C (R ₆)-O-and-C (R ₆)-N (OR ₉)-;

V is selected from-C (R ₆)-,-O-C (R ₆)-,-N (R ₈)-C (R ₆)-and-S (O) _2-

W be selected from key ,-C (O)-and-S (O) _2-

A and b are 1 to 6 integer independently, and condition is a+b≤7;

R _AAnd R _BBe independently selected from:

Hydrogen,

Halogen,

Alkyl,

Thiazolinyl,

Alkoxyl group,

The alkyl sulfenyl and

-N(R ₉) ₂；

Or R _AAnd R _BForm fused-aryl ring unsubstituted or that replaced by one or more Ra groups altogether, or form unsubstituted or by one or more R _c5 to 7 yuan of saturated rings of condensed that group replaces;

R _aBe selected from:

Fluorine,

Alkyl,

Haloalkyl,

Alkoxyl group and

-N(R ₉) ₂；

R _bBe selected from:

Halogen,

Hydroxyl,

Alkyl,

Thiazolinyl,

Haloalkyl,

Alkoxyl group and

-N (R ₉) ₂With

R _cBe selected from:

Halogen,

Hydroxyl,

Alkyl,

Thiazolinyl,

Haloalkyl,

Alkoxyl group,

The alkyl sulfenyl and

-N(R ₉) ₂；

Or its pharmacologically acceptable salt.

In one embodiment, the present invention also provides the compound with following formula (Ib):

Wherein:

R ₁And R ₁' be independently selected from:

Hydrogen,

Alkyl,

Thiazolinyl,

Aryl,

Aryl alkylene,

Heteroaryl,

The heteroaryl alkylidene group,

Heterocyclic radical,

The heterocyclic radical alkylidene group and

Hydroxyl,

Alkyl,

Haloalkyl,

Hydroxyalkyl,

Alkoxyl group,

Halogenated alkoxy,

Halogen,

Cyano group,

Nitro,

Aryl sulfonyl,

Alkyl sulphonyl and

-N(R ₉) ₂，

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

X is selected from alkylidene group, alkenylene, alkynylene, arylidene, inferior heteroaryl and inferior heterocyclic radical, wherein alkylidene group, alkenylene and alkynylene can be chosen wantonly by arylidene, inferior heteroaryl or inferior heterocyclic radical and interrupt or end-blocking, and optional by one or more-O-group interruption;

Y is selected from:

-O-、

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

With

R ₅Be selected from:

With

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

A ' is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-,-N (R ₄)-and-N (Q-R ₄)-;

Q be selected from key ,-C (R ₆)-,-C (R ₆)-C (R ₆)-,-S (O) ₂-,-C (R ₆)-N (R ₈)-W-,-S (O) ₂-N (R ₈)-,-C (R ₆)-O-and-C (R ₆)-N (OR ₉)-;

V is selected from-C (R ₆)-,-O-C (R ₆)-,-N (R ₈)-C (R ₆)-and-S (O) ₂-;

W be selected from key ,-C (O)-and-S (O) ₂-;

A and b are 1 to 6 integer independently, and condition is a+b≤7; With

R _{A '}And R _{B '}Be independently selected from:

Hydrogen,

Halogen,

Alkyl,

Thiazolinyl,

Alkoxyl group,

The alkyl sulfenyl and

-N(R ₉) ₂；

Or its pharmacologically acceptable salt.

In one embodiment, the present invention also provides the compound by following formula (II) expression:

Wherein:

R ₁And R ₁' be independently selected from:

Hydrogen,

Alkyl,

Thiazolinyl,

Aryl,

Aryl alkylene,

Heteroaryl,

The heteroaryl alkylidene group,

Heterocyclic radical,

The heterocyclic radical alkylidene group and

Hydroxyl,

Alkyl,

Haloalkyl,

Hydroxyalkyl,

Alkoxyl group,

Halogenated alkoxy,

Halogen,

Cyano group,

Nitro,

Aryl sulfonyl,

Alkyl sulphonyl and

-N(R ₉) ₂，

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

With

R ₅Be selected from:

With

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

W be selected from key ,-C (O)-and-S (O) ₂-;

A and b are 1 to 6 integer independently, and condition is a+b≤7;

Ra be selected from fluorine, alkyl, haloalkyl, alkoxyl group and-N (R ₉) ₂With

N is 0 to 4;

Or its pharmacologically acceptable salt.

In one embodiment, the present invention also provides the compound of being represented by Formula Il a:

Wherein:

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

With

R ₅Be selected from:

With

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

Q be selected from key ,-C (R ₆)-,-C (R ₆)-C (R ₆)-,-S (O) ₂-,-(R ₆)-N (R ₈)-W-,-S (O) ₂-N (R ₈)-,-C (R ₆)-O-and-C (R ₆)-N (OR ₉)-;

W be selected from key ,-C (O)-and-S (O) ₂-;

A and b are 1 to 6 integer independently, and condition is a+b≤7;

N is O to 4;

Or its pharmacologically acceptable salt.

In one embodiment, the present invention also provides the compound of being represented by Formula Il I:

Wherein:

R ₁And R ₁' be independently selected from:

Hydrogen,

Alkyl,

Thiazolinyl,

Aryl,

Aryl alkylene,

Heteroaryl,

The heteroaryl alkylidene group,

Heterocyclic radical,

The heterocyclic radical alkylidene group and

Hydroxyl,

Alkyl,

Haloalkyl,

Hydroxyalkyl,

Alkoxyl group,

Halogenated alkoxy,

Halogen,

Cyano group,

Nitro,

Aryl sulfonyl,

Alkyl sulphonyl and

-N(R ₉) ₂，

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

With

R ₅Be selected from:

With

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

Q be selected from key ,-C (R ₆)-,-C (R ₆)-C (R ₆)-,-S (O) _2-,-C (R ₆)-N (R ₈)-W-,-S (O) ₂-N (R ₈)-,-C (R ₆)-O-and-C (R ₆)-N (OR ₉)-;

V is selected from-C (R ₆)-,-O-C (R ₆)-,-N (R ₈)-C (R ₆)-and-S (O) _2-

W be selected from key ,-C (O)-and-S (O) _2-

A and b are 1 to 6 integer independently, and condition is a+b≤7;

R _cBe selected from halogen, hydroxyl, alkyl, thiazolinyl, haloalkyl, alkoxyl group, alkyl sulfenyl and-N (R ₉) ₂With

N is O to 4;

Or its pharmacologically acceptable salt.

In other embodiments, the present invention also provides the compound of being represented by following formula I V, V, VI and VII:

Wherein:

R ₁And R ₁' be independently selected from:

Hydrogen,

Alkyl,

Thiazolinyl,

Aryl,

Aryl alkylene,

Heteroaryl,

The heteroaryl alkylidene group,

Heterocyclic radical,

The heterocyclic radical alkylidene group and

Hydroxyl,

Alkyl,

Haloalkyl,

Hydroxyalkyl,

Alkoxyl group,

Halogenated alkoxy,

Halogen,

Cyano group,

Nitro,

Aryl sulfonyl,

Alkyl sulphonyl and

-N(R ₉) ₂，

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

With

R ₅Be selected from:

With

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

W be selected from key ,-C (O)-and-S (O) ₂-;

A and b are 1 to 6 integer independently, and condition is a+b≤7;

R _bBe selected from halogen, hydroxyl, alkyl, thiazolinyl, haloalkyl, alkoxyl group and-N (R ₉) ₂With

M is 0 to 3;

Or its pharmacologically acceptable salt.

In other embodiments, the present invention also provides the compound of being represented by following formula VIII, IX, X and XI:

Wherein:

R ₁And R ₁' be independently selected from:

Hydrogen,

Alkyl,

Thiazolinyl,

Aryl,

Aryl alkylene,

Heteroaryl,

The heteroaryl alkylidene group,

Heterocyclic radical,

The heterocyclic radical alkylidene group and

Hydroxyl,

Alkyl,

Haloalkyl,

Hydroxyalkyl,

Alkoxyl group,

Halogenated alkoxy,

Halogen,

Cyano group,

Nitro,

Aryl sulfonyl,

Alkyl sulphonyl,

With-N (R ₉) ₂,

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

With

R ₅Be selected from:

With

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

W be selected from key ,-C (O)-and-S (O) ₂-;

A and b are 1 to 6 integer independently, and condition is a+b≤7;

M is 0 to 3;

Or its pharmacologically acceptable salt.

In one embodiment, the present invention also provides the midbody compound of being represented by following formula XII:

Wherein:

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

With

R ₅Be selected from:

With

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

W be selected from key ,-C (O)-and-S (O) ₂-;

A and b are 1 to 6 integer independently, and condition is a+b≤7;

N is 0 to 4;

Or its pharmacologically acceptable salt.

In one embodiment, the present invention also provides the midbody compound of being represented by following formula XIII:

Wherein:

R ₁And R ₁' be independently selected from:

Hydrogen,

Alkyl,

Thiazolinyl,

Aryl,

Aryl alkylene,

Heteroaryl,

The heteroaryl alkylidene group,

Heterocyclic radical,

The heterocyclic radical alkylidene group and

Hydroxyl,

Alkyl,

Haloalkyl,

Hydroxyalkyl,

Alkoxyl group,

Halogenated alkoxy,

Halogen,

Cyano group,

Nitro,

Aryl sulfonyl,

Alkyl sulphonyl and

-N(R ₉) ₂，

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

With

R ₅Be selected from:

With

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

W be selected from key ,-C (O)-and-S (O) ₂-;

A and b are 1 to 6 integer independently, and condition is a+b≤7;

R _aBe selected from fluorine, alkyl, haloalkyl, alkoxyl group and-N (R ₉) ₂With

N is 0 to 4;

Or its pharmacologically acceptable salt.

In one embodiment, the present invention also provides the midbody compound of being represented by following formula XIV:

Wherein:

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

With

R ₅Be selected from:

With

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

W be selected from key ,-C (O)-and-S (O) ₂-;

A and b are 1 to 6 integer independently, and condition is a+b≤7;

M is 0 to 3;

Or its pharmacologically acceptable salt.

In one embodiment, the present invention also provides the midbody compound of being represented by following formula XV:

Wherein:

R ₁And R ₁' be independently selected from:

Hydrogen,

Alkyl,

Thiazolinyl,

Aryl,

Aryl alkylene,

Heteroaryl,

The heteroaryl alkylidene group,

Heterocyclic radical,

The heterocyclic radical alkylidene group and

Hydroxyl,

Alkyl,

Haloalkyl,

Hydroxyalkyl,

Alkoxyl group,

Halogenated alkoxy,

Halogen,

Cyano group,

Nitro,

Aryl sulfonyl,

Alkyl sulphonyl and

-N(R ₉) ₂，

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

With

R ₅Be selected from:

With

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

W be selected from key ,-C (O)-and-S (O) ₂-;

A and b are 1 to 6 integer independently, and condition is a+b≤7;

R _bBe selected from halogen, hydroxyl, alkyl, thiazolinyl, haloalkyl, alkoxyl group and-N (R ₉) ₂

With

M is 0 to 3;

Or its pharmacologically acceptable salt.

In one embodiment, the present invention also provides the midbody compound of being represented by following formula XVI:

Wherein:

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) _2-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

With

R ₅Be selected from:

With

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

W be selected from key ,-C (O)-and-S (O) ₂-;

A and b are 1 to 6 integer independently, and condition is a+b≤7;

R _A, and R _{B '}Be selected from independently of one another hydrogen, halogen, alkyl, thiazolinyl, alkoxyl group, alkyl sulfenyl and-N (R ₉) ₂

Or its pharmacologically acceptable salt.

In one embodiment, the present invention also provides the midbody compound of being represented by following formula XVII:

Wherein:

R ₁And R ₁' be independently selected from:

Hydrogen,

Alkyl,

Thiazolinyl,

Aryl,

Aryl alkylene,

Heteroaryl,

The heteroaryl alkylidene group,

Heterocyclic radical,

The heterocyclic radical alkylidene group and

Hydroxyl,

Alkyl,

Haloalkyl,

Hydroxyalkyl,

Alkoxyl group,

Halogenated alkoxy,

Halogen,

Cyano group,

Nitro,

Aryl sulfonyl,

Alkyl sulphonyl and

-N(R ₉) ₂，

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

With

R ₅Be selected from:

With

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

W be selected from key ,-C (O)-and-S (O) ₂-;

A and b are 1 to 6 integer independently, and condition is a+b≤7;

R _{A '}And R _{B '}Be selected from independently of one another hydrogen, halogen, alkyl, thiazolinyl, alkoxyl group, alkyl sulfenyl and-N (R ₉) ₂

Or its pharmacologically acceptable salt.

As used in this article, term " alkyl ", " thiazolinyl ", " alkynyl " and prefix " alkane-" comprise straight chain and branched group, and cyclic group, i.e. cycloalkyl and cycloalkenyl group.Unless otherwise mentioned, these groups comprise 1 to 20 carbon atom, and thiazolinyl comprises 2 to 20 carbon atoms, and alkynyl comprises 2 to 20 carbon atoms.In some embodiments, these groups have maximum altogether 10 carbon atoms, maximum 8 carbon atoms, maximum 6 carbon atoms or maximum 4 carbon atoms.Cyclic group can be monocycle or many rings, and preferably has 3 to 10 ring carbon atoms.Exemplary cyclic group comprise cyclopropyl, cyclopropyl methyl, cyclopentyl, cyclohexyl, adamantyl and replace with unsubstituted bornyl, norcamphyl and norbornene (norborneyl).

Unless otherwise mentioned, " alkylidene group ", " alkenylene " and " alkynylene " are " alkyl " of above-mentioned definition, the bivalent form of " thiazolinyl " and " alkynyl ".Be respectively under the substituted situation at " alkylidene group ", " alkenylene " and " alkynylene ", use term " alkylidene group " " thiazolinyl subunit " and " alkynyl subunit ".For example, aryl alkylene comprises the alkylene moiety that is connected with aryl.

Term " haloalkyl " comprises the group that is replaced by one or more halogen atoms, comprises fully-fluorinated group.This also is applicable to other group that comprises prefix " halo-".The example of suitable haloalkyl is chloro methyl, trifluoromethyl etc.

As used in this article, term " aryl " comprises isocyclic aromatic nucleus or loop systems.The example of aryl comprises phenyl, naphthyl, xenyl, fluorenyl and indenyl.

Unless otherwise indicated, term " heteroatoms " is meant O, S or N atom.

Term " heteroaryl " comprise contain at least one ring hetero atom (as, O, S, N) aromatic nucleus or loop systems.Suitable heteroaryl comprises furyl, thienyl, pyridyl, quinolyl, isoquinolyl, indyl, isoindolyl, triazolyl, pyrryl, tetrazyl, imidazolyl, pyrazolyl,  azoles base, thiazolyl, benzofuryl, benzothienyl, carbazyl, benzoxazol base, pyrimidyl, benzimidazolyl-, quinoxalinyl, benzothiazolyl, naphthyridine base, different  azoles base, isothiazolyl, purine radicals, quinazolyl, pyrazinyl, 1-oxo pyridine base, pyridazinyl, triazinyl, tetrazine base,  di azoly, thiadiazolyl group etc.

Term " heterocyclic radical " comprise contain at least one ring hetero atom (as, O, S, N) non-aromatic ring or loop systems and comprise all complete saturated and undersaturated derivative of part of above-mentioned heteroaryl.Exemplary heterocyclic group comprises pyrrolidyl, tetrahydrofuran base, morpholinyl, thio-morpholinyl, piperidyl, piperazinyl, thiazolidyl, imidazolidyl, isothiazole alkyl, THP trtrahydropyranyl, quinuclidinyl, homopiperidinyl (azepan base), high piperazinyl (Diazesuberane base), 1,3-dioxolane, aziridinyl, dihydro-isoquinoline-(1H)-Ji, octahydro isoquinoline 99.9-(1H)-Ji, dihydroquinoline-(2H)-Ji, octahydro quinoline-(2H)-Ji, dihydro-1H-imidazolyl or the like.When " heterocyclic radical " when comprising nitrogen-atoms, the tie point of heterocyclic radical can be a nitrogen-atoms.

Term " arylidene ", " inferior heteroaryl " and " inferior heterocyclic radical " are the bivalent form of " aryl ", " heteroaryl " and " heterocyclic radical " as defined above.Under " arylidene ", the substituted situation of " inferior heteroaryl " and " inferior heterocyclic radical " difference, use term " arylidene (arylenyl) " " inferior heteroaryl (heteroarylenyl) " and " heterocyclic radical subunit (heterocyclylenyl) ".For example, alkyl arylene comprises the arylidene part that is connected with alkyl.

The present invention includes described compound and salt thereof herein, it can be any pharmaceutically acceptable form, comprise isomer (as, diastereomer and enantiomorph), solvate, polymorphic form etc.Particularly, if compound is optically active, then the present invention comprises the every kind of enantiomorph of compound and the racemic mixture of enantiomorph especially.

In this article, " non-interfering " be meant the adjusting that comprises substituent compound of non-interfering or salt (as, induce or suppress) the biosynthetic ability of one or more cytokines do not destroyed by the non-interfering substituting group.For some embodiment, R " is hydrogen or non-interfering substituting group." group comprises herein for R exemplary non-interfering R ₂Described those.

When occurring more than once in the described in this article any formula of group (or substituting group or variable), whether each group (or substituting group or variable) is selected independently, no matter offer some clarification on.For example, for formula-N (R ₉) ₂, each R ₉Group is selected independently.In another example, work as R ₂And A ' group all comprises R ₄During group, each R ₄Group is selected independently.

The present invention includes described compound herein, it can be any pharmaceutically acceptable form, comprise isomer (as, diastereomer and enantiomorph), salt, solvate, polymorphic form etc.Particularly, if compound is optically active, then the present invention comprises the every kind of enantiomorph of compound and the racemic mixture of enantiomorph especially.Should be appreciated that term " compound " comprises any or all these forms, no matter whether carried out clearly stating (is " salt " though clearly state sometimes).

For any compound of introducing herein, in the what embodiment in office, following variable (as, wherein: R ₁, R ", R ₂, R ₁', R _A, R _B, R _A', R _B', R _a, R _b, R _c, X ', n, m or the like) in any can with any its embodiment in one or individual other set of variables merge with described any one formula is relevant herein, as understood by a person skilled in the art.In the combination of the variable that obtains each all is embodiment of the present invention.

For some embodiment, R " is hydrogen or non-interfering substituting group.

For some embodiment, R ₁And R ₁' be independently selected from hydrogen, alkyl, thiazolinyl, aryl, aryl alkylene, heteroaryl, heteroaryl alkylidene group, heterocyclic radical, heterocyclic radical alkylidene group and be independently selected from alkyl, thiazolinyl, aryl, aryl alkylene, heteroaryl, heteroaryl alkylidene group, heterocyclic radical or the heterocyclic radical alkylidene groups that following substituting group replaces by one or more: hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxyl group, halogenated alkoxy, halogen, cyano group, nitro, amino, alkylamino, dialkyl amido, aryl sulfonyl and alkyl sulphonyl.

For some embodiment (the particularly embodiment of formula I, Ia, Ib, II, III, IV, V, VI, VII, VIII, IX, X and XI), R ₁And R ₁' be independently selected from hydrogen, alkyl, thiazolinyl, aryl, aryl alkylene, heteroaryl, heteroaryl alkylidene group, heterocyclic radical, heterocyclic radical alkylidene group and be independently selected from alkyl, thiazolinyl, aryl, aryl alkylene, heteroaryl, heteroaryl alkylidene group, heterocyclic radical or the heterocyclic radical alkylidene groups that following substituting group replaces by one or more: hydroxyl, alkyl, haloalkyl, hydroxyalkyl, alkoxyl group, halogenated alkoxy, halogen, cyano group, nitro, aryl sulfonyl, alkyl sulphonyl and-N (R ₉) ₂

For some embodiment (the particularly embodiment of formula I, Ia, Ib, II, III, IV, V, VI, VII, VIII, IX, X and XI), R ₁Be selected from hydrogen, alkyl, aryl, substituted aryl, aryl alkylene, substituted aryl alkylidene group and heteroaryl.

For some embodiment (the particularly embodiment of formula I, Ia, Ib, II, III, IV, V, VI, VII, VIII, IX, X and XI), R ₁Be selected from hydrogen, methyl, ethyl, propyl group, butyl, cyclohexyl, phenyl, 4-p-methoxy-phenyl, benzyl, 4-methoxy-benzyl, 2-pyridyl and 3-pyridyl.

For some embodiment (the particularly embodiment of formula I, Ia, Ib, II, III, IV, V, VI, VII, VIII, IX, X and XI), R ₁Be selected from hydrogen, methyl, ethyl, propyl group, butyl, cyclohexyl, phenyl, 4-chloro-phenyl-, 4-fluorophenyl, 4-p-methoxy-phenyl, benzyl, 4-methoxy-benzyl, 2-pyridyl and 3-pyridyl.

For some embodiment (the particularly embodiment of formula I, Ia, Ib, II, III, IV, V, VI, VII, VIII, IX, X and XI), R ₁Be selected from hydrogen, methyl and sec.-propyl.

For some embodiment (the particularly embodiment of formula I, Ia, Ib, II, III, IV, V, VI, VII, VIII, IX, X and XI), R ₁' be hydrogen or alkyl.

For some embodiments (the particularly embodiment of formula I, Ia, Ib, II, III, IV, V, VI, VII, VIII, IX, X and XI), R ₁' be hydrogen or methyl.

For some embodiment, R ₁And R ₁' can be combined together to form the ring shown in the following formula:

Wherein A ' be selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-,-N (R ₄)-and-N (Q-R ₄)-.。

For some embodiment (the particularly embodiment of formula I, Ia, Ib, II, III, IV, V, VI, VII, VIII, IX, X and XI), R ₁And R ₁' can be combined together to form the ring shown in the following formula:

Wherein A ' be selected from-O-,-CH ₂-,-NR ₄-and-N (Q-R ₄)-.

For some embodiment (the particularly embodiment of formula I, Ia, Ib, II, III, IV, V, VI, VII, VIII, IX, X and XI), R ₁And R ₁' be combined together to form the morpholine ring.

For some embodiment (the particularly embodiment of formula I, Ia, Ib, III, IV, V, VI, VII, VIII, IX, X and XII), R ₁And R ₁' all be hydrogen.

For some embodiment, R ₂Be selected from :-R ₄,-X-R ₄,-X-Y-R ₄With-X-R ₅

For some embodiment (the particularly embodiment of formula Ia, Ib, II, IIa, III, IV, V, VI, VII, VIII, IX, X and XI), R ₂Be selected from hydrogen, alkoxyl group alkylidene group ,-R ₄,-X-R ₄With-X-Y-R ₄

For some embodiment (the particularly embodiment of formula Ia, Ib, II, IIa, III, IV, V, VI, VII, VIII, IX, X and XI), R ₂Be selected from hydrogen, alkoxyl group alkylidene group, hydroxy alkylidene ,-R ₄,-X-R ₄With-X-Y-R ₄

For some embodiment (the particularly embodiment of formula Ia, Ib, II, IIa, III, IV, V, VI, VII, VIII, IX, X and XI), R ₂Be selected from hydrogen, alkoxyl group alkylidene group ,-R ₄,-X-R ₄With-X-Y-R ₄, wherein X is C ₁-2 alkyl; Y is-S (O) _0-2-,-S (O) ₂-N (Rs)-,-C (R ₆)-,-C (R ₆)-O-,-O-C (R ₆)-,-O-C (O)-O-,-N (R ₈)-Q-,-C (R ₆)-N (R ₈)-,-O-C (R ₆)-N (R ₈)-or-C (R ₆)-N (OR ₉)-; And R ₄Be alkyl.

For some embodiment (the particularly embodiment of formula Ia, Ib, II, IIa, III, IV, V, VI, VII, VIII, IX, X and XI), R ₂Be selected from hydrogen, alkyl, alkoxyl group alkylidene group, hydroxy alkylidene and-X-R ₄With-X-Y-R ₄, wherein X is C _1-2Alkyl; Y is-S (O) _0-2-,-S (O) ₂-N (R ₈)-,-C (R ₆)-,-C (R ₆)-O-,-O-C (R ₆)-,-O-C (O)-O-,-N (R ₈)-Q-,-C (R ₆)-N (R ₈)-,-O-C (R ₆)-N (R ₈)-or-C (R ₆)-N (OR ₉)-; And R ₄Be alkyl.

For some embodiment (the particularly embodiment of formula Ia, Ib, II, IIa, III, IV, V, VI, VII, VIII, IX, X and XI), R ₂Be selected from hydrogen, C _1-4Alkyl, C _1-4Alkyl-O-C _1-4Alkylidene group and HO-C _1-3Alkylidene group.

For some embodiment (the particularly embodiment of formula Ia, Ib, II, IIa, III, IV, V, VI, VII, VIII, IX, X and XI), R ₂Be selected from hydrogen, C _1-4Alkyl and C _1-4Alkyl-O-C _1-4Alkylidene group.

For some embodiment, R ₂Be selected from hydrogen, alkyl and alkoxyl group alkylidene group.

For some embodiment, R ₂Be selected from hydrogen, methyl, ethyl, n-propyl, normal-butyl, hydroxymethyl, 2-hydroxyethyl, ethoxyl methyl and 2-methoxy ethyl.

For some embodiment, R ₂Be selected from methyl, ethyl, n-propyl, normal-butyl, hydroxymethyl, 2-hydroxyethyl, ethoxyl methyl and 2-methoxy ethyl.

For some embodiment, R ₂Be selected from methyl, ethyl, propyl group, butyl, ethoxyl methyl and 2-methoxy ethyl.

For some embodiment, R ₄Be selected from hydrogen, alkyl, thiazolinyl, alkynyl, aryl, aryl alkylene, the aryloxy alkylidene group, alkyl arylene, heteroaryl, the heteroaryl alkylidene group, heteroaryl oxygen base alkylidene group, alkyl inferior heteroaryl and heterocyclic radical, alkyl wherein, thiazolinyl, alkynyl, aryl, aryl alkylene, the aryloxy alkylidene group, alkyl arylene, heteroaryl, the heteroaryl alkylidene group, heteroaryl oxygen base alkylidene group, alkyl inferior heteroaryl and heterocyclic radical can be unsubstituted or are independently selected from following substituting group and replace by one or more: alkyl, alkoxyl group, hydroxyalkyl, haloalkyl, halogenated alkoxy, halogen, nitro, hydroxyl, sulfydryl, cyano group, aryl, aryloxy, aryl alkylene oxygen base, heteroaryl, heteroaryl oxygen base, heteroaryl alkylidene group oxygen base, heterocyclic radical, amino, alkylamino, dialkyl amido, (dialkyl amido) alkylidene group oxygen base and at alkyl, thiazolinyl, replaced by oxo in the situation of alkynyl and heterocyclic radical.

For some embodiment (the particularly embodiment of formula Ia, Ib, II, IIa, III, IV, V, VI, VII, VIII, IX, X and XI), R ₄Be alkyl.

For some embodiment, R ₅Be selected from:

With

For some embodiment, R ₆Be selected from=O and=S.

For some embodiment, R ₇Be C _2-7Alkylidene group.

For some embodiment, R ₈Be selected from hydrogen, alkyl, alkoxyl group alkylidene group and aryl alkylene.

For some embodiment, R ₉Be selected from hydrogen and alkyl.

For some embodiment, R ₁₀Be C _3-8Alkylidene group.

For some embodiment, R _AAnd R _BBe independently selected from hydrogen, halogen, alkyl, thiazolinyl, alkoxyl group, alkyl sulfenyl and-N (R ₉) ₂

For some embodiment, R _AAnd R _BForm unsubstituted altogether or by one or more R _aThe fused-aryl ring that group replaces, or form unsubstituted or by one or more R _c5 to 7 yuan of saturated rings of condensed that group replaces.

For some embodiment, R _AAnd R _BForm altogether and comprise heteroatomic condensed heteroaryl ring or 5 to the 7 yuan of saturated rings that are selected from N and S, wherein heteroaryl ring is unsubstituted or by one or more R _bGroup replaces, and 5 to 7 yuan of saturated rings are unsubstituted or by one or more R _cGroup replaces.

For some embodiment, R _AAnd R _BBe independently selected from hydrogen and C _1-4Alkyl.

For some embodiment, R _{A '}And R _{B '}Be independently selected from hydrogen, halogen, alkyl, thiazolinyl, alkoxyl group, alkyl sulfenyl and-N (R ₉) ₂

For some embodiment, R _{A '}And R _{B '}Be independently selected from hydrogen and C _1-4Alkyl.

For some embodiment, R _{A '}And R _{B '}It all is methyl.

For some embodiment, R _aBe selected from alkyl, alkoxyl group, hydroxyl, fluorine, trifluoromethyl, amino, alkylamino and dialkyl amido.

For some embodiment, R _aBe selected from fluorine, alkyl, haloalkyl, alkoxyl group and-N (R ₉) ₂

For some embodiment, R _bBe selected from halogen, hydroxyl, alkyl, thiazolinyl, haloalkyl, alkoxyl group and-N (R ₉) ₂

For some embodiment, R _cBe selected from halogen, hydroxyl, alkyl, thiazolinyl, haloalkyl, alkoxyl group, alkyl sulfenyl, amino, alkylamino and dialkyl amido.

For some embodiment, R _cBe selected from halogen, hydroxyl, alkyl, thiazolinyl, haloalkyl, alkoxyl group, alkyl sulfenyl and-N (R ₉) ₂

For some embodiment, A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-.

For some embodiment, A ' is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-,-N (R ₄)-and-N (Q-R ₄)-.

For some embodiment, A ' is selected from-O-,-CH ₂-,-N (R ₄)-and-N (Q-R ₄)-.

For some embodiment, Q be selected from key ,-C (R ₆)-,-C (R ₆)-C (R ₆)-,-S (O) _2-,-C (R ₆)-N (R ₈)-W-,-S (O) ₂-N (R ₈)-,-C (R ₆)-O-and-C (R ₆)-N (OR ₉)-.

For some embodiment, V is selected from-C (R ₆)-,-O-C (R ₆)-,-N (R ₈)-C (R ₆)-and-S (O) ₂-.

For some embodiment, W be selected from key ,-C (O)-and-S (O) ₂-.

For some embodiment, X is selected from alkylidene group, alkenylene, alkynylene, arylidene, inferior heteroaryl and inferior heterocyclic radical, wherein alkylidene group, alkenylene and alkynylene can be chosen wantonly by arylidene, inferior heteroaryl or inferior heterocyclic radical and interrupt or end-blocking, and optional by one or more-O-group interruption.

For some embodiment (the particularly embodiment of formula Ia, Ib, II, IIa, III, IV, V, VI, VII, VIII, IX, X and XI), X is C _1-2Alkylidene group.

For some embodiment, X ' is selected from-CH (R ₉)-,-CH (R ₉)-alkylidene group and-CH (R ₉)-alkenylene; Wherein alkylidene group and alkenylene are optional is interrupted by one or more-O-group.

For some embodiment, X ' is alkylidene group or alkenylene, and it can be chosen wantonly separately by one or more-O-group and interrupt.

For some embodiment (the particularly embodiment of formula I, Ia, Ib, II, III, IV, V, VI, VII, VIII, IX, X and XI), X ' is-(CH ₂) _2-4-O-(CH ₂) _2-4-.

For some embodiment (the particularly embodiment of formula I, Ia, Ib, II, III, IV, V, VI, VII, VIII, IX, X and XI), X ' is-(CH ₂) _1-7-.

For some embodiment (the particularly embodiment of formula I, Ia, Ib, II, III, IV, V, VI, VII, VIII, IX, X and XI), X ' is-(CH ₂) ₂-,-(CH ₂) ₃-,-(CH ₂) ₄-,-(CH ₂) ₅-or-CH ₂C (CH ₃) ₂CH ₂-.

For some embodiment (the particularly embodiment of formula I, Ia, Ib, II, III, IV, V, VI, VII, VIII, IX, X and XI), X ' is (CH ₂)-C (CH ₃) ₂-.

For some embodiment, Y is selected from :-O-,-S (O) _0-2-,-S (O) ₂-N (R ₈)-,-C (R ₆)-,-C (R ₆)-O-,-O-C (R ₆)-,-O-C (O)-O-,-N (R ₈)-Q-,-C (R ₆)-N (R ₈)-,-O-C (R ₆)-N (R ₈)-,-C (R ₆)-N (OR ₉)-,

With

For some embodiment, Y is selected from :-S (O) _0-2-,-S (O) ₂-N (R ₈)-,-C (R ₆)-,-C (R ₆)-O-,-O-C (R ₆)-,-O-C (O)-O-,-N (R ₈)-Q-,-C (R ₆)-N (R ₈)-,-O-C (R ₆)-N (R ₈)-,-C (R ₆)-N (OR ₉)-,

With

For some embodiment (the particularly embodiment of formula Ia, Ib, II, IIa, III, IV, V, VI, VII, VIII, IX, X and XI), Y is-S (O) _0-2-,-S (O) ₂-N (R ₈)-,-C (R ₆)-,-C (R ₆)-O-,-O-C (R ₆)-,-O-C (O)-O-,-N (R ₈)-Q-,-C (R ₆)-N (R ₈)-,-O-C (R ₆)-N (R ₈)-or-C (R ₆)-N (OR ₉)-.

For some embodiment, a and b are 1 to 6 integer independently, and condition is a+b≤7.

For some embodiment, m is 0 to 3.For some embodiment (the particularly embodiment of formula IV, V, VI, VII, VIII, IX, X and XI), m is 0.

For some embodiment, n is 0 to 4.For some embodiment, n is 0 to 3.For some embodiment (the particularly embodiment of formula II, IIa and III), n is 0.

For some embodiment (the particularly embodiment of formula I, Ia, Ib, II, III, IV, V, VI, VII, VIII, IX, X and XI), R ₁' be hydrogen or alkyl, R ₁Be selected from hydrogen, alkyl, aryl, substituted aryl, aryl alkylene, substituted aryl alkylidene group and heteroaryl.

For some embodiments (the particularly embodiment of formula I, Ia, Ib, II, III, IV, V, VI, VII, VIII, IX, X and XI), R ₁' be hydrogen or methyl, R ₁Be selected from hydrogen, methyl, ethyl, propyl group, butyl, cyclohexyl, phenyl, 4-chloro-phenyl-, 4-fluorophenyl, 4-p-methoxy-phenyl, benzyl, 4-methoxy-benzyl, 2-pyridyl and 3-pyridyl.

For some embodiments (the particularly embodiment of formula I, Ia, Ib, II, III, IV, V, VI, VII, VIII, IX, X and XI), R ₁' be hydrogen or methyl, R ₁Be selected from hydrogen, methyl, ethyl, propyl group, butyl, cyclohexyl, phenyl, 4-p-methoxy-phenyl, benzyl, 4-methoxy-benzyl, 2-pyridyl and 3-pyridyl.

The preparation of compound

Compound of the present invention can be according to reaction scheme I preparation, wherein R _a, R ₁, R ₁', R ₂, X ' and n as above define.

In the step (1) of reaction scheme I, with formula HO-X '-NH ₂Amine add in the 4-chloro-3-nitroquinoline of formula XX, obtain 3-nitroquinoline-4-amine that the hydroxyl of formula XXI replaces.This reaction by in appropriate solvent such as methylene dichloride in the presence of alkali such as triethylamine with formula HO-X '-NH ₂Amine mix with the quinoline of formula XX and carry out easily.Reaction can be carried out in envrionment temperature, and product can use ordinary method to separate.Some formula HO-X '-NH ₂Amine be commercially available as the 4-amino butanol, other can be by the preparation of known synthetic method.The compound of formula XX is known, and can prepare according to currently known methods.Referring to for example, United States Patent (USP) 4,689,338; 4,929,624; 5,268,376; 5,346,905; 5,3 89,640; With 5,756,747.

In the step (2) of reaction scheme I, the use ordinary method is carried out chlorination with the hydroxyl of 3-nitroquinoline-4-amine of formula XXI, obtains 3-nitroquinoline-4-amine of formula XXII.Chlorination reaction is by in the 3-nitroquinoline-solution of 4-amine in appropriate solvent such as methylene dichloride that thionyl chloride is joined formula XXI and carry out easily.Reaction can be lower than envrionment temperature as 0 ℃ or carry out in envrionment temperature, and product can use ordinary method to separate.

In the step (3) of reaction scheme I,, obtain the quinoline-3 of formula XXIII, the 4-diamines with 3-nitroquinoline-4-amine reduction of formula XXII.The reduction of nitro joins by the aqueous solution with V-Brite B in the 3-nitroquinoline-4-amine of the formula XXII in appropriate solvent such as ethanol or acetonitrile and alcoholic acid mixture and carries out easily.Reaction can be carried out in envrionment temperature, and product can separate by ordinary method.

Perhaps, step (3) can by carry at heterogeneous hydrogenation catalyst such as carbon palladium or carbon carry platinum in the presence of hydrogenation carry out.Reaction can carried out in appropriate solvent such as acetonitrile, ethyl acetate, toluene or ethanol on the Parr device easily.Product can separate by ordinary method.

In the step (4) of reaction scheme I, with the quinoline-3 of formula XXIII, the 4-diamines is handled with carboxylic acid equivalent, obtains 1H-imidazo [4, the 5-c] quinoline of formula XXIV.Suitable carboxylic acid equivalent comprises formula R ₂C (O-alkyl) ₃Ortho ester, formula R ₂C (O-alkyl) ₂(O-C (O)-alkyl) 1,1-dialkoxy alkyl chain alkanoic acid ester and formula R ₂The chloride of acid of C (O) Cl.The selection of carboxylic acid equivalent is by required R ₂The substituting group decision.For example, triethyl orthopropionate provides wherein R ₂Be the compound of ethyl, original acid methyl ester provides wherein R ₂Compound for butyl.Reaction is by joining carboxylic acid equivalent in the quinoline-3 of the formula XXIII in appropriate solvent such as toluene or pyridine, in the 4-diamines and carry out easily.The pyridine hydrochloride that randomly, can add katalysis.Be reflected at sufficiently high temperature and carry out, to distillate alcohol or the water that forms in reaction process, for example the reflux temperature at solvent carries out.

Perhaps, as the formula of use R ₂The chloride of acid of C (O) Cl is during as carboxylic acid equivalent, and step (4) can be divided into two steps and carry out.The part (i) of step (4) is by joining chloride of acid in the quinoline-3 of formula XXIII, obtains acid amides in the solution of 4-diamines in appropriate solvent such as methylene dichloride or acetonitrile and carries out easily.Randomly, can add tertiary amine such as triethylamine, pyridine or 4-Dimethylamino pyridine.Reaction can be carried out as 0 ℃ in envrionment temperature or being lower than envrionment temperature.Amide product can use ordinary method to separate and purifying randomly.The part of step (4) (ii) relates to the acid amides heating with preparation in part (i), with 1H-imidazo [4, the 5-c] quinoline that formula XXIV is provided.This is reflected in appropriate solvent such as the toluene, carries out easily in the temperature that enough distillates the water that forms in reaction process.This reaction can also carried out in solvent such as ethanol or methyl alcohol in the presence of alkali such as the aqueous sodium hydroxide solution.Product can use ordinary method to separate.

In the step (5) of reaction scheme I, the chloro group of 1H-imidazo [4, the 5-c] quinoline of formula XXIV is replaced with thioacetic acid potassium, obtain 1H-imidazo [4, the 5-c] quinoline of formula XXV.1H-imidazo [4, the 5-c] quinoline of reaction by thioacetic acid potassium being joined formula XXIV be at appropriate solvent such as N, in the solution in the dinethylformamide and carry out easily.Reaction can be carried out in envrionment temperature, and product can use ordinary method to separate.

In the step (6) of reaction scheme I,, obtain 1H-imidazo [4, the 5-c] quinoline that the mercaptan of formula XXVI replaces with thioacetic acid ester group hydrolysis under alkaline condition of 1H-imidazo [4, the 5-c] quinoline of formula XXV.Reaction joins by the methanol solution with sodium methylate in the methanol solution of 1H-imidazo [4,5-c] quinoline of formula XXV and carries out easily.Reaction can be carried out in envrionment temperature, and product can use ordinary method to separate.

In the step (7) of reaction scheme I, 1H-imidazo [4, the 5-c] thiol group of quinoline of formula XXVI is oxidized to the SULPHURYL CHLORIDE of formula XII.In the solution of 1H-imidazo [4,5-c] quinoline in hydrochloric acid that reaction replaces by the mercaptan that the solution of sodium chlorate in appropriate solvent such as water is joined formula XXVI and carry out easily.Reaction can be carried out as 0 ℃ being lower than envrionment temperature, and product can use ordinary method to separate.

In the step (8) of reaction scheme I, the SULPHURYL CHLORIDE of formula XII is handled with amine or amine salt, to obtain the sulphonamide of formula XIII.Reaction is passed through formula NH (R ₁) (R ₁') amine join the SULPHURYL CHLORIDE of the formula XII in appropriate solvent such as methylene dichloride or pyridine and carry out easily.Reaction can be carried out in envrionment temperature, and product can use ordinary method to separate.

Perhaps, step (8) can be by adding formula (R in the solution of SULPHURYL CHLORIDE in appropriate solvent such as methylene dichloride of formula XII ₁) (R ₁') NHHCl, add wet chemical subsequently and carry out.Reaction can be carried out in envrionment temperature, and product can use ordinary method to separate.

In the step (9) of reaction scheme I, use can form 1H-imidazo [4,5-c] the quinoline oxidation of the conventional oxidant of N-oxide compound with formula XIII, with 1H-imidazo [4,5-c] quinoline-5N-oxide compound that formula XXVII is provided.Reaction is by in the compound that the 3-chloro-peroxy benzoic acid is joined the formula XIII in solvent such as methylene dichloride or chloroform and carry out easily.Reaction can be carried out in envrionment temperature, and product can use ordinary method to separate.

In the step (10) of reaction scheme I,, obtain 1H-imidazo [4,5-c] quinoline-4-amine of formula II with 1H-imidazo [4,5-c] quinoline-5N-oxide compound amination of formula XXVII.Step (10) can be that ester activates, then ester and aminating agent reaction carried out by the N-oxygenate conversion with formula XXVII.Suitable activator comprises alkyl sulfonyl chloride or aryl sulfonyl chloride such as benzene sulfonyl chloride, methylsulfonyl chloride or Tosyl chloride.Suitable aminating agent comprises as the ammonia of ammonium hydroxide form and ammonium salt such as volatile salt, bicarbonate of ammonia and ammonium phosphate.The N-oxide compound of reaction by ammonium hydroxide being joined formula XXVII in appropriate solvent such as methylene dichloride or chloroform solution and add Tosyl chloride subsequently and carry out easily.Reaction can be carried out in envrionment temperature.Product or its pharmacologically acceptable salt can use ordinary method to separate.

Step (9) and (10) also can be used as (one-pot) operation of cooking different foods in one pot carries out, in 1H-imidazo [4, the 5-c] quinoline that at first the 3-chloro-peroxy benzoic acid is joined the formula XIII in solvent such as methylene dichloride or chloroform.Reacting the stirring sufficiently long time, sequentially add ammonium hydroxide and Tosyl chloride with after finishing oxidation.Reaction can be carried out in envrionment temperature, and the product of formula II or its pharmacologically acceptable salt can use ordinary method to separate.

Reaction scheme I

Compound of the present invention can be according to reaction scheme II preparation, wherein R _a, R ₁, R ₁', R ₂, X ' and n as above define.

In the step (1) of reaction scheme II,, obtain the quinoline-3 of formula XXVIII, the 4-diamines with 3-nitroquinoline-4-amine reduction of formula XXI.The reduction of nitro can be carried out described in the step (3) of reaction scheme I easily.Product can separate by ordinary method.

In the step (2) of reaction scheme II, with the quinoline-3 of formula XXVIII, 4-diamines and carboxylic acid or its Equivalent react, and obtain 1H-imidazo [4, the 5-c] quinoline of formula XXIX.Reaction can be as carrying out described in the step (4) of reaction scheme I easily, and product can separate by ordinary method.

In the step (3) of reaction scheme II, the use ordinary method is carried out bromination with the hydroxyl of 1H-imidazo [4, the 5-c] quinoline of formula XXIX, obtains 1H-imidazo [4, the 5-c] quinoline of formula XXX.1H-imidazo [4, the 5-c] quinoline of bromination reaction by thionyl bromide being joined formula XXIX in appropriate solvent such as methylene dichloride solution and carry out easily.Reaction can be carried out in envrionment temperature, and product can use ordinary method to separate.

In the step (4) of reaction scheme II, the bromo group of 1H-imidazo [4, the 5-c] quinoline of formula XXX is replaced with the sodium sulfhydrate hydrate, obtain 1H-imidazo [4, the 5-c] quinoline that the mercaptan of formula XXVI replaces.Reaction is by in the solution of 1H-imidazo [4,5-c] quinoline in appropriate solvent such as ethanol that the sodium sulfhydrate hydrate is joined formula XXX and carry out easily.Reaction can be carried out as 45 ℃ in envrionment temperature or at high temperature.Product can use ordinary method to separate.

In the step (5) of reaction scheme II, 1H-imidazo [4, the 5-c] thiol group of quinoline of formula XXVI is oxidized to the SULPHURYL CHLORIDE of formula XII.Reaction can be as carrying out described in the step (7) of reaction scheme I easily, and product can use ordinary method to separate.

In the step (6) of reaction scheme II, the SULPHURYL CHLORIDE of formula XII is handled with amine or amine salt, to obtain the sulphonamide of formula XIII.Reaction can be as carrying out described in the step (8) of reaction scheme I.Product can use ordinary method to separate.

In the step (7) of reaction scheme II, use can form 1H-imidazo [4,5-c] the quinoline oxidation of the conventional oxidant of N-oxide compound with formula XIII, obtains 1H-imidazo [4,5-c] quinoline-5N-oxide compound of formula XXVII.Reaction can be as carrying out described in the step (9) of reaction scheme I.Product can use ordinary method to separate.

In the step (8) of reaction scheme II,, obtain 1H-imidazo [4,5-c] quinoline-4-amine of formula II with 1H-imidazo [4,5-c] quinoline-5N-oxide compound amination of formula XXVII.Reaction can be as carrying out described in the step (10) of reaction scheme I.Product or its pharmacologically acceptable salt can use ordinary method to separate.

Reaction scheme II

Compound of the present invention can be according to reaction scheme III preparation, wherein R _a, R ₁, R ₁', R ₂, X ' and n as above define.

In the step (1) of reaction scheme III, the bromo group of the phthalic imidine of formula XXXI is replaced with thiocarbamide, obtain the phthalic imidine hydrobromate that the thiocarbamide of formula XXXII replaces.Reaction is by mixing the phthalic imidine of formula XXXI and thiocarbamide and carrying out easily in appropriate solvent such as ethanol.Reaction can be carried out at high temperature such as reflux temperature, and product can use ordinary method to separate.The phthalic imidine of some formula XXXI is commercially available as N-(3-bromopropyl) phthalic imidine, and other can use known synthetic method preparation.

In the step (2) of reaction scheme III, the phthalic imidine hydrobromate that the thiocarbamide of formula XXXII is replaced is converted into the phthalic imidine acetate that the thiocarbamide of formula XXXIII replaces.Reaction adds aqueous sodium acetate solution by the aqueous solution to the phthalic imidine hydrobromate of formula XXXII and carries out.Reaction can be carried out as 100 ℃ temperature at high temperature, and product can use ordinary method to separate.

In the step (3) of reaction scheme III, use the thiourea group of the phthalic imidine that the thiocarbamide of formula XXXIII is replaced in the condition described in the step (7) of reaction scheme I to be converted into SULPHURYL CHLORIDE.

In the step (4) of reaction scheme III, the phthalic imidine that the SULPHURYL CHLORIDE of formula XXXIV replaces is handled with amine, obtain the phthalic imidine of sulfo group amide group-replacement of formula XXXV.Reaction is passed through formula NH (R ₁) (R ₁') amine join in the phthalic imidine that the SULPHURYL CHLORIDE of the formula XXXIV in appropriate solvent such as tetrahydrofuran (THF) replaces and carry out easily.Reaction can be carried out in envrionment temperature, and product can use ordinary method to separate.

In the step (5) of reaction scheme III,, obtain the amine that the sulfo group amide group of formula XXXVI replaces with the phthalic imidine hydrolysis that the sulfo group amide group of formula XXXV replaces.Reaction by in the suspension of phthalic imidine in appropriate solvent such as ethanol of formula XXXV, add hydrazine hydrate to and carry out easily.Reaction can be carried out at high temperature such as reflux temperature, and product can use ordinary method to separate.

In the step (6) of reaction scheme III, amine that the sulfo group amide group of formula XXXVI replaces and the 4-chloro-3-nitroquinoline of formula XX are reacted, obtain 3-nitroquinoline-4-amine of formula XXXVII.This reaction is by at appropriate solvent such as N, in the presence of alkali such as triethylamine the amine of formula XXXVI mixed with the quinoline of formula XX in the dinethylformamide and carries out easily.Reaction can be carried out in envrionment temperature, and product can use ordinary method to separate.

In the step (7) of reaction scheme III,, obtain the quinoline-3 of formula XXVIII, the 4-diamines with 3-nitroquinoline-4-amine reduction of formula XXXVII.The reduction of nitro by carry at heterogeneous hydrogenation catalyst such as carbon palladium or carbon carry platinum in the presence of hydrogenation carry out.Reaction can carried out in appropriate solvent such as ethanol on the Parr device easily.Product can separate by ordinary method.

In the step (8) of reaction scheme III, with the quinoline-3 of formula XXVIII, 4-diamines and carboxylic acid or its Equivalent react, and obtain 1H-imidazo [4, the 5-c] quinoline of formula XIII.Reaction can be as carrying out described in the step (4) of reaction scheme I easily, and product can separate by ordinary method.

In the step (9) of reaction scheme III, use can form 1H-imidazo [4,5-c] the quinoline oxidation of the conventional oxidant of N-oxide compound with formula XIII, obtains 1H-imidazo [4,5-c] quinoline-5N-oxide compound of formula XXVII.Reaction can be as carrying out described in the step (9) of reaction scheme I.Product can use ordinary method to separate.

In the step (10) of reaction scheme III,, obtain 1H-imidazo [4,5-c] quinoline-4-amine of formula II with 1H-imidazo [4,5-c] quinoline-5N-oxide compound amination of formula XXVII.Reaction can be as carrying out described in the step (10) of reaction scheme I.Product or its pharmacologically acceptable salt can use ordinary method to separate.

Reaction scheme III

Compound of the present invention can also be according to reaction scheme IV preparation, wherein R _dFor alkyl, alkoxyl group or-N (R ₉) ₂, and R _2b, R _1bAnd R _1b' be R as defined above ₂, R ₁And R ₁' subclass, it does not comprise those substituting groups of reduction sensitivity that well known to a person skilled in the art under the acid hydrogenation conditions of reaction.These responsive groups comprise for example thiazolinyl, alkynyl and aryl and have the group of nitro substituent.

As shown in reaction scheme IV, the 1H-imidazo of formula IIb [4,5-c] quinoline can be reduced to 6,7,8 of formula III b, 9-tetrahydrochysene-1H-imidazo [4,5-c] quinoline-4-amine.Reaction is by adding platinum oxide (IV) and reaction being placed under the hydrogen pressure and carry out easily in the solution of compound at trifluoroacetic acid of heterogeneous hydrogenation conditions downdraft mode IIb.Reaction can be carried out in envrionment temperature on the Parr device.Product or its pharmacologically acceptable salt can separate by ordinary method.

Reaction scheme IV

Compound of the present invention can prepare according to V, wherein R _b, R ₁, R ₁', R ₂, X ' and m as above define.Reaction scheme V begins from 4-chloro-3-nitro [1,5]-naphthyridine of formula XL.The compound of formula XL and be prepared as is knownly participated in for example United States Patent (USP) 6,194,425 (Gerster) and 6,518,280 (Gerster).The step of reaction scheme V (1) to (10) can be carried out described in corresponding step (1) to (10) among the reaction scheme I, obtains 1H-imidazo [4,5-c] [1,5]-naphthyridine 4-amine of formula IV.Product or its pharmacologically acceptable salt can separate by ordinary method.

Reaction scheme V

For some embodiments, pyridine of the present invention is according to reaction scheme VI preparation, wherein R ₁, R ₁', R ₂, R _A', R _B' and X ' as above define, and Ph is a phenyl.In the step (1) of reaction scheme VI, the chloro group of the 7H-imidazo of formula XLVIII [4,5-c] tetrazolo [1,5-a] pyridine is replaced by thioacetic acid potassium, obtains 7H-imidazo [4,5-c] tetrazolo [1, the 5-a] pyridine of formula XLIX.Reaction can be as carrying out described in the step (5) of reaction scheme I easily, and product can separate by ordinary method.The compound of formula XLVIII and be prepared as known.Referring to for example, people such as Dellaria, the open WO 03/103584 of U.S. Patent Publication US2004/0010007 and international monopoly.

In the step (2) of reaction scheme VI, thioacetic acid ester group hydrolysis under alkaline condition of the 7H-imidazo of formula XLIX [4,5-c] tetrazolo [1,5-a] pyridine obtains 7H-imidazo [4,5-c] tetrazolo [1, the 5-a] pyridine that the mercaptan of formula L replaces.Reaction can be as carrying out described in the step (6) of reaction scheme I, and product can separate by ordinary method.

In the step (3) of reaction scheme VI,, obtain the SULPHURYL CHLORIDE of formula XVI according to the thiol group oxidation of the method described in the step (7) of reaction scheme I with 7H-imidazo [4,5-c] tetrazolo [1, the 5-a] pyridine of formula L.Product can separate by ordinary method.

In the step (4) of reaction scheme VI, the SULPHURYL CHLORIDE of formula XVI is handled to obtain the sulphonamide of formula XVII with amine or amine salt.Reaction can be according to carrying out in the method described in the step (8) of reaction scheme I, and the 7H-imidazo of formula XVII [4,5-c] tetrazolo [1,5-a] pyridine can separate by ordinary method.

In the step (5) of reaction scheme VI, remove tetrazole ring from 7H-imidazo [4,5-c] tetrazolo [1,5-a] the pyridine reduction of formula XVII, obtain 1H-imidazo [4,5-c] pyridine-4-amine or its pharmacologically acceptable salt of formula Ib.Reaction can be by carrying out 7H-imidazo [4,5-c] tetrazolo [1,5-a] pyridine and the hydrogen reaction of formula XVII in the presence of catalyzer and acid.Hydrogenation can be used carrying out easily as trifluoroacetic acid of suitable catalyzer such as platinum oxide (IV) and suitable acid at ambient temperature on the Parr device.Can use ordinary method separated product or its pharmacologically acceptable salt from reaction mixture.

Perhaps, can as shown in step (5a), remove tetrazole ring by 7H-imidazo [4,5-c] tetrazolo [1, the 5-a] pyridine from formula XVII, itself and triphenyl phosphine are reacted to form N-triphenyl phosphinidene (phosphinyl) intermediate of formula LI.Can under nitrogen atmosphere, heat as under reflux temperature, carry out in the 2-dichlorobenzene in appropriate solvent such as toluene or 1 with the reaction of triphenyl phosphine.In the step (5b) of reaction scheme VI,, obtain 1H-imidazo [4,5-c] pyridine-4-amine of formula Ib with the N-triphenyl phosphinidene intermediate hydrolysis of formula LI.Hydrolysis can be undertaken by well known to a person skilled in the art general method, is for example undertaken by heating in low-grade alkane alcohol in the presence of acid.Can use ordinary method that the compound or pharmaceutically acceptable salt thereof of product as formula Ib separated from reaction mixture.

Reaction scheme VI

For some embodiments, naphthyridine of the present invention is according to the tetrazolo compound of reaction scheme VII from formula LII and LV, wherein R ₁, R ₁', R ₂, R _b, X ' and m as above define ,-OTf is the trifluoromethanesulfonic acid ester group.The compound of formula LII and LV and the synthetic route of these compounds are known, referring to for example, and United States Patent (USP) 6,194,425 (Gerster) and 6,518,280 (Gerster).

In the step (1) of reaction scheme VII with (1a), tetrazolo-naphthyridine of formula LII or LV and formula HO-X '-NH ₂Amino alcohol reaction, form the compound of formula LIII or LVI.Reaction can be carried out described in the step (1) of reaction scheme 1.Tetrazolo-the naphthyridine that the hydroxyl of formula LIII or LVI is replaced according to the method for the step (2) to (8) of reaction scheme I is converted into the compound of formula LIV or LVII.Remove the tetrazolo group of the compound of formula LIV or LVII then, obtain 1H-imidazo [4,5-c]-1,5 naphthyridine-4-amine of formula VII or VL.The tetrazolo group remove can be or (5a) and (5b) as the step (5) of reaction scheme VI as described in carry out or undertaken by the method described in United States Patent (USP) 6,194,425 (Gerster) and 6,518,280 (Gerster).Product or its pharmacologically acceptable salt can separate by ordinary method.

Reaction scheme VII

Compound of the present invention can be according to reaction scheme VIII preparation, wherein R _a, R ₁, R ₁', R ₂, X ' and n as above define.

In the step (1) of reaction scheme VIII, 1H-imidazo [4, the 5-c] quinoline that the chlorine of formula XXIV is replaced carries out oxidation amination then, obtains 1H-imidazo [4, the 5-c] quinoline that the chloro of formula LVIII replaces.Reaction can be carried out described in the step (9) of reaction scheme I and (10).Product can use ordinary method to separate.

In the step (2) of reaction scheme VIII, the chloro group of 1H-imidazo [4, the 5-c] quinoline of formula LVIII is replaced with thioacetic acid potassium, obtain 1H-imidazo [4, the 5-c] quinoline that the thioacetate of formula LIX replaces.Reaction can be as carrying out described in the step (5) of reaction scheme I.Product can use ordinary method to separate.

In the step (3) of reaction scheme VIII,, obtain 1H-imidazo [4, the 5-c] quinoline that the mercaptan of formula LX replaces with 1H-imidazo [4,5-c] quinoline-4-amine hydrolysis that the thioacetate of formula LIX replaces.Reaction can be as carrying out described in the step (6) of reaction scheme I.Product can use ordinary method to separate.

In the step (4) of reaction scheme VIII, 1H-imidazo [4, the 5-c] quinoline that the mercaptan of formula LX is replaced is oxidized to the SULPHURYL CHLORIDE of formula LXI.Reaction can be as carrying out described in the step (7) of reaction scheme I.Product can use ordinary method to separate.

In the step (5) of reaction scheme VIII, the SULPHURYL CHLORIDE of formula LXI is handled to obtain the sulphonamide of formula II with amine or amine salt.Reaction can be as carrying out described in the step (8) of reaction scheme I.Product or its pharmacologically acceptable salt can use ordinary method to separate.

Reaction scheme VIII

Compound of the present invention can be according to reaction scheme IX preparation, wherein R _a, R ₁, R ₁', R ₂, X ' and n as above define, Ts is (4-aminomethyl phenyl) alkylsulfonyl.

In the step (1) of reaction scheme IX, 3-nitroquinoline-4-amine that the hydroxyl of formula XXI is replaced reacts with Tosyl chloride, obtains tosic acid 4-amino-3-nitroquinoline base ester of formula LXII.Reaction is by mixing Tosyl chloride in the presence of the 4-Dimethylamino pyridine in appropriate solvent such as pyridine and carrying out easily with the quinoline of formula XXI.Reaction can be carried out in envrionment temperature, and product can use ordinary method to separate.

In the step (2) of reaction scheme IX,, obtain the tosic acid 3 of formula LXIII, 4-diamino quinolyl ester with tosic acid 4-amino-3-nitroquinoline base ester reduction of formula LXII.Reduction can be carried out as described in the step (3) of reaction scheme I, and product can use ordinary method to separate.

In the step (3) of reaction scheme IX, with the tosic acid 3 of formula LXIII, 4-diamino quinolyl ester and carboxylic acid or its Equivalent react, and obtain 1H-imidazo [4, the 5-c] quinoline of formula LXIV.Reaction can be carried out as described in the step (3) of reaction scheme I, and product can use ordinary method to separate.

In the step (4) of reaction scheme IX, the tosic acid ester group of 1H-imidazo [4, the 5-c] quinoline of formula LXIV is replaced with potassium sulfocyanate, obtain 1H-imidazo [4, the 5-c] quinoline that the thiocyanic ester of formula LXV replace.Reaction is by in the solution of 1H-imidazo [4,5-c] quinoline in appropriate solvent such as n-propyl alcohol that potassium sulfocyanate is joined formula LXIV and carry out easily.Reaction can use microwave synthesizer to carry out in the temperature of high temperature such as 180-190 ℃, and product can use ordinary method to separate.

In the step (5) of reaction scheme IX,, obtain 1H-imidazo [4, the 5-c] quinoline that the mercaptan of formula XXVI replaces with the thiocyanic ester group cracking of 1H-imidazo [4, the 5-c] quinoline of formula LXV.Reaction is by carrying out in the solution of 1H-imidazo [4,5-c] quinoline in appropriate solvent such as ethanol that sodium borohydride is joined formula LXV.Reaction can be carried out as 0 ℃ being lower than envrionment temperature, and product can use ordinary method to separate.

In the step (6) of reaction scheme IX,, obtain the SULPHURYL CHLORIDE of formula XXII with the thiol group oxidation of 1H-imidazo [4, the 6-c] quinoline of formula XXVI.Reaction by use 1H-imidazo [4,5-c] quinoline from the chlorine treatment formula XXVI of benzyl trimethyl ammonium chloride and trichloroisocyanuric acid original place preparation in appropriate solvent such as methylene dichloride solution carry out.Reaction can be carried out as 0 ℃ being lower than envrionment temperature, and product can use ordinary method to separate.

In the step (7) of reaction scheme IX, the SULPHURYL CHLORIDE of formula XXII and amine or amine salt react, and obtain 1H-imidazo [4, the 5-c] quinoline of the sulfonamide substitutions of formula XIII.Reaction can be described the carrying out of step (8) of reaction scheme I, and product can use ordinary method to separate.

Carry out as the operation of cooking different foods in one pot preferred steps (6) and (7), by at first using from the cooling solution of 1H-imidazo [4,5-c] quinoline in appropriate solvent such as methylene dichloride of the chlorine treatment formula XXVI of benzyl trimethyl ammonium chloride and the preparation of trichloroisocyanuric acid original place.Stir the sufficiently long time with after finishing oxidation will reacting, add amine and allow the reaction mixture envrionment temperature of rising again.

In the step (8) and (9) of reaction scheme IX,, obtain 1H-imidazo [4,5-c] quinoline-4-amine of formula II with 1H-imidazo [4,5-c] the quinoline oxidation ammonification then of formula XIII.Reaction can be respectively carried out described in the step (9) of reaction scheme I and (10).Product or its pharmacologically acceptable salt can use ordinary method to separate.

Reaction scheme IX

Compound of the present invention can also use the variant preparation of reaction scheme I to synthetic route shown in the IX.For example, can use the method for reducing for preparing tetrahydroquinoline in being used to described in the reaction scheme IV to prepare tetrahydrochysene-naphthyridine.Compound of the present invention can also use the synthetic route preparation described in following examples.

Pharmaceutical composition and biological activity

Pharmaceutical composition of the present invention comprises the compound or the salt of the invention described above of the treatment significant quantity that makes up with pharmaceutically acceptable carrier.

Term " treatment significant quantity " and " significant quantity " are meant enough inductive treatments or prophylactic effect, as the amount of the compound or the salt of cytokine induction, immunomodulatory, antitumour activity and/or antiviral activity.Though being used for the active compound of pharmaceutical composition of the present invention or the exact amount of salt changes according to multiple factor well known by persons skilled in the art (as physics and chemical property, the character of carrier and the dosage regimen of being scheduled to of compound or salt), but expect that composition of the present invention comprises enough active ingredients, be used to main body that the dosage of about 100 nanogram/kilograms (ng/kg) to about 50 mg/kg (mg/kg) is provided, preferred about 10 microgram/kilograms (μ g/kg) are to compound or the salt of about 5mg/kg.Can use multiple formulation, as tablet, lozenge, capsule, parenteral formulation, syrup, creme, paste, aerosol, percutaneous plaster, saturating mucous membrane paster etc.

Compound of the present invention or salt can be as independent therapeutical agent administrations in treatment plan, with compound of the present invention or salt combination with one another or with other promoting agent combination administration, other promoting agent comprises other immune response modifier, antiviral drug, microbiotic, antibody, protein, peptide, oligonucleotide etc.

Compound of the present invention or salt show the generation of inducing some cytokine in the experiment of carrying out according to the test of the following stated.These results show that this compound or salt can be used as immune response modifier, and it can regulate immunne response in many different modes, makes them can be used for treating various disease conditions.

Can induce the cytokine of generation to generally include interferon-' alpha ' (IFN-α) and/or tumor necrosis factor-alpha (TNF-α) and some interleukin-(IL) by administration compound of the present invention or salt.Can induce biosynthetic cytokine to comprise IFN-α, TNF-α, IL-1, IL-6, IL-10, IL-12 and multiple other cytokine by compound of the present invention or salt.Except other effect, these and other cytokine can suppress virus and produce and growth of tumour cell, makes compound or salt can be used for treating virus disease and tumorigenesis disease.Therefore, the invention provides the biosynthetic method of cytokine in the induced animal, it comprises the compound of the present invention of animals administer significant quantity or salt or composition.Be used for the disease that the biosynthetic animal of the inducing cell factor can have the following stated for drug compound or salt or composition, as virus disease or tumorigenesis disease, and the administration of compound or salt can provide therapeutic treatment.Perhaps, can with compound or salt before animal suffers from disease to animals administer, make the administration of compound or salt that prophylactic treatment can be provided.

Except can the generation of the inducing cell factor, compound of the present invention or salt can influence the others of innate immune responses.For example, but stimulating natural killer cell activity, and it is the effect that is produced by cytokine induction.But compound or salt is activated macrophage also, and this cell stimulates nitric oxide production secretion and other production of cytokines subsequently.In addition, compound or salt can cause lymphocytic propagation of B-and differentiation.

Compound of the present invention or salt can also be replied influential to acquired immunity.For example, can induce T auxiliary type 1 (T indirectly _H1) generation of cytokine IFN-γ, and can when giving drug compound or salt, suppress T auxiliary type 2 (T _H2) generation of cytokine IL-4, IL-5 and IL-13.

No matter be used for the preventative or therapeutic treatment of disease and no matter be used to influence immunity congenital or that obtain, compound or salt or composition can be in vaccine auxiliary for example individually dosed or with one or more active ingredient combination medicine-feedings.When with other component administration, compound or salt and other one or more components can be distinguished administration; Administration is still independently of one another together, as in solution; Or administration and being bonded to each other together, as (a) with covalent bonds or (b) non covalent bond combination, as in colloidal suspension.

Specified compound of this paper or the treatable situation of salt include but not limited to:

(a) virus disease, such as for example, come from by the disease of following virus infection: adenovirus, simplexvirus (as, HSV-I, HSV-II, CMV, or VZV), poxvirus (as, vaccinia subgroup virus such as smallpox or cowpox, or molluscum contagiosum), pico+ribonucleic acid+virus (as, rhinovirus or enterovirus), orthomyxovirus (as, influenza virus), paramyxovirus (as, parainfluenza virus, mumps virus, Measles virus and respiratory syncytial virus (RSV)), coronavirus (as, SARS), papovavirus (as, papilloma virus, as cause Genital warts, verruca vulgaris, or waste time those of wart of foot), have a liking for Hepadnavirus (as, hepatitis B virus), yellow fever virus (as, hepatitis C virus or dengue fever virus), or retrovirus (as, slow virus such as HIV);

(b) bacteriosis, such as for example, come from by the disease of following infectation of bacteria: as Escherichia, enterobacter, salmonella, Staphylococcus, Shigella, Listera belongs to, aerobacter, the convolution Bacillaceae, klebsiella, proteus, Rhodopseudomonas, streptococcus, chlamydozoan, mycoplasma, Pn, Neisseria, genus clostridium, bacillus, corynebacterium, Mycobacterium, campylobacter, Vibrio, serratia, Providencia, chromobacterium, Brucella, Yersinia, hemophilus, or bordetella belongs to;

(c) other communicable disease is as chlamydozoan, mycosis (including but not limited to moniliosis, aspergillosis, histoplasmosis, crypotococcal) or parasitosis (including but not limited to that malaria, Pneumocystis carinii pneumonia, leishmaniasis, cryptosporidiosis, toxoplasmosis and trypanosome infect);

(d) tumorigenesis disease, as above intracutaneous tumorigenesis (intraepithelial neoplasias), cervical dysplasia, actinic keratosis, rodent cancer, squamous cell carcinoma, renal cell carcinoma, Kaposi's sarcoma, melanoma, leukemia (including but not limited to myelogenous leukemia, chronic lymphocytic leukemia, multiple myeloma, non Hodgkin lymphoma, cutaneous T cell lymphoma, B cell lymphoma and hairy cell leukemia) and other cancer;

(e) atopic disorder of TH2-mediation is as atopic dermatitis or eczema, eosinophilia, asthma, supersensitivity, allergic rhinitis and Ao Men syndrome (Ommen ' s syndrome);

(f) some autoimmune disease is as systemic lupus erythematous, substantive thrombocythemia (essential thrombocythaemia), multiple sclerosis, discoid lupus, alopecia areata; With

(g) with the trauma repair diseases associated, such as for example, to keloid form and the inhibition of other type scar (as, strengthen wound healing, comprise chronic trauma).

In addition, compound of the present invention or salt can be used as the vaccine auxiliary, are used for and any combinations of substances that body fluid and/or cell-mediated immune responses are provided, and described material is such as immunogen for example live virus, bacterium or parasitic; The virus of deactivation, from tumour, protozoic, from the immunogen of organism, fungi or bacterium, toxoid, toxin; Autoantigen; Polysaccharide; Protein; Glycoprotein; Peptide; Cell vaccine; Dna vaccination; Autovaccine; Recombinant protein; Or the like; Be used for for example BCG, cholera, pestilence, typhoid fever, hepatitis A, hepatitis B, hepatitis C, influenza A, influenza B, parainfluenza, poliomyelitis, rabies, measles, parotitis, rubella, yellow jack, tetanus, diphtheria, hemophilus influenzae b, pulmonary tuberculosis, meningococcal and pneumococcal vaccine, adenovirus, HIV, varicella, cytomegalovirus, singapore hemorrhagic fever, the cat family leukemia, checken pest, HSV-1 and HSV-2, hog cholera, Japanese encephalitis, respiratory syncytial virus, rotavirus, papilloma virus, yellow jack and Alzheimer.

Compound of the present invention or salt are individual particularly useful for immune function depression.For example, compound or salt can be used for treating among for example transplant patient, cancer patients and the HIV patient opportunistic infection and the tumour of generation after suppressing cell-mediated immunity.

Therefore, there are one or more above-mentioned diseases in the animal that needs (suffering from this disease) or disease type such as virus disease or tumorigenesis disease to obtain medical treatment by compound of the present invention or salt to animals administer treatment significant quantity.

Effectively the amount of biosynthetic compound of the inducing cell factor or salt is for causing that enough one or more cell types such as monocyte, scavenger cell, dendritic cell and a certain amount of one or more cytokines of B cell generation are (such as for example, IFN-α, TNF-α, IL-1, IL-6, IL-10 and IL-12), this a certain amount of increase (inducing) surpasses the background level of this cytokine.Accurate amount changes with factor known in the art, but it should be the dosage of about 100ng/kg to about 50mg/kg, and preferred about 10 μ g/kg are to about 5mg/kg.The present invention also provides the method for virus infection in the treatment animal and treats the method for tumorigenesis disease in the animal, and it comprises the compound of the present invention of animals administer significant quantity or salt or composition.Effectively the amount of treatment or inhibition virus infection is for causing the amount of one or more virus infectiones performances (producing speed and the mortality ratio of comparing with untreated control animal as virus infringement, virus quantity, virus) minimizing.Accurate amount changes with factor known in the art, but it should be the dosage of about 100ng/kg to about 50mg/kg, and preferred about 10 μ g/kg are to about 5mg/kg.Effectively the amount of the compound of treatment tumour situation or salt is the amount that causes that tumor size or knurl focus number reduce.Accurate amount also changes with factor known in the art, but it should be the dosage of about 100ng/kg to about 50mg/kg, and preferred about 10 μ g/kg are to about 5mg/kg.

Further specify objects and advantages of the present invention by following examples, but the concrete material narrated in these embodiments and amount thereof and other condition and details should be interpreted as it is to excessive qualification of the present invention.

Embodiment

In following examples, efficient hurried chromatography (HPFC) uses HORIZON HPFC system (to derive from Biotage, Inc, Charlottesville, Virginia, the efficient hurried purified product of the automatization of USA) or the hurried chromatographic system of INTELLIFLASH (derive from AnaLogix, Inc, Burlington, Wisconsin, the hurried purification system of the automatization of USA) carry out.The elutriant that is used for each purifying provides in an embodiment.In some chromatographic separation, use the polar compound of chloroform/methanol/strong aqua (CMA) of solvent mixture 80/18/2v/v/v as elutriant.In these separate, with CMA with shown in ratio mix with chloroform.

Embodiment 1

N-methyl 3-(4-amino-2-ethyl-1H-imidazo [4,5-c] quinoline-1-yl) propane-1-sulphonamide

Part A

With N-(3-bromo propyl group) phthalic imidine (10.0g, 37.3mmol, 1.0eq) and thiocarbamide (2.84g, suspension reflux 1.0eq) 8 hours make it be cooled to envrionment temperature then and spend the night.The throw out that obtains by filtering separation and with ethanol (3 * 7mL) rinsings obtain 2-[3-(1,3-dioxo-1, the 3-xylylenimine-2-yl) propyl group of 12.16g] the isothiourea hydrobromate, be white solid, m.p.170-172 ℃.

Part B

With the aqueous sodium acetate solution of saturated heat (～7mL ,～4eq) join 2-[3-(1,3-dioxo-1, the 3-xylylenimine-2-yl) propyl group of stirring] (12.16g is 35.32mmol) in water (90mL) solution of heat (100 ℃) for the isothiourea hydrobromate.Reaction mixture is cooled to envrionment temperature to spend the night.The throw out that obtains is by filtering separation, with cold water (2 * 15mL) washings, and under vacuum 35 ℃ of dryings, obtain 2-[4-(1,3-dioxo-1, the 3-xylylenimine-2-yl) propyl group of 8.77g] the isothiourea acetate, be white solid, m.p.152-153 ℃.

Portion C

Under agitation in 5 minutes with sodium chlorate (983mg, 1.25eq) water (2mL) solution drip 2-[3-(1,3-oxo-1, the 3-xylylenimine-2-yl) propyl group of cooling (0 ℃)] isothiourea acetate (2.39g, 7.39mmol, 1.0eq) in the suspension in concentrated hydrochloric acid (10mL).Reaction mixture was stirred 30 minutes.Light yellow solid is by filtering separation, and (2 * 10mL) wash, and vacuum-drying, obtain the product of 1.81g with icy water.This material and chloroform (25mL) are stirred and remove by filter insoluble white solid.Filtrate decompression concentrates, and obtains 3-(1,3-dioxo-1, the 3-xylylenimine-2-yl) propane-1-SULPHURYL CHLORIDE of 1.33g, is crystalline solid, m.p.76-79 ℃.

Part D

Under agitation (in tetrahydrofuran (THF), (1.28g, 4.45mmol is in tetrahydrofuran (THF) 1.0eq) (THF) solution 2.0eq) to be added drop-wise to 3-(1,3-dioxo-1,3-xylylenimine-2-yl) propane-1-SULPHURYL CHLORIDE for 4.45mL, 2.0M with methylamine.Reaction mixture stirred 2 hours, then concentrating under reduced pressure.Resistates is dissolved in chloroform (110mL) and water (35mL) washing.Aqueous washings extracts with chloroform (40mL) is anti-.The organic layer that merges obtains N-methyl 3-(1,3-dioxo-1, the 3-xylylenimine-2-yl) propane-1-sulphonamide of 1.11g with dried over mgso and concentrating under reduced pressure, is white solid.

Part E

Under agitation (290 μ L, (1.10g, 3.90mmol is 1.0eq) in the suspension of ethanol (20mL) 1.3eq) to be added drop-wise to N-methyl 3-(1,3-dioxo-1,3-xylylenimine-2-yl) propane-1-sulphonamide with hydrazine hydrate.Reaction mixture is heated to backflow.After 3.5 hours, reacting by the analysis demonstration of 1H NMR is about 60: 40 mixture of product and starting raw material.At 4.5 hours, add other hydrazine hydrate (0.7eq).After other 2 hours, finish by the analysis demonstration reaction of 1HNMR.Make reaction through being cooled to envrionment temperature concentrating under reduced pressure then weekend.Resistates is dissolved in the water (10mL).(0.65mL 2.0eq), obtains thick white depositions to drip concentrated hydrochloric acid.Mixture water (10mL) dilution was stirred 20 minutes and was filtered; (3 * 10mL) rinsings of filter cake water.Filtrate decompression concentrates, and obtains N-methyl 3-aminopropane-1-sulfonamide hydrochloride of 0.82g, is light yellow solid.

Part F

With triethylamine (1.14mL, 2.1eq) join stirring N-methyl 3-aminopropane-1-sulfonamide hydrochloride (0.82g, 3.90mmol, N 1.0eq), (DMF is 19.5mL) in the solution for dinethylformamide.With 4-chloro-3-nitroquinoline (813mg, 3.90mmol, 1.0eq) disposable joining in the suspension that obtains.Reaction mixture stirs 1 hour concentrating under reduced pressure then at ambient temperature.Resistates is distributed between chloroform (100mL) and water (30mL).Water layer extracts with chloroform (20mL) is anti-.The organic layer dried over mgso that merges, concentrating under reduced pressure obtains crude product then, is yellow solid.Solid and ether (30mL) are ground, by filtering separation, and with ether (3 * 10mL) rinsings obtain N-methyl 3-[(3-nitroquinoline-4-yl of 0.85g) amino] propane-1-sulphonamide, be yellow solid.

Part G

With N-methyl 3-[(3-nitroquinoline-4-yl) amino] (0.45g 1.39mmol) carries the suspension of platinum (90mg) in ethanol (30mL) at 35psi (2.4 * 10 with 5% carbon to propane-1-sulphonamide ⁵Pa) hydrogenation down.After 3 hours, tlc (TLC) analysis shows to react finishes.With reaction mixture filter with remove catalyzer and with filter cake with ethanol (2 * 15mL) rinsings.Filtrate decompression concentrates, and obtains N-methyl 3-[(3-quinolylamine-4-yl of 0.43g) amino] propane-1-sulphonamide, be orange.

Section H

(308 μ L, (1.39mmol is in pyridine 1.0eq) (7mL) solution 1.1eq) to join the material that derives from part G of stirring for triethyl orthopropionate.(16mg 0.1eq) and with reaction mixture heated 2 hours at 100 ℃ to add pyridine hydrochloride.TLC analyzes and shows that being reflected at 1.5 hours finishes.Reaction mixture is cooled to envrionment temperature concentrating under reduced pressure then.Resistates distributes between chloroform (60mL) and water (35mL).Water layer extracts with chloroform (20mL) is anti-.The organic layer that merges obtains crude product with dried over mgso concentrating under reduced pressure then, is brown oil.Oily matter obtains N-methyl 3-(2-ethyl-1H-imidazo [4, the 5-c] quinoline-1-yl) propane-1-sulphonamide of 336mg by column chromatography purifying (silica gel is with 10/90 methyl alcohol/chloroform wash-out), is brown solid.

Part I

(98mg 1.2eq) joins N-methyl 3-(2-ethyl-1H-imidazo [4,5-c] quinoline-1-yl) propane-1-sulphonamide (110mg, 0.33mmol, 1.0eq) suspension in chloroform (1.7mL) with the 3-chloroperoxybenzoic acid.All suspended matters little by little dissolve.After 30 minutes, TLC analyzes and shows that all starting raw materials exhaust.After 1 hour, add dense ammonium hydroxide (2mL) add subsequently toluene sulfonyl chloride (76mg, 1.2eq).The two-phase mixture vigorous stirring that obtains was separated organic layer in 3 hours then.(3 * 2mL) extract water layer with chloroform.Extracting solution and organic layer are merged,, obtain the crude product of 0.12g, be the brown foam with dried over mgso and concentrating under reduced pressure.(～3mL) recrystallization is by filtering separation, and with ice-cold THF (2 * 2mL) rinsings from THF for foam, obtain N-methyl 3-(the 4-amino-2-ethyl-1H-imidazo [4 of 32mg, 5-c] quinoline-1-yl) propane-1-sulphonamide, be brown powder, mp 225-228 ℃. ¹HNMR(300MHz，DMSO-d ₆)：δ8.11(d，J＝7.6Hz，1H)，7.61(dd，J＝1.1，8.4Hz，1H)，7.42(t，J＝7.2Hz，1H)，7.25(dd，J＝1.2，8.1Hz，1H)，6.95(q，J＝4.9Hz，1H)，6.45(s，2H)，4.64(t，J＝7.7Hz，2H)，3.29(m，2H)，2.96(q，J＝7.5Hz，2H)，2.56(d，J＝4.9Hz，3H)，2.14(m，2H)，1.38(t，J＝7.4Hz，3H)；MS(APCI)m/z：348(M+H)。Ultimate analysis: C ₁₆H ₂₁N ₅O ₂S0.08THF0.14 H ₂O, theoretical value: C, 55.10; H, 6.21; N, 19.69; Measured value: C, 55.04; H, 6.19; N, 19.37.

Embodiment 2

N, N-dimethyl 3-(4-amino-2-ethyl-1H-imidazo [4,5-c] quinoline-1-yl) propane-1-sulphonamide

Part A

Under agitation (in tetrahydrofuran (THF), (5.04g, 17.5mmol is in tetrahydrofuran (THF) 1.0eq) (THP) solution 2.1eq) to be added drop-wise to 3-(1,3-dioxo-1,3-xylylenimine-2-yl) propane-1-SULPHURYL CHLORIDE for 4.7mL, 2.0M with dimethylamine.Reaction mixture was stirred 1.5 hours, then concentrating under reduced pressure.Resistates is dissolved in middle chloroform (120mL), and water (50mL) washing with dried over mgso and concentrating under reduced pressure, obtains the thick N of 3.80g, and N dimethyl 3-(1,3-dioxo-1,3-xylylenimine-2-yl) propane-1-sulphonamide is white solid.

Part B

Under agitation (0.95mL 1.3eq) is added drop-wise in the suspension of crude product (1.0eq) in ethanol (60mL) that derives from part A with hydrazine hydrate.With reaction mixture reflux 3 hours, make it be cooled to envrionment temperature, then concentrating under reduced pressure.Resistates is suspended in the water (80mL).The dropping concentrated hydrochloric acid (1.6mL, 1.5eq).With suspension vigorous stirring 45 minutes and the filtration that obtains, (2 * 35mL) rinsings of filter cake water.Filtrate decompression concentrates, and obtains white solid.This material and methyl alcohol (50mL) are merged concentrating under reduced pressure then.(100mL) repeats this process with acetonitrile, obtains the N of 2.50g, and N-dimethyl 3-aminopropane-1-sulfonamide hydrochloride is white solid.

Portion C

(1.0eq) (12.3mmol is in DMF 1.10eq) (45mL) solution for the disposable material that derives from part B that joins stirring for 2.34g, 11.2mmol with 4-chloro-3-nitroquinoline.The dropping triethylamine (3.3mL, 2.1eq).After 1 hour, TLC analyzes the demonstration reaction and finishes.With the reaction mixture concentrating under reduced pressure.Resistates distributes between chloroform (200mL) and water (50mL).Water layer extracts with chloroform (75mL) is anti-.The organic layer that merges obtains the N of 2.72g, N-dimethyl 3-[(3-nitroquinoline-4-yl with dried over mgso concentrating under reduced pressure then) amino] propane-1-sulphonamide, be red solid.

Part D

With sodium borohydride (1.20g, 4.0eq) slowly join the N of stirring, N-dimethyl 3-[(3-nitroquinoline-4-yl) amino] propane-1-sulphonamide (2.68g, 7.92mmol, 1.0eq) and nickelous chloride (II) hexahydrate (188mg is 0.1eq) in the solution in methyl alcohol/chloroform (40mL) of 1/1.After 30 minutes, TLC analyzes the demonstration reaction and finishes.With the reaction mixture concentrating under reduced pressure.Resistates is suspended in the chloroform (200mL), and (dried over mgso is used in 2 * 60mL) washings to water, and concentrating under reduced pressure obtains brown oil then.The TLC of oily matter analyzes and shows various ingredients.With the water lotion alkalization (pH8-9) that merges, (2 * 75mL) extract to use chloroform then.Chloroform extracted solution is merged, use dried over mgso, concentrating under reduced pressure then obtains the N of 1.46g, N-dimethyl 3-[(3-quinolylamine-4-yl) amino] propane-1-sulphonamide, be brown foam.

Part E

(55mg, (4.73mmol is in pyridine 1.0eq) (24mL) solution 0.1eq) to join the material that derives from part D of stirring with pyridine hydrochloride.(1.05mL 1.1eq) and with reaction mixture heated 2.5 hours at 100 ℃ to add triethyl orthopropionate.TLC analyzes the demonstration reaction and finishes.With the reaction mixture concentrating under reduced pressure.Resistates is dissolved in the chloroform (140mL), and (dried over mgso is used in 2 * 35mL) washings to water, and concentrating under reduced pressure obtains crude product then, is brown foam.This material obtains the N of 1.08g by column chromatography purifying (silica gel is with 1.5/98.5 methyl alcohol/chloroform wash-out), and N-dimethyl 3-(2-ethyl-1H-imidazo [45-c] quinoline-1-yl) propane-1-sulphonamide is brown foam.

Part F

((0.95g, 2.74mmol is in chloroform 1.0eq) (14mL) solution for N-dimethyl 3-(2-ethyl-1H-imidazo [4,5-c] quinoline-1-yl) propane-1-sulphonamide for 810mg, 1.2eq) the disposable N that joins with the 3-chloroperoxybenzoic acid.After 30 minutes, TLC analyzes and shows that all starting raw materials exhaust.After 2 hours, add dense ammonium hydroxide (14mL) add subsequently toluene sulfonyl chloride (679mg, 1.3eq).The two-phase mixture vigorous stirring that obtains was separated organic layer in 2.5 hours then.(2 * 20mL) extract water layer with chloroform.All organic phase is merged,, obtain the crude product of 1.25g, be brown foam with dried over mgso concentrating under reduced pressure then.Foam and ethyl acetate (7mL) are ground, merge, by filtering separation, with (3 * 2mL) rinsings, and, obtain the pale powder of 770mg of 1/1 ethyl acetate/petroleum ether 70 ℃ of vacuum-dryings 4 days with sherwood oil.Powder and chloroform (80mL) are merged,, use dried over mgso, then concentrating under reduced pressure with saturated sodium bicarbonate aqueous solution (30mL) washing.The solid that obtains is from ethanol (～25mL) recrystallization, pass through filtering separation, with (2 * 5mL) rinsings of ice-cold ethanol, dry then, obtain the N of 553mg, N-dimethyl 3-(4-amino-2-ethyl-1H-imidazo [4,5-c] quinoline-1-yl) propane-1-sulphonamide, be pale powder, mp 209-211 ℃. ¹H NMR (300MHz, DMSO-d ₆): δ 8.11 (m, 1H), 7.61 (dd, J=1.0,8.3Hz, 1H), 7.42 (m, 1H), 7.25 (m, 1H), 6.45 (br s, 2H), 4.64 (t, J=8.0Hz, 2H), 3.35 (m, 2H), 2.96 (q, J=7.4Hz, 2H), 2.77 (s, 6H), 2.18 (m, 2H), 1.38 (t, J=7.4Hz, 3H); MS (APCI) m/z:362 (M+H) ⁺Ultimate analysis: theoretical value: C ₁₇H ₂₃N ₅O ₂S, C, 56.49; H, 6.41; N, 19.37.Measured value: C, 56.56; H, 631; N, 19.44.

Embodiment 3

N, N-dimethyl 4-(4-amino-2-ethyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide

Part A

((20g, 47.9mmol is 1eq) in the suspension in methylene dichloride (200mL) 1.1eq) to join 4-chloro-3-nitroquinoline for 11.8g, 57.2mmol with triethylamine.Slowly add 4-amino butanol (9.6g, 52.7mmol, methylene dichloride 1.1eq) (50mL) solution.After 2 hours, with the reaction mixture concentrating under reduced pressure.Resistates and water were pulled an oar about one hour.The solid by filtration that obtains is separated and dry air, obtains crude product.This material obtains 4-[(3-nitroquinoline-4-yl of 24.1g by column chromatography purifying (silica gel is sequentially with methylene dichloride and the methylene dichloride wash-out that contains 5% methyl alcohol)) amino] butanols.

Part B

With 4-[(3-nitroquinoline-4-yl) amino] (18.2g 69.6mmol) carries the hydrogenation on the Parr device of the suspension of palladium in the mixture of toluene (450mL) and ethanol (60mL) with 5% carbon and shows that up to the TLC analysis starting raw material exhausts butanols.By CELITE filtration adjuvant filtering layer, concentrating under reduced pressure then obtains 4-[(3-quinolylamine-4-yl of 17g with reaction mixture) amino] butanols.

Portion C

With triethyl orthopropionate (15.1mL, 76.1mmol, 1.1eq) and pyridine hydrochloride (catalytic amount) join 4-[(3-quinolylamine-4-yl) amino] (16g, 69mmol is in pyridine 1eq) (150mL) solution for butanols.With reaction mixture reflux 1 hour, at this moment TLC analyzed and shows that all starting raw materials exhaust.With the reaction mixture concentrating under reduced pressure.Resistates and water (300mL) grind.The solid by filtration that obtains is separated, and from re-crystallizing in ethyl acetate, by filtering separation, with the cold ethyl acetate washing, dry air then obtains 4-(2-ethyl-1H-imidazo [4, the 5-c] quinoline-1-yl) butanols of 8.2g, is solid.

Part D

(3.35g, (3.13g, 11.6mmol is 1.0eq) in the suspension in THF (50mL) 1.1eq) to join 4-(2-ethyl-1H-imidazo [4, the 5-c] quinoline-1-yl) butanols of stirring with triphenyl phosphine.In the time of～1min, repeatedly add on a small quantity N-bromosuccinimide (2.28g, 1.1eq).After 45 minutes, add other triphenyl phosphine (0.2eq) and N-bromosuccinimide (0.2eq).After other one hour, TLC analyzes the demonstration reaction and finishes basically.Reaction mixture methyl alcohol (2mL) cancellation concentrating under reduced pressure then.Resistates is dissolved in the chloroform (200mL), and water (50mL), 5% S-WAT (50mL) and salt solution (50mL) washing are used dried over mgso, then concentrating under reduced pressure continuously.Resistates obtains 1-(4-bromo butyl)-2-ethyl-1H-imidazo [4,5-c] quinoline of 3.07g by column chromatography purifying (silica gel, the gradient elution of usefulness are the methyl alcohol/chloroform of 100% chloroform to 4/96), is orange solids.

Part E

(9.21mmol, suspension 1.0eq) leniently heats up to obtaining solution with the material that derives from part D.With solution be cooled near the disposable then adding sodium sulfhydrate of envrionment temperature hydrate (671mg, 1.3eq).Reaction mixture stirred in envrionment temperature rise again then weekend 45 ℃, kept 4 hours.Reaction mixture is cooled to envrionment temperature spends the night, add other sodium sulfhydrate hydrate (0.3eq) then.After 6 hours, add chloroform (10mL).Reaction mixture is stirred the concentrating under reduced pressure then that spends the night.Resistates and chloroform (175mL) are merged, continuously water (2 * 50mL) and salt solution (75mL) wash, use dried over mgso, concentrating under reduced pressure then obtains the pink foam of 2.75g.This material obtains 4-(2-ethyl-1H-imidazo [4, the 5-c] quinoline-1-yl) butane-1-mercaptan of 1.87g by column chromatography purifying (silica gel, the methyl alcohol/chloroform with 3/97 to 4/96 carries out gradient elution), is white foam.

Part F

Under agitation with sodium chlorate (103mg, 1.3eq) water (0.5mL) drips of solution be added to 4-(the 2-ethyl-1H-imidazo [4 of cooling (0 ℃), 5-c] quinoline-1-yl) (211mg, 0.74mmol is 1.0eq) in the solution in concentrated hydrochloric acid (1.0mL) for butane-1-mercaptan.Reaction mixture was stirred 1.5 hours.Adding chloroform (5mL) adds SODIUM PHOSPHATE, MONOBASIC subsequently, and (2.76g, water 23mmol) (4mL) solution is to pH～3.Reaction mixture water (20mL) and chloroform (30mL) further dilution under agitation add saturated sodium bicarbonate aqueous solution then up to pH～5.Separate water layer and use chloroform (30mL) to extract water layer.The organic layer that merges obtains 4-(2-ethyl-1H-imidazo [4, the 5-c] quinoline-1-yl) butane-1-SULPHURYL CHLORIDE of 190mg with dried over mgso concentrating under reduced pressure then, is light yellow semisolid.

Part G

(in water, (0.54mmol is in methylene dichloride 1.0eq) (5.4mL) solution 2.4eq) to join the material that derives from part F of stirring for 160 μ L, 40%w/w with dimethylamine.After 1 hour, add other dimethylamine (1eq).Make reaction mixture sat cross concentrating under reduced pressure then at weekend.Resistates is with chloroform (60mL) dilution, continuously water (2 * 25mL) and saturated sodium bicarbonate (25mL) wash, use dried over mgso, concentrating under reduced pressure then obtains the yellow oil of 138mg.Oily matter and the material that derives from another time operation are merged, by column chromatography purifying (silica gel, the methyl alcohol with 5/95/chloroform wash-out), obtain the N of 222mg, N-dimethyl 4-(2-ethyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide is white foam.

Section H

Use the general method of the part F of embodiment 2, with the material that derives from part G 3-chloroperoxybenzoic acid (167mg, 1.1eq) oxidation amination then (toluene sulfonyl chloride of dense ammonium hydroxide of 3mL and 135mg).Crude product is by column chromatography purifying (silica gel, with 5/95 methyl alcohol/chloroform wash-out), grind with ethyl acetate, then under vacuum 65 ℃ of dryings 12 hours, obtain the N of 129mg, N-dimethyl 4-(4-amino-2-ethyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide, be white powder, mp 193-195 ℃. ¹H NMR (300MHz, DMSO-d ₆): δ 8.05 (d, J=8.1Hz, 1H), 7.60 (dd, J=1.2,8.4Hz, 1H), 7.41 (ddd, J=1.4,7.1,8.4Hz, 1H), 7.25 (ddd, J=1.2,7.1,8.4Hz, 1H), 6.43 (s, 2H), 4.56 (t, J=7.5Hz, 2H), 3.10 (t, J=7.5Hz, 2H), 2.96 (q, J-7.5Hz, 2H), 2.73 (s, 6H), 1.88, (m, 4H), 1.38 (t, J=7.5Hz, 3H); MS (APCI) m/z:376 (M+H); Ultimate analysis: C ₁₈H ₂₅N ₅O ₂S, theoretical value: C, 57.58; H, 6.71; N, 18.65.Measured value: C, 57.54; H, 6.58; N, 18.65.

Embodiment 4

N-methyl 4-(4-amino-2-ethyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide

Part A

(504mg, (1.25g, 3.55mmol is 1.0eq) and in the mixture of methylene dichloride (36mL) 2.1eq) to join 4-(2-ethyl-1H-imidazo [4, the 5-c] quinoline-1-yl) butane-1-SULPHURYL CHLORIDE of stirring with methylamine hydrochloride.The adding wet chemical (1.30mL, 6M, 2.2eq).After 2 hours, reaction mixture is with chloroform (100mL) dilution, with salt solution (30mL) washing, use dried over mgso, concentrating under reduced pressure then obtains N-methyl 4-(the 2-ethyl-1H-imidazo [4 of 1.24g, 5-c] quinoline-1-yl) butane-1-sulphonamide, be the light brown solid.

Part B

(1.02g, 77%max is 1.15eq) in chloroform (36mL) solution of the disposable material that derives from part A (1.0eq) that joins stirring with the 3-chloroperoxybenzoic acid.After 50 minutes, add dense ammonium hydroxide (8mL) and toluene sulfonyl chloride (819mg, 1.2eq).Reaction mixture was stirred 2 hours, under reduced pressure remove most of chloroform then.Resistates is filtered, and (2 * 8mL) wash, and vacuum-drying then obtains the brown solid of 722mg for water (10mL) and Virahol continuously.This material is from 1, the 2-ethylene dichloride (～45mL) recrystallization obtains N-methyl 4-(4-amino-2-ethyl-1H imidazo [4, the 5-c] quinoline-1-yl) butane-1-sulphonamide of 491mg then 50 ℃ of following vacuum-dryings 18 hours, be pale powder, mp 190-191 ℃. ¹H NMR (300MHz, DMSO-d ₆): δ 8.03 (d, J=8.4Hz, 1H), 7.61 (dd, J=1.2,8.4Hz, 1H), 7.41 (ddd, J=1.2,7.1,8.3Hz, 1H), 7.25 (ddd, J=1.2,7.1,8.3Hz, 1H), 6.90 (q, J=4.8Hz, 1H), 6.43 (br s, 2H), 4.54 (t, J=7.3Hz, 2H), 3.08 (t, J=7.3Hz, 2H), 2.96 (q, J=7.5Hz, 2H), 2.54 (d, J=4.8Hz, 3H), 1.94 (m, 2H), 1.81 (m, 2H), 1.38 (t, J=7.5Hz, 3H); MS (APCI) m/z:362 (M+H); Ultimate analysis: C ₁₇H ₂₃N ₅O ₂S0.05C ₂H ₄Cl ₂, theoretical value: C, 56.05; H, 6.38; N, 19.11.Measured value: C, 55.83; H, 6.13; N, 18.92.

Embodiment 5

N-(4-methoxy-benzyl) 4-(4-amino-2-ethyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide

Part A

((0.62g, 1.76mmol is in methylene dichloride 1.0eq) (17mL) solution 1.2eq) to join 4-(2-ethyl-1H-imidazo [4, the 5-c] quinoline-1-yl) butane-1-SULPHURYL CHLORIDE of stirring for 0.35mL, 6M with wet chemical.(0.25mL 1.1eq) and with reaction mixture stirred 2 hours to drip 4-methoxy-benzyl amine.Add other wet chemical (1.2eq) and 4-methoxy-benzyl amine (1.1eq) and reaction mixture was stirred weekend.(dried over mgso is used in 2 * 40mL) washings to reaction mixture, and concentrating under reduced pressure obtains brown oil then with chloroform (140mL) dilution, water.Oily matter obtains N-(4-methoxy-benzyl) 4-(2-ethyl-1H-imidazo [4, the 5-c] quinoline-1-yl) butane-1-sulphonamide of 412mg by twice of column chromatography purifying (silica gel is with 5/95 methyl alcohol/chloroform wash-out), is white foam.

Part B

(257mg, 77%max 1.15eq) join in chloroform (9.1mL) solution of the material that derives from part A (1.0eq) of stirring with the 3-chloroperoxybenzoic acid.After 1 hour, add dense ammonium hydroxide (3mL) and toluene sulfonyl chloride (207mg, 1.2eq).With reaction mixture vigorous stirring 20 hours, water (4mL) dilution and under reduced pressure partly concentrating.Chloroform is used in resistates water (5mL) dilution then, and (1 * 40mL uses 4 * 20mL) to extract then.The extracting solution that merges obtains the brown foam of 0.47g with dried over mgso concentrating under reduced pressure then.Foam by column chromatography purifying (silica gel is with 25,/75 80/18/2 chloroform/methanol/ammonium hydroxide (CMA)/chloroform wash-out), is obtained the brown foam of 0.20g.This material is from the ethylacetate/ether reconcentration of heat, from ethyl alcohol recrystallization, pass through filtering separation, with ethanol (2 * 2mL) rinsings, and, obtain N-(4-methoxy-benzyl) 4-(4-amino-2-ethyl-1H-imidazo [4, the 5-c] quinoline-1-yl) butane-1-sulphonamide of 80mg 80 ℃ of vacuum-dryings 24 hours, be white powder, mp 176-177 ℃. ¹HNMR (300MHz, DMSO-d ₆): δ 8.00 (d, J=8.1Hz, 1H), 7.61 (dd, J=1.1,8.3Hz, 1H), 7.56 (t, J=5.9Hz, 1H), 7.42 (ddd, J=1.1,7.2,8.3Hz, 1H), 7.25 (m, 3H), 6.84 (m, 2H), 6.43 (br s, 2H), 4.48 (t, J=7.6Hz, 2H), 4.03 (d, J=5.9Hz, 2H), 3.67 (s, 3H), 2.93 (m, 4H), 1.80 (m, 4H), 1.38 (t, J=7.5Hz, 3H); MS (APCI) m/z:468 (M+H); Ultimate analysis: C ₂₄H ₂₉N ₅O ₃S0.05EtOH, theoretical value: C, 61.60; H, 6.28; N, 14.90.Measured value: C, 61.39; H, 6.53; N, 14.84.

Embodiment 6

4-(4-amino-2-ethyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide

Be dissolved in N-(4-methoxy-benzyl) 4-(4-amino-2-ethyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide (180mg) in the trifluoroacetic acid (3mL) and stirred 5.5 hours.With the reaction mixture concentrating under reduced pressure.Resistates is suspended in the methyl alcohol (15mL) concentrating under reduced pressure then.With resistates and methyl alcohol (～3mL) grind, by filtering separation,, obtain the white solid of 168mg with methyl alcohol (2mL) rinsing, vacuum-drying then.With the methylene dichloride of this solid and heat (～3mL) grind, by filtering separation, (2 * 2mL) washings, vacuum-drying then obtain the solid of 124mg with methylene dichloride.(～8mL is evaporated to～3mL) recrystallization this material, obtains 4-(4-amino-2-ethyl-1H-imidazo [4, the 5-c] quinoline-1-yl) butane-1-sulphonamide trifluoroacetate of 67mg, is white powder, mp 225-227 ℃ from methyl alcohol. ¹H NMR (300MHz, DMSO-d ₆): δ 13.43 (br s, 1H), 8.89 (br, 2H), 8.24 (d, J=8.1Hz, 1H), 7.83 (d, J=8.4Hz, 1H), 7.72 (t, J=8.0Hz, 1H), 7.58 (dd, J=1.2,8.3Hz, 1H), 6.80 (br s, 2H), 4.62 (t, J=7.3Hz, 2H), 3.05 (m, 4H), 1.92 (m, 4H), 1.41 (t, J=7.3Hz, 3H); MS (APCI) m/z:348 (M+H); Ultimate analysis: C ₁₆H ₂₁N ₅O ₂SCF ₃CO ₂H, theoretical value: C, 46.85; H, 4.81; N, 15.18, measured value: C, 46.65; H, 4.82; N, 15.07.

Embodiment 7

N, N-dimethyl 3-(4-amino-1H-imidazo [4,5-c] quinoline-1-yl) propane-1-sulphonamide

Part A

With V-Brite B (4.12g, 85%, water 5.0eq) (16mL) drips of solution is added to the N of stirring, N-dimethyl 3-[(3-nitroquinoline-4-yl) amino] propane-1-sulphonamide (1.60g, 4.72mmol, in 1/1 acetonitrile/methanol (48mL) solution 1.0eq).In adition process, form white depositions.The reaction mixture vigorous stirring was filtered in 1 hour then.Filter cake methyl alcohol (2 * 20mL) rinsings.Filtrate decompression concentrates vacuum-drying then and spends the night, and obtains the thick N of 4.1g, N-dimethyl 3-[(3-quinolylamine-4-yl) amino] propane-1-sulphonamide, be the yellow/orange solid.

Part B

With trimethyl orthoformate (0.62mL, 1.2eq) and pyridine hydrochloride (55mg 0.1eq) sequentially joins in the suspension of the material that derives from part A (1.0eq) in pyridine of stirring.Reaction is heated to 100 ℃ and stirred 2 hours.Add other trimethyl orthoformate (1.2eq) and reaction mixture was heated other 6 hours.Make reaction mixture be cooled to envrionment temperature and spend the night, TLC analyzes the demonstration reaction and finishes.The reaction mixture concentrating under reduced pressure also distributes resistates between methylene dichloride (100mL) and water (75mL).Water layer extracts with methylene dichloride (50mL) is anti-.The organic layer that merges obtains N with dried over mgso and concentrating under reduced pressure, and N-dimethyl 4-(2-ethyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide is yellow foam.(silica gel is sequentially used 0-10% methyl alcohol/chloroform to this material, with 10 times of column volumes by the HPFC purifying; With 10% methyl alcohol/chloroform, with 5 times of column volume wash-outs).The material that obtains from the acetonitrile reconcentration then vacuum-drying spend the night, obtain the N of 1.26g, N-dimethyl 3-(1H-imidazo [4,5-c] quinoline-1-yl) propane-1-sulphonamide is orange foam.

Portion C

(1.17g, 77%max 1.2eq) join in chloroform (20mL) solution of the material that derives from part B (1.0eq) of stirring with the 3-chloroperoxybenzoic acid.After 1 hour, (943mg 1.25eq), formed white depositions after 10 minutes to add dense ammonium hydroxide (2mL) and toluene sulfonyl chloride under vigorous stirring; TLC analyzes the demonstration reaction and finishes.After 1 hour, with the reaction mixture filtration and with filter cake chloroform (2 * 15mL) rinsings.Filtrate water (20mL) washing.(2 * 25mL) instead extract water layer with chloroform.The organic layer that merges obtains the brown foam of 1.5g with dried over mgso and concentrating under reduced pressure.Foam and methyl alcohol (10-15mL) are ground, by filtering separation, usefulness methyl alcohol (3 * 4mL) rinsings, and, obtain the white solid of 435mg 100 ℃ of vacuum-dryings.With this material and methyl alcohol (3mL) making beating that comprises several 10% aqueous sodium hydroxide solutions, pass through filtering separation, with methyl alcohol (2 * 2mL) rinsings and 110 ℃ of vacuum-dryings [0.10 Torr (13Pa)] 6 hours, obtain N-methyl 3-(the 4-amino-1H-imidazo [4 of 330mg, 5-c] quinoline-1-yl) propane-1-sulphonamide, be white powder, mp 155-157 ℃. ¹H NMR (300MHz, DMSO-d ₆): δ 8.19 (s, 1H), 8.11 (d, J=7.5Hz, 1H), 7.63 (dd, J=8.3,0.8Hz, 1H), 7.46 (m, 1H), 7.27 (m, 1H), 6.59 (br s, 2H), 4.72 (t, J=7.2Hz, 2H), 3.19 (t, J=7.6Hz, 2H), 2.74 (s, 6H), 2.27 (pentet, J=7.4Hz, 2H); MS (APCI) m/z:334 (M+H)+; Ultimate analysis, C ₁₅H ₁₉N ₅O ₂S, theoretical value: C, 54.04; H, 5.74; N, 21.01.

Measured value: C, 53.71; H, 6.06; N, 20.96.

Embodiment 8

N-(4-p-methoxy-phenyl) 4-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide

Part A

Under agitation with thionyl chloride (49.6g, methylene dichloride 1.1eq) (100mL) drips of solution is added to the 4-[(3-nitroquinoline-4-yl of cooling (0 ℃)) amino] (99g, 379mmol is in methylene dichloride 1eq) (900mL) suspension for butanols.Reaction mixture stirred to spend the night then at ambient temperature regulate pH to pH 10 by adding wet chemical (6M).Separate water layer and (4 * 100mL) extract the organic layer salt water washing that will merge, and use dried over mgso, and concentrating under reduced pressure obtains crude product then with methylene dichloride with water layer.This material is by chromatography purification (silica gel is with containing the methylene dichloride wash-out of 7% methyl alcohol), obtains～N-(4-chlorobutyl)-3-nitroquinoline-4-amine of 96g.

Part B

(3.00g, water 5.0eq) (11mL) drips of solution is added to N-(4-the chlorobutyl)-3-nitroquinoline-4-amine of stirring, and (964mg, 3.45mmol is 1.0eq) in the suspension in ethanol (34mL) with V-Brite B.In adition process, form throw out.After 45 minutes, with the reaction mixture filtration and with filter cake ethanol (3 * 12mL) rinsings.Filtrate decompression concentrates and resistates is distributed between methylene dichloride (150mL) and 50% sodium bicarbonate (60mL).Organic layer is used dried over mgso with 50% sodium bicarbonate (60mL) washing, and concentrating under reduced pressure then obtains the N of 0.45g ⁴-(4-chlorobutyl) quinoline-3, the 4-diamines is for yellow semi-solid.

Portion C

Under agitation (243mg 1.1eq) is added drop-wise in methylene dichloride (9mL) solution of the material that derives from part B (1.0eq) of cooling (0 ℃) with the oxyethyl group Acetyl Chloride 98Min..Reaction mixture stirred made its envrionment temperature and stirring 1 hour of rising again in 5 minutes then.With the reaction mixture concentrating under reduced pressure, obtain thick N-[4-(4-chlorobutyl) quinolylamine-3-yl]-2-oxyethyl group acetamide hydrochloride, be yellow oil.

Part D

(1.28mL, 2M 1.5eq) join in ethanol (17mL) solution of the material that derives from portion C (1.0eq) of stirring with aqueous sodium hydroxide solution.Reaction mixture 60-70 ℃ of heating 30 minutes, is at this moment shown to react by high performance liquid chromatography (HPLC) analysis and finishes.Reaction mixture is cooled to envrionment temperature crosses concentrating under reduced pressure then at weekend.Resistates and the material that derives from another time operation are merged distribution between ethyl acetate (120mL) and water (40mL) then.Organic layer obtains the yellow oil of 0.55g with dried over mgso and concentrating under reduced pressure.This material obtains 1-(4-chlorobutyl)-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline by purifying HPFC (silica gel is used from 100% ethyl acetate to the ethyl acetate gradient elution that contains 10% methyl alcohol), is yellow oil.

Part E

(2.95g, 1.1eq) (7.46g, 23.5mmol is in DMF 1.0eq) (110mL) solution for disposable 1-(4-chlorobutyl)-2-ethoxyl methyl-1H-imidazo [4, the 5-c] quinoline that joins stirring with thioacetic acid potassium.Solution is stirred the concentrating under reduced pressure then that spends the night in envrionment temperature.Resistates is dissolved in the methylene dichloride (200mL), and water (100mL) and salt solution (100mL) washing continuously with dried over mgso and concentrating under reduced pressure, obtains the product of 8.06g, is brown solid.Solid further by washing with water and stirring purifying with gac, is obtained S-[4-(2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) butyl] thioacetate.

Part F

With S-[4-(2-ethoxyl methyl-1H-imidazo [4, the 5-c] quinoline-1-yl) butyl that stirs] (methyl alcohol 1.0eq) (59mL) solution is with the nitrogen several minutes that outgases for 4.19g, 11.7mmol for thioacetate.(5.90mL, 25 weight % are in methyl alcohol, 2.2eq) and with the reaction mixture several minutes that outgases again to add sodium methylate.1 hour afterwards with the reaction mixture concentrating under reduced pressure.Resistates dilutes with methylene dichloride (150mL) and water (50mL); Add hydrochloric acid (2M) then to pH～7.Separate water layer and use methylene dichloride (50mL) instead to extract water layer.The organic layer that merges obtains the crude product of 3.72g with dried over mgso and concentrating under reduced pressure, is yellow oil.(silica gel is used the chloroform that contains 0-20%CMA to oily matter, is used for 5 times of column volumes by the HPFC purifying, be used for 5 times of column volume wash-outs with the chloroform that contains 20%CMA then), obtain 4-(2-ethoxyl methyl-1H-imidazo [4, the 5-c] quinoline-1-yl) butane-1-mercaptan of 2.20g, be yellow oil.

Part G

Under agitation (965mg, 1.3eq) drips of solution is added to the hydrochloric acid of the material that derives from part F (1.0eq) of cooling (0 ℃) (17mL is 7M) in the solution with sodium chlorate.The reaction mixture stirring was added methylene dichloride (100mL) in 90 minutes then.The dropping wet chemical (10mL, 6M).The reaction mixture envrionment temperature of rising again is poured over it in mixture of methylene dichloride (100mL) and water (50mL) then.Be adjusted to pH 4 by adding wet chemical (6M).Separate water layer and use methylene dichloride (50mL) instead to extract water layer.The organic layer that merges obtains 4-(2-ethoxyl methyl-1H-imidazo [4, the 5-c] quinoline-1-yl) butane-1-SULPHURYL CHLORIDE of 2.04g with dried over mgso and concentrating under reduced pressure, is yellow foam.

Section H

(689mg, (1.78g, 4.66mmol is in pyridine 1.0eq) (15mL) solution 1.2eq) to join 4-(2-ethoxyl methyl-1H-imidazo [4, the 5-c] quinoline-1-yl) butane-1-SULPHURYL CHLORIDE of stirring with the 4-anisidine.Reaction mixture is stirred 1 hour concentrating under reduced pressure then at ambient temperature.Resistates is dissolved in methylene dichloride (350mL), continuously water (2 * 100mL) and salt solution (100mL) washing, with dried over mgso and concentrating under reduced pressure, obtain the crude product of 1.90g, be red oil.This oily matter is by HPFC purifying (silica gel, carry out 5 times of column volumes with the chloroform that contains 0-20%CMA, carry out 7 times of column volume wash-outs with the chloroform that contains 20%CMA then), obtain N-(4-p-methoxy-phenyl) 4-(the 2-ethoxyl methyl-1H-imidazo [4 of 1.19g, 5-c] quinoline-1-yl) butane-1-sulphonamide, be brown solid.

Part I

With 3-chloroperoxybenzoic acid (622mg, 77%max 1.2eq) joins N-(4-p-methoxy-phenyl) 4-(2-ethoxyl methyl-1H-imidazo [4, the 5-c] quinoline-1-yl) butane-1-sulphonamide (986mg of stirring, 2.10mmol, in chloroform 1.0eq) (21mL) solution.After 45 minutes, TLC analyzes the demonstration oxidation and finishes.Adding dense ammonium hydroxide (2mL) and toluene sulfonyl chloride under vigorous stirring (943mg, 1.25eq).After 30 minutes, TLC analyzes the demonstration reaction and finishes.After 1 hour, reaction mixture is distributed between chloroform (200mL) and water (60mL).Water layer extracts with chloroform (50mL) is anti-.The organic layer that merges obtains the crude product of 1.38g with dried over mgso and concentrating under reduced pressure, is brown foam.This material grinds with chloroform subsequently by HPFC purifying (silica gel carries out 12 times of column volumes with the chloroform that contains 0-25%CMA, carries out 6 times of column volume wash-outs with the chloroform that contains 25%CMA then), obtains the white solid of 207mg.With this substance dissolves concentrating under reduced pressure then in the 9/1 methyl alcohol/chloroform (400mL) of heat, obtain N-(4-p-methoxy-phenyl) 4-(the 4-amino-2-ethoxyl methyl-1H-imidazo [4 of 130mg, 5-c] quinoline-1-yl) butane-1-sulphonamide, be brown powder, mp 229-230 ℃. ¹H NMR (300MHz, DMSO-d ₆): δ 9.48 (brs, 1H), 8.01 (d, J=7.9Hz, 1H), 7.61 (dd, J=1.0,8.3Hz, 1H), 7.45 (m, 1H), 7.25 (m, 1H), 7.10 (m, 2H), 6.85 (m, 2H), 6.61 (br s, 2H), 4.75 (s, 2H), 4.57 (t, J=6.8Hz, 2H), 3.70 (s, 3H), 3.52 (q, J=7.0Hz, 2H), 3.03 (m, 2H), 1.87 (m, 4H), 1.11 (t, J=7.0Hz, 3H); MS (APCI) m/z 484 (M+H) ⁺C ₂₄H ₂₉N ₅O ₄S, theoretical value: C, 59.61; H, 6.04; N, 14.48.Measured value: C, 59.43; H, 6.41; N, 14.31.

Embodiment 9

2-ethoxyl methyl-1-[4-(4-morpholine-4-alkylsulfonyl) butyl]-1H-imidazo [4,5-c] quinoline-4-amine

Part A

(0.54mL, (1.95g, 5.0mmol is in pyridine 1.0eq) (20mL) solution 1.2eq) to join 4-(2-ethoxyl methyl-1H-imidazo [4, the 5-c] quinoline-1-yl) butane-1-SULPHURYL CHLORIDE of stirring with morpholine.Reaction mixture stirred 1.5 hours at ambient temperature, then concentrating under reduced pressure.Resistates is dissolved in the methylene dichloride (300mL) and washs with 50% sodium bicarbonate aqueous solution.Water layer extracts with methylene dichloride (100mL) is anti-.The organic layer that merges obtains the crude product of 1.39g with dried over mgso and concentrating under reduced pressure, is brown oil.Oily matter is by HPFC purifying (silica gel; carry out 8 times of column volumes with the chloroform that contains 0-20%CMA; carry out 5 times of column volume wash-outs with the chloroform that contains 20%CMA then); obtain 2-ethoxyl methyl-1-[4-(4-morpholine-4-alkylsulfonyl) butyl of 1.05g]-1H-imidazo [4; 5-c] quinoline, be light yellow foam.

Part B

(711mg, 77%max 1.2eq) join in chloroform (24mL) solution of the material that derives from part A (1.0eq) of stirring with the 3-chloroperoxybenzoic acid.After 45 minutes, and adding dense ammonium hydroxide (2.4mL) and toluene sulfonyl chloride under vigorous stirring (573mg, 1.25eq).After 10 minutes, TLC analyzes the demonstration reaction and finishes.After 1 hour, with reaction mixture at chloroform (100mL) with comprise between the water (50mL) (pH of the aqueous solution～11) of 10% sodium hydroxide (3mL) and distribute.Organic layer obtains the crude product of 1.7g with dried over mgso and concentrating under reduced pressure, is brown foam.This material grinds with ethyl acetate subsequently by HPFC purifying (silica gel carries out 12 times of column volumes with the chloroform that contains 0-20%CMA, carries out 6 times of column volume wash-outs with the chloroform that contains 20%CMA then), obtains the white solid of 695mg.In chloroform (200mL), (～15mL) washing is with dried over mgso and concentrating under reduced pressure with 10% sodium hydroxide with this substance dissolves.Resistates and 10% sodium hydroxide grind, and by filtering separation, (2 * 4mL) wash water, and vacuum-drying, obtain the brown solid of 624mg.This material obtains the white solid of 410mg by HPFC purifying (silica gel carries out 5 times of column volumes with the chloroform that contains 10-20%CMA, carries out 7 times of column volume wash-outs with the chloroform that contains 20%CMA then).With this material and ethyl acetate (～7mL) grinding; pass through filtering separation; with ethyl acetate (2 * 2mL) rinsings and at 60 ℃ of vacuum [0.10 Torr; (13Pa)] it's weekend is past drying; obtain 2-ethoxyl methyl-1-[4-(4-morpholine-4-alkylsulfonyl) butyl of 365mg]-1H-imidazo [4; 5-c] quinoline-4-amine, be white powder, 206-208 ℃. ¹H NMR (300MHz, DMSO-d ₆): δ 8.08 (d, J=7.8Hz, 1H), 7.62 (dd, J=1.0,8.3Hz, 1H), 7.45 (m, 1H), 7.27 (m, 1H), 6.59 (br s, 2H), 4.78 (s, 2H), 4.63 (t, J=7.3Hz, 2H), 3.59 (m, 6H), 3.13 (m, 6H), 2.00 (m, 2H), 1.87 (m, 2H), 1.18 (t, J=7.0Hz, 3H); MS (APCI) m/z 448 (M+H) ⁺Ultimate analysis: C ₂₁H ₂₉N ₅O ₄S, theoretical value: C, 56.36; H, 6.53; N, 15.65.Measured value: C, 56.13; H, 6.62; N, 15.47.

Embodiment 10

N-methyl 4-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide

Part A

Methylamine hydrochloride (2.2eq) is joined 4-(2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-SULPHURYL CHLORIDE, and (2g, 5.23mmol is 1eq) and in the mixture of methylene dichloride (20mL).(2mL, 6M 2.2eq) and with the reaction mixture stirring spend the night to add wet chemical.Reaction mixture water (10mL) dilution.Separate organic layer, continuously water (2 * 10mL) and the salt water washing, with dried over mgso and concentrating under reduced pressure, obtain N-methyl 4-(2-ethoxyl methyl-1H-imidazo [4, the 5-c] quinoline-1-yl) butane-1-sulphonamide of 1.39g.

Part B

With the 3-chloroperoxybenzoic acid (1.08g, 65%, 1.1eq) repeatedly join in methylene dichloride (15mL) solution of the material that derives from part A on a small quantity.After 45 minutes, add dense ammonium hydroxide (5mL).(1.58g 1.1eq) and with reaction mixture stirred 2 hours repeatedly to add toluene sulfonyl chloride on a small quantity.Regulate pH to pH 8 by adding hydrochloric acid (6M).Reaction mixture filters to remove solid.The organic layer concentrating under reduced pressure obtains the crude product of 2g, is the dark oil thing.This material passes through chromatography purification.Toluene recrystallization then under heating the vacuum-drying of resistates from comprising gac, obtain N-methyl 4-(the 4-amino-2-ethoxyl methyl-1H-imidazo [4 of 0.18g, 5-c] quinoline-1-yl) butane-1-sulphonamide, be yellow particle, mp 170.0-172.0 ℃. ¹H NMR (300MHz, DMSO d6) δ 8.06 (d, J=7.6Hz, 1H), 7.61 (dd, J=8.2,0.9Hz, 1H), 7.45 (m, 1H), 7.27 (m, 1H), 6.89 (q, J=4.9Hz, 1H), 6.58 (s, 2H), 4.78 (s, 2H), 4.60 (t, J=7.5Hz, 2H), 3.57 (q, T=7.0Hz, 2H), 3.07 (t, J=7.5Hz, 2H), 2.56 (d, J=4.9Hz, 3H), 1.98 (m, 2H), 1.84 (m, 2H), 1.17 (t, J=7.0Hz, 3H); MS (APCI) m/z 392 (M+H) ⁺Ultimate analysis: C ₁₈H ₂₅N ₅O ₃S, theoretical value: C, 55.22; H, 6.44; N, 17.89.Measured value: C, 55.16; H, 6.56; N, 17.78.

Embodiment 11

N, N-dimethyl 4-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide

Part A

(0.65g, (1.4g, 3.6mmol is 1eq) and in the mixture of methylene dichloride (15mL) 2.2eq) to join 4-(2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-SULPHURYL CHLORIDE with dimethylamine hydrochloride.(2mL, 6M 2.2eq) and with the reaction mixture stirring spend the night to add wet chemical.Reaction mixture water (10mL) dilution.Separate organic layer, continuously water (2 * 10mL) and the salt water washing, with dried over mgso and concentrating under reduced pressure, obtain the N of 1.26g, N-dimethyl 4-(2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide.

Part B

With the 3-chloroperoxybenzoic acid (1.23g, 65%, 1.1.eq) repeatedly join in methylene dichloride (16mL) solution of the material that derives from part A on a small quantity.After 30 minutes, add other 3-chloroperoxybenzoic acid (0.1g) and reaction mixture stirred and spend the night.Add dense ammonium hydroxide (5mL).(4.9g 1.1eq) and with reaction mixture stirred 2 hours repeatedly to add toluene sulfonyl chloride on a small quantity.Reaction mixture water (100mL) and methylene dichloride (50mL) dilution.Separate organic layer and concentrating under reduced pressure, obtain the crude product of 2.6g, be brown oil.This material is by chromatography purification (silica gel is with the methylene dichloride wash-out that contains 5% methyl alcohol), and product obtains the solid of 0.3g further by HPFC purifying (silica gel is with 5% methanol/ethyl acetate wash-out).This material is dissolved in the methyl alcohol of heat then from the toluene recrystallization.The methyl alcohol vacuum is removed, obtain the N of 0.17g, N-dimethyl 4-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide is buff powder, mp 173.0-174.0 ℃. ¹H NMR (300MHz, DMSO d ₆) δ 8.07 (d, J=7.4Hz, 1H), 7.62 (dd, J=8.3,1.1Hz, 1H), 7.45 (m, 1H), 7.27 (m, 1H), 6.59 (s, 2H), 4.78 (s, 2H), 4.62 (t, J=7.5Hz, 2H), 3.57 (q, J=7.0Hz, 2H), 3.09 (t, J=7.5Hz, 2H), 2.74 (s, 6H), 1.99 (m, 2H), 1.86 (m, 2H), 1.17 (t, J=6.9Hz, 3H); MS (APCI) m/z 406 (M+H) ⁺Ultimate analysis: C ₁₉H ₂₇N ₅O ₃S, theoretical value: C, 56.28; H, 6.71; N, 17.27.Measured value: C, 55.90; H, 6.44; N, 17.17.

Embodiment 12

2-ethoxyl methyl-1-[4-(piperidines-1-alkylsulfonyl) butyl]-1H-imidazo [4,5-c] quinoline-4-amine

Part A

(0.71mL, (2.5g, 6.5mmol is 1eq) and in the mixture of methylene dichloride (25mL) 1.1eq) to join 4-(2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-SULPHURYL CHLORIDE with piperidines.(2mL, 6M 2.2eq) and with reaction mixture stirred 2 days to add wet chemical.Separate organic layer and concentrating under reduced pressure, obtain the crude product of 2.4g, be brown oil.Oily matter obtains 2-ethoxyl methyl-1-[4-(piperidines-1-alkylsulfonyl) butyl of 2g by HPFC purifying (silica gel is with the chloroform wash-out that contains 10%CMA)]-1H-imidazo [4,5-c] quinoline.

Part B

With the 3-chloroperoxybenzoic acid (1.35g, 65%, 1.1.eq) join in chloroform (20mL) solution of the material (1.0eq) that derives from part A.The reaction mixture stirring is analyzed the demonstration oxidation up to HPLC to be finished.Add dense ammonium hydroxide (6mL), form throw out.Under vigorous stirring, repeatedly add on a small quantity toluene sulfonyl chloride (1.05g, 1.2eq).The reaction mixture stirring is finished up to analyzing the demonstration reaction.Reaction mixture dilutes with methylene dichloride (50mL).Separate water layer and (3 * 30mL) extract with methylene dichloride with water layer.Organic layer water and the salt water washing sequentially that merges with dried over mgso and concentrating under reduced pressure, obtains the brown oil of 0.6g.Oily matter is by HPFC purifying (silica gel; with the chloroform that contains 10-18%CMA; amount to 1200mL; gradient elution) subsequently from 1; 2-ethylene dichloride recrystallization obtains 2-ethoxyl methyl-1-[4-(piperidines-1-alkylsulfonyl) butyl of 80mg]-1H-imidazo [4,5-c] quinoline-4-amine; be white powder, mp 185.0-188.0 ℃. ¹HNMR (300MHz, DMSO d ₆) δ 8.07 (d, J=7.7Hz, 1H), 7.61 (dd, J=8.3,1.1Hz, 1H), 7.45 (m, 1H), 7.26 (m, 1H), 6.61 (s, 2H), 4.78 (s, 2H), 4.62 (t, J=7.3Hz, 2H), 3.57 (q, J=7.0Hz, 2H), 3.08 (m, 6H), 1.98 (m, 2H), 1.84 (m, 2H), 1.48 (m, 6H), 1.17 (t, J=7.0Hz, 3H); MS (APCI) m/z 446 (M+H) ⁺Ultimate analysis: C ₂₂H ₃₁N ₅O ₃S, theoretical value: C, 59.30; H, 7.01; N, 15.72.Measured value: C, 59.05; H, 7.35; N, 15.62.

Embodiment 13

N-cyclohexyl 4-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide

Part A

(1.48g, (2.6g, 6.8mmol is 1eq) and in the mixture of methylene dichloride (25mL) 2.2eq) to join 4-(2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-SULPHURYL CHLORIDE with cyclo-hexylamine.(2mL, 6M 2.2eq) and with reaction mixture stirred 2 hours to add wet chemical.Reaction mixture water (10mL) and methylene dichloride (25mL) dilution.Separate organic layer, water (2 * 10mL) and the salt water washing continuously, with dried over mgso and concentrating under reduced pressure. resistates is by HPFC purifying (silica gel, with the chloroform wash-out that contains 2% methyl alcohol), obtain N-cyclohexyl 4-(2-ethoxyl methyl-1H-imidazo [4, the 5-c] quinoline-1-yl) butane-1-sulphonamide of 2g.

Part B

With the 3-chloroperoxybenzoic acid (2g, 65%, 1.1.eq) join in methylene dichloride (20mL) solution of the material (1.0eq) that derives from part A.Reaction mixture stirred 1 hour.Add dense ammonium hydroxide (6mL).(1.03g 1.2eq) and with reaction mixture stirred 4 hours repeatedly to add toluene sulfonyl chloride under vigorous stirring on a small quantity.Regulate pH to pH 8 by adding hydrochloric acid (6M).Reaction mixture is filtered to remove solid.The organic layer concentrating under reduced pressure obtains the crude product of 2.2g, is light brown oily thing.Oily matter is by HPFC purifying (silica gel, with the chloroform wash-out that contains 3%CMA) subsequently from ethyl alcohol recrystallization, obtain N-cyclohexyl 4-(4-amino-2-ethoxyl methyl-1H-imidazo [4, the 5-c] quinoline-1-yl) butane-1-sulphonamide of 0.88g, be buff powder, mp197.0-198.0 ℃. ¹H NMR (300MHz, DMSO d ₆) δ 8.04 (d, J=7.8Hz, 1H), 7.62 (dd, J=8.2,0.9Hz, 1H), 7.45 (dd, J=7.8,0.7, Hz, 1H), 7.26 (dd, J=8.0,1.0Hz, 1H), 7.03 (d, J=7.6Hz, 1H), 6.59 (s, 2H), 4.78 (s, 2H), 4.60 (t, J=7.4Hz, 2H), 3.56 (q, J=7.0Hz, 2H), 3.04 (t, J=7.5Hz, 3H), 1.98 (m, 2H), 1.79 (m, 4H), 1.63 (m, 2H), 1.50 (m, 1H), 1.17 (t, J=6.9Hz, 3H), 1.13 (m, 5H); MS (APCI) m/z 460 (M+H) ⁺Ultimate analysis: C ₂₃H ₃₃N ₅O ₃S, theoretical value: C, 60.11; H, 7.24; N, 15.24.Measured value: C, 59.83; H, 7.07; N, 15.06.

Embodiment 14

N-butyl 4-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide

Part A

(0.71mL, (2.5g, 6.5mmol is 1eq) and in the mixture of methylene dichloride (25mL) 1.1eq) to join 4-(2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-SULPHURYL CHLORIDE with butylamine.(2.0mL, 6M 2.2eq) and with the reaction mixture stirring spend the night to add wet chemical.Organic layer is dropped out and concentrating under reduced pressure from the salt decant.Resistates obtains N-butyl 4-(2-ethoxyl methyl-1H-imidazo [4, the 5-c] quinoline-1-yl) butane-1-sulphonamide of 2g by HPFC purifying (silica gel is with the chloroform wash-out that contains 2% methyl alcohol).

Part B

With the 3-chloroperoxybenzoic acid (1.39g, 65%, 1.1.eq) join in chloroform (20mL) solution of the material (1.0eq) that derives from part A.The reaction mixture stirring added other 3-chloroperoxybenzoic acid (0.1eq) in 2 hours then and the reaction mixture stirring is spent the night.Add dense ammonium hydroxide (6mL), form throw out.Under vigorous stirring, repeatedly add on a small quantity toluene sulfonyl chloride (1.14g, 1.2eq).Reaction mixture stirred 4 hours, used the dilution of methylene dichloride (60mL) and water (20mL) then.

Organic layer is sequentially used 10% sodium hydroxide and salt water washing, with dried over mgso and concentrating under reduced pressure, obtains the crude product of 1.8g, is foam.Foam obtains light yellow solid by HPFC purifying (silica gel is with the chloroform wash-out that contains 14%CMA).This material obtains N-butyl 4-(4-amino-2-ethoxyl methyl-1H-imidazo [4, the 5-c] quinoline-1-yl) butane-1-sulphonamide of 0.6g from ethyl alcohol recrystallization and 50 ℃ of vacuum-dryings 4 hours, is white powder, mp 148.0-149.0 ℃. ¹HNMR (300MHz, DMSO d ₆) δ 8.05 (d, J=8.0Hz, 1H), 7.61 (dd, J=8.3,1.0Hz, 1H), 7.45 (m, 1H), 7.27 (m, 1H), 7.02 (t, J=5.9Hz, 1H), 6.61 (brs, 2H), 4.78 (s, 2H), 4.60 (t, J=7.5Hz, 2H), 3.56 (q, J=7.0Hz, 2H), 3.05 (t, J=7.5Hz, 2H), 2.88 (q, J=6.5Hz, 2H), 1.97 (m, 2H), 1.84 (m, 2H), 1.40 (m, 2H), 1.29 (m, 2H), 1.17 (t, J=7.0Hz, 3H), 0.85 (t, J=7.2Hz, 3H); MS (APCI) m/z 434 (M+H) ⁺Ultimate analysis: C ₂₁H ₃₁N ₅O ₃S, theoretical value: C, 58.17; H, 7.21; N, 16.15.Measured value: C, 58.23; H, 7.28; N, 16.16.

Embodiment 15

N, N-dimethyl 3-[2-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) oxyethyl group] propane-1-sulphonamide

Part A

With triethylamine (46.8mL, 3.5eq) and 4-chloro-3-nitroquinoline ((29.9g is 2.0eq) and in the mixture of methylene dichloride (320mL) 1.0eq) sequentially to join 3-(2-amino ethoxy) propyl alcohol of stirring for 20.0g, 95.9mmol.Reaction mixture was stirred 1 hour, and at this moment TLC analyzes and shows that all starting raw materials exhaust.Reaction mixture washs with methylene dichloride (250mL) dilution and water (300mL).Organic layer obtains the crude product of 32g with dried over mgso and concentrating under reduced pressure, is yellow oil.Oily matter is dissolved in the short column that also passes through silica gel (300g) in the chloroform to be filtered, sequentially use methyl alcohol/chloroform (2L) wash-out of chloroform (100mL) and 2/98, obtain 3-{2-[(3-nitroquinoline-4-yl of 25.78g) amino] oxyethyl group } propyl alcohol, be yellow solid.

Part B

Thionyl chloride (3.43mL, 1.1.eq)) is added drop-wise to 3-{2-[(3-nitroquinoline-4-yl) amino] oxyethyl group } (12.46g, 42.77mmol is 1.0eq) in the mixture in methylene dichloride (143mL) for propyl alcohol.Obtain solution and it was stirred 20 hours.Reaction mixture is used the (～250mL) cancellation of 50% sodium bicarbonate then with methylene dichloride (250mL) dilution.Organic layer obtains N-[2-(the 3-chlorine propoxy-) ethyl of 9.39g with dried over mgso and concentrating under reduced pressure]-3-nitroquinoline-4-amine, be yellow oil, it slowly solidifies.

Portion C

Under agitation acetonitrile (50mL) is joined in the suspension of material (1.0eq) in warm ethanol (100mL) that derives from part B, obtain solution.Add V-Brite B (26.30g, 85%, water 5.0eq) (100mL) solution.Observe heat release (37 ℃) and form white depositions.The reaction mixture vigorous stirring was filtered in 30 minutes then.(2 * 30mL) wash filter cake with acetonitrile.Filtrate decompression is concentrated.With resistates in methylene dichloride (350mL) and saturated sodium bicarbonate aqueous solution (200mL), the pH of the aqueous solution～7) between distribute.(4 * 75mL) instead extract water layer with methylene dichloride.The organic layer that merges obtains the N of 7.28g with dried over mgso and concentrating under reduced pressure ⁴-[2-(3-chlorine propoxy-) ethyl] quinoline-3, the 4-diamines is yellow oil.

Part D

(2.93mL 1.1eq) is added drop-wise in methylene dichloride (130mL) solution of the material that derives from portion C (1.0eq) of stirring with the oxyethyl group Acetyl Chloride 98Min..With the reaction mixture concentrating under reduced pressure, obtain N-{4-[2-(3-chlorine propoxy-) ethylamino after 1 hour] quinoline-3-yl }-2-oxyethyl group ethanamide, be yellow foam.

Part E

(19.5mL, 2M 1.5eq) join in ethanol (130mL) solution of the material that derives from part D of stirring with sodium hydroxide.Make reaction mixture rise again 50 ℃ and stirred 1.5 hours, at this moment TLC analyzes and shows that reaction finishes.Reaction mixture is cooled to envrionment temperature concentrating under reduced pressure then.Resistates distributes between methylene dichloride (250mL) and water (75mL).Water layer extracts with methylene dichloride (50mL) is anti-.The organic layer that merges with dried over mgso and concentrating under reduced pressure, obtains the crude product of 8.40g with salt solution (50mL) washing, is oily matter.Oily matter is by HPFC purifying (silica gel, carry out 5 times of column volumes with the chloroform that contains 0-20%CMA, carry out 4 times of column volume wash-outs with the chloroform that contains 20%CMA then), obtain 1-[2-(the 3-chlorine propoxy-) ethyl of 7.64g]-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline, be yellow oil.

Part F

With thioacetic acid potassium (1.01g 1.1eq) joins 1-[2-(the 3-chlorine propoxy-) ethyl of stirring]-(2.80g, 8.05mmol is in DMF 1.0eq) (16mL) solution for 2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline.The suspension vigorous stirring that obtains is spent the night.Add other thioacetic acid potassium (0.1eq) and reaction mixture was stirred other 2 hours.With the reaction mixture concentrating under reduced pressure.Resistates dilutes with methylene dichloride (250mL) and water (75mL) and salt solution (100mL) washing sequentially.Organic layer obtains S-{3-[2-(2-ethoxyl methyl-1H-imidazo [4, the 5-c] quinoline-1-yl) oxyethyl group of 3.07g with dried over mgso and concentrating under reduced pressure } the propyl dithiocarbamate acetic ester, be light yellow solid.

Part G

With methyl alcohol (40mL) solution of the material that derives from part F (1.0eq) that stirs with the nitrogen several minutes that outgases.Add sodium methylate (4.0mL, 25 weight %, in methyl alcohol, 2.2eq) and the degassing carry out other several minutes.1 hour afterwards with the reaction mixture concentrating under reduced pressure.Resistates dilutes with methylene dichloride (200mL) and water (100mL) and regulates pH to pH～7 with 2M hydrochloric acid.Separate water layer and use methylene dichloride (50mL) instead to extract water layer.The organic layer that merges obtains the crude product of 2.80g with dried over mgso and concentrating under reduced pressure, is yellow oil.Oily matter is by HPFC purifying (silica gel, carry out 5 times of column volumes with the chloroform that contains 0-20%CMA, carry out 5 times of column volume wash-outs with the chloroform that contains 20%CMA then), obtain 3-[2-(the 2-ethoxyl methyl-1H-imidazo [4 of 2.39g, 5-c] quinoline-1-yl) oxyethyl group] propane-1-mercaptan, be yellow oil.

Section H

(953mg, water 1.3eq) (1.5mL) drips of solution is added to the hydrochloric acid of the material that derives from part G (1.0eq) of cooling (0 ℃), and (17mL is 7M) in the solution with sodium chlorate in～30 seconds time.Reaction mixture is stirred 90 minutes then with the nitrogen several minutes that outgases.Add methylene dichloride (60mL) drip subsequently wet chemical (10mL, 6M).With the reaction mixture envrionment temperature of rising again, water layer pH～2.Reaction mixture is poured in the mixture of methylene dichloride (150mL) and water (60mL) and and regulates pH to pH 4 with 6M salt of wormwood.Separate water layer and use methylene dichloride (50mL) instead to extract water layer.The organic layer that merges obtains 3-[2-(2-ethoxyl methyl-1H-imidazo [4, the 5-c] quinoline-1-yl) oxyethyl group of 2.25g with dried over mgso and concentrating under reduced pressure] propane-1-SULPHURYL CHLORIDE, be light yellow oil.

Part I

(935mg 2.1eq) joins in methylene dichloride (27mL) solution of the material that derives from section H (1.0eq) of stirring with dimethylamine hydrochloride.(2.0mL, 6M 2.2eq), form white depositions to add wet chemical.The TLC analysis is presented at 10 minutes internal reactions and finishes.After 1 hour, reaction mixture is washed with methylene dichloride (125mL) dilution and water (40mL).Organic layer obtains the crude product of 2.03g with dried over mgso and concentrating under reduced pressure, is yellow oil.Oily matter is by HPFC purifying (silica gel, carry out 9 times of column volumes with the chloroform that contains 0-20%CMA, carry out 4 times of column volume wash-outs with the chloroform that contains 20%CMA then), obtain the N of 1.46g, N-dimethyl 3-[2-(2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) oxyethyl group] propane-1-sulphonamide, be yellow oil.

Part J

With the 3-chloroperoxybenzoic acid (1.02g, 70%, 1.2eq) join in chloroform (17mL) solution of the material that derives from part I of stirring.After 1 hour, under vigorous stirring, sequentially add dense ammonium hydroxide (3mL) and toluene sulfonyl chloride (822mg, 1.25eq).After 10 minutes, TLC analyzes and shows that reaction is near finishing.After 1 hour, with reaction mixture at chloroform (100mL) with comprise between the water (50mL) (aqueous solution, pH～11) of 10% sodium hydroxide (3mL) and distribute.Organic layer obtains the crude product of 1.7g with dried over mgso and concentrating under reduced pressure, is brown foam.Foam obtains the light brown foam of 0.847g by HPFC purifying (silica gel carries out 12 times of column volumes with the chloroform that contains 0-20%CMA, carries out 6 times of column volume wash-outs with the chloroform that contains 20%CMA then).With foam hexane (～15-20mL) in heating begin to melt up to foam.The methylene dichloride that adds equivalent under eddy current is up to forming solid.Mixture is ground up to all oily mater curing.Solid by filtration is separated, (2 * 3mL) rinsings and of hexanes/ch with 3/1 40 ℃ of vacuum-dryings [0.1Torr (13Pa.)] 3 days, obtain the N of 614mg, N-dimethyl 3-[2-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) oxyethyl group] propane-1-sulphonamide, be white powder, mp 61-64 ℃.1H-NMR (300MHz, DMSO-d ₆): δ 8.13 (d, J=7.6Hz, 1H), 7.61 (dd, J=1.0,8.3Hz, 1H), 7.44 (m, 1H), 7.24 (m, 1H), 6.57 (br s, 2H), 4.83 (t, J=5.3Hz, 2H), 4.79 (s, 2H), 3.87 (t, J=5.4Hz, 2H), 3.56 (q, J=7.0Hz, 2H), 3.42 (t, J=6.1Hz, 2H), 2.79 (m, 2H), 2.63 (s, 6H), 1.75 (m, 2H), 1.17 (t, J=7.0Hz, 3H); MS (APCI) m/z 436 (M+H) ⁺Ultimate analysis: C ₂₀H ₂₉N ₅O ₄S, theoretical value: C, 55.15; H, 6.71; N, 16.08.Measured value: C, 54.94; H, 7.00; N, 16.00.

Embodiment 16

N-methyl 5-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) pentane-1-sulphonamide

Part A

(26.68g 1.1eq) joins 4-chloro-3-nitroquinoline (50g, 240mmol, 1.0eq) the suspension matter in methylene dichloride (500mL), all solid dissolvings with triethylamine.Dropwise 5 in 30 minutes-amino amylalcohol (27.2g, methylene dichloride 1.1eq) (100mL) solution.Reaction mixture is stirred the volume to～200mL of concentrating under reduced pressure then that spends the night.Add frozen water and mixture was ground about one hour.Add hydrochloric acid (10%) with pH is reduced to 10～7, form throw out.With mixture stir about 1 hour.Solid by filtration is separated and dry air, obtains 5-[(3-nitroquinoline-4-yl of 59g) amino] amylalcohol.

Part B

Under agitation with thionyl chloride (20mL, methylene dichloride 1.1eq) (50mL) drips of solution is added to the 5-[(3-nitroquinoline-4-yl of cooling (0 ℃)) amino] (50.4g, 183mmol is 1.0eq) in the suspension in methylene dichloride (300mL) for amylalcohol.Reaction mixture was stirred 3 hours, filter then to remove solid.Regulate the pH of filtrate to 7-8 with 5% aqueous sodium carbonate.Separatory, (6 * 20mL) instead extract water layer with methylene dichloride.Organic layer water and the salt water washing sequentially that merges with dried over mgso and concentrating under reduced pressure, obtains N-(5-chlorine amyl group)-3-nitroquinoline-4-amine of 47.4g.

Portion C

The mixture hydrogenation on the Parr device that derives from material, catalyzer (5% carbon carries platinum) and the acetonitrile (1.5L) of part B is analyzed the demonstration reaction up to TLC to be finished.Reaction mixture is filtered to remove catalyzer and filtrate decompression is concentrated, obtain the N of 39.8g ⁴-(5-chlorine amyl group) quinoline-3, the 4-diamines is yellow brown oil.

Part D

(21.66g 1.1eq) is added drop-wise in methylene dichloride (400mL) solution of the material that derives from portion C (1.0eq) of cooling (0 ℃) with the oxyethyl group Acetyl Chloride 98Min. in 15 minutes.Make the reaction mixture envrionment temperature concentrating under reduced pressure then that spends the night of rising again, obtain N-[4-(the 5-chlorine amyl group) quinolylamine-3-yl of 51.7g]-2-oxyethyl group ethanamide.

Part E

(82mL 2M) is heated to 60 ℃ with deriving from the ethanolic soln of material (1.0eq) of part D and sodium hydroxide.After 4 hours, HPLC analyzes the demonstration reaction and finishes, with the reaction mixture concentrating under reduced pressure.Resistates and methylene dichloride (200mL) merging are filtered then to remove solid.Filtrate decompression is concentrated, obtain 1-(5-chlorine amyl group)-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline of 45.1g, be dark oily matter.

Part F

With derive from part E material (1.0eq), thioacetic acid potassium (18.2g, 1.1eq) and the mixture of DMF (100mL) stir in envrionment temperature and spend the night.Reaction mixture is distributed between methylene dichloride (300mL) and cold water (100mL).(8 * 100mL) washings of organic layer water.The water layer that merges extracts with methylene dichloride (50mL) is anti-.The organic layer salt water washing that merges is with dried over mgso and concentrating under reduced pressure.Resistates obtains S-[5-(2-ethoxyl methyl-1H-imidazo [4, the 5-c] quinoline-1-yl) amyl group of 50g by silica gel short column wash-out purifying] thioacetate, be brown oil.

Part G

With S-[5-(2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) amyl group] (methyl alcohol 1.0eq) (50mL) solution outgased about 20 minutes with nitrogen thioacetate for 6.4g, 17.2mmol.(4.1g, 25 weight % in methyl alcohol, 1.1eq) dilute with methyl alcohol (20mL) and similarly outgas with sodium methylate.Two kinds of solution are merged and stirred 1 hour, at this moment HPLC analyzes and shows that all starting raw materials exhaust.With the reaction mixture concentrating under reduced pressure.Resistates dilutes with methylene dichloride (50mL) and water (30mL) and regulates pH to pH 8 with 6M hydrochloric acid.Separate water layer and use methylene dichloride (20mL) instead to extract water layer.The organic layer salt water washing that merges with dried over mgso and concentrating under reduced pressure, obtains 5-[2-(2-ethoxyl methyl-1H-imidazo [4, the 5-c] quinoline-1-yl) oxyethyl group of 5.9g] pentane-1-mercaptan, be yellow-green colour oily matter.

Section H

With sodium chlorate (1.67g, water 1.3eq) (3mL) drips of solution is added to refrigerative 5-[2-(2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) oxyethyl group] ((50mL is 6N) in the solution for hydrochloric acid 1.0eq) for 4g, 12mmol for pentane-1-mercaptan.After about 1 hour, reaction mixture is added salt of wormwood to regulate the aqueous solution to pH 6 then with methylene dichloride (120ml) dilution.With the organic layer concentrating under reduced pressure, obtain 5-[2-(2-ethoxyl methyl-1H-imidazo [4, the 5-c] quinoline-1-yl) oxyethyl group of 3.5g] pentane-1-SULPHURYL CHLORIDE.

Part I

With derive from section H material (1eq), methylamine hydrochloride (1.5g, 2.2.eq), salt of wormwood (1.53g, 2.2eq) and the mixture of methylene dichloride stir and spend the night.Add other methylamine hydrochloride (1eq) and salt of wormwood (1eq) and reaction mixture stirred and spend the night.Reaction mixture and the mixture that derives from another time operation are merged the salt that exists with dissolving with sufficient water dilution then.With the organic layer concentrating under reduced pressure, obtain N-methyl 5-(2-ethoxyl methyl-1H-imidazo [4, the 5-c] quinoline-1-yl) pentane-1-sulphonamide of 3.65g, be oily matter.

Part J

With the 3-chloroperoxybenzoic acid (2.61g, 65%, 1.1eq) repeatedly join on a small quantity in methylene dichloride (20mL) solution of the material that derives from part I (1eq) of stirring.After 2 hours, add other 3-chloroperoxybenzoic acid (0.6eq) and reaction mixture was stirred 45 minutes.Reaction mixture water (15mL) dilution.Water layer extracts with methylene dichloride (5mL) is anti-.The organic layer salt water washing that merges is with dried over mgso concentrating under reduced pressure then.(5mL 18M) joins in the resistates with ammonium hydroxide.(2.04g 1.2eq) and with the reaction mixture stirring spends the night repeatedly to add toluene sulfonyl chloride on a small quantity.Reaction mixture dilutes with methylene dichloride (100mL).Water layer extracts with methylene dichloride (20mL) is anti-.Dried over mgso is used in organic layer water and the salt water washing sequentially that merges, and filters concentrating under reduced pressure then, obtains brown solid.Solid, spends the night with toluene rinsing and vacuum-drying by filtering separation from the toluene recrystallization, obtain N-methyl 5-(the 4-amino-2-ethoxyl methyl-1H-imidazo [4 of 1.7g, 5-c] quinoline-1-yl) pentane-1-sulphonamide, be yellow particle, mp175.0-179.0 ℃. ¹H NMR (300MHz, DMSO d ₆) δ 8.02 (d, J=8.0Hz, 1H), 7.62 (dd, J=8.3,0.7Hz, 1H), 7.45 (t, J=7.5Hz, 1H), 7.28 (m, 1H), 6.85 (q, J=4.9Hz, 1H), 6.60 (s, 2H), 4.78 (s, 2H), 4.56 (t, J=7.5Hz, 2H), 3.56 (q, J=6.9Hz, 2H), 3.01 (t, J=7.5Hz, 2H), 2.54 (d, J=4.8Hz, 3H), 1.89 (m, 2H), 1.70 (m, 2H), 1.58 (m, 2H), 1.16 (t, J=6.9Hz, 3H); MS (APCI) m/z 406 (M+H) ⁺Ultimate analysis: C ₁₉H ₂₇N ₅O ₃S, theoretical value: C, 56.28; H, 6.71; N, 17.27.Measured value: C, 55.97; H, 6.78; N, 17.10.

Embodiment 17

N, N-dimethyl 5-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) pentane-1-sulphonamide

Part A

With dimethylamine hydrochloride (1.61g, 2.2eq) and salt of wormwood (1.36g, 2.2eq) water (1mL) solution sequentially join 5-[2-(2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) oxyethyl group] pentane-1-SULPHURYL CHLORIDE (3.5g, 8.9mmol, in methylene dichloride 1eq) (60mL) solution.Reaction mixture is stirred water (10mL) dilution then of spending the night.Organic layer washes concentrating under reduced pressure then with water, obtains the N of 3.6g, N-dimethyl 5-(2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) pentane-1-sulphonamide.

Part B

With the 3-chloroperoxybenzoic acid (2.38g, 65%, 1.1eq) repeatedly join on a small quantity in methylene dichloride (20mL) solution of the material that derives from part A (1eq) of stirring.After 3 hours, reaction mixture water (15mL) dilution.Water layer extracts with methylene dichloride (5mL) is anti-.The organic layer salt water washing that merges is with dried over mgso concentrating under reduced pressure then.(5mL 18M) joins in the resistates with ammonium hydroxide.(1.86g 1.2eq) and with the reaction mixture stirring spends the night repeatedly to add toluene sulfonyl chloride on a small quantity.Reaction mixture dilutes with methylene dichloride (100mL).Water layer extracts with methylene dichloride (20mL) is anti-.With organic layer water and the salt water washing sequentially that merges, use dried over mgso, filter, concentrating under reduced pressure obtains brown solid then.Solid by filtering separation, is used the toluene rinsing from the toluene recrystallization, and vacuum-drying is spent the night, and obtains the N of 1.7g, N-dimethyl 5-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) pentane-1-sulphonamide, be white powder, mp 138.0-142.0 ℃. ¹H NMR (300MHz, CDCl ₃) δ 7.93 (dd, J=8.3,0.7Hz, 1H), 7.82 (dd, J=8.2,0.7Hz, 1H), 7.53 (ddd, J=8.3,7.2,1.2Hz, 1H), 7.35 (m, 1H), 5.38 (s, 2H), 4.80 (s, 2H), 4.59 (t, J=7.8Hz, 2H), 3.62 (q, J=7.0Hz, 2H), 2.90 (t, J=7.5Hz, 2H), 2.85 (s, 6H), 2.04 (m, 2H), 1.91 (m, 2H), 1.67 (m, 2H), 1.25 (s, J=6.9Hz, 3H); MS (APCI) m/z420 (M+H) ⁺Ultimate analysis: C ₂₀H ₂₉N ₅O ₃S, theoretical value: C, 57.26; H, 6.97; N, 16.69.Measured value: C, 57.10; H, 7.10; N, 16.58.

Embodiment 18

N-methyl 4-(4-amino-2-ethoxyl methyl-6,7,8,9-tetrahydrochysene-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide

With N-methyl 4-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) (1.01g, the platinum oxide (IV) of (2mL) solution of trifluoroacetic acid 2.5mmo1) and catalytic amount merge and finish up to showing to react by the HPLC/ mass spectroscopy in the hydrogenation of Parr device butane-1-sulphonamide.Reaction mixture is passed through CELITE filtration adjuvant filtering layer.Filter cake concentrates with new trifluoroacetic acid rinsing and with filtrate decompression, obtains the crude product of 0.8g, is dark oily matter.Oily matter is suspended in the hydrochloric acid (5mL) and stir about 1 hour.Be adjusted to about pH 7 with 10% sodium hydroxide.The solid by filtration that obtains is separated, dry under about 78 ℃ of following high vacuum then from ethyl alcohol recrystallization, obtain N-methyl 4-(the 4-amino-2-ethoxyl methyl-6 of 0.4g, 7,8,9-tetrahydrochysene-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide, mp 188-192 ℃.Ultimate analysis: C ₁₈H ₂₉N ₅O ₃S, theoretical value: C, 54.66; H, 7.39; N, 17.71.Measured value: C, 54.42; H, 7.39; N, 17.52.

Embodiment 19

N, N-dimethyl 4-(4-amino-2-ethoxyl methyl-6,7,8,9-tetrahydrochysene-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide

With N, N-dimethyl 4-(4-amino-2-ethoxyl methyl-1h-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide (1.25g, 3.0mmol), trifluoroacetic acid (10mL) and the hydrogenation on the Parr device of platinum oxide (IV) mixture (1.22g), up to showing that by the LC/ mass spectroscopy reaction finishes.Reaction mixture is passed through CELITE filtration adjuvant filtering layer.Filter cake obtains crude product with new trifluoroacetic acid (2mL) and chloroform (20mL) rinsing and filtrate decompression is concentrated, is oily matter.Oily matter is dissolved in the concentrated hydrochloric acid (5mL) and stirs and spend the night.Solution with 6M salt of wormwood (6mL) neutralization, with methylene dichloride (25mL) dilution, is adjusted to pH 13 stir about 2 hours then with 10% sodium hydroxide.Separate organic layer and concentrating under reduced pressure.Resistates (0.7g) obtains the white solid of 0.6g by chromatography purification (silica gel carries out 10.6 times of column volume gradient elutions with the chloroform that contains 13%CMA to the chloroform that contains 28%CMA).White solid is from recrystallizing methanol, and is dry under high vacuum then by filtering separation, obtains the N of 0.4g, N-dimethyl 4-(4-amino-2-ethoxyl methyl-6,7,8,9-tetrahydrochysene-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide, be the white needles thing, mp 165-167 ℃.Ultimate analysis: C ₁₉H ₃₁N ₅O ₃S, theoretical value: C, 55.72; H, 7.63; N, 17.10.Measured value: C, 55.84; H, 7.54; N, 17.19.

Embodiment 20

N-(4-methoxy-benzyl) 4-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide

Use 4-methoxy-benzyl amine to replace butylamine to repeat the general method of embodiment 14, obtain N-(4-methoxy-benzyl) 4-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide, 101 ℃ of mp.Ultimate analysis: C ₂₅H ₃₁N ₅O ₄S0.59H ₂O.Theoretical value: C, 59.08; H, 6.38; N, 13.78; Measured value: C, 59.21; H, 6.74; N, 13.59.

Embodiment 21

4-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide

With N-(4-methoxy-benzyl) 4-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) trifluoroacetic acid (5mL) solution of butane-1-sulphonamide (0.81g) stirs in envrionment temperature, up to showing that by the LC/ mass spectroscopy all starting raw materials exhaust.The reaction mixture concentrating under reduced pressure is placed under the high vacuum then.Resistates is suspended in the concentrated hydrochloric acid (5mL) and stir about 1 hour.The solid by filtration that obtains is separated,, pass through filtering separation from recrystallizing methanol, then 78 ℃ of following high vacuum dry, obtain 4-(4-amino-2-ethoxyl methyl-1H-imidazo [4, the 5-c] quinoline-1-yl) butane-1-sulphonamide of 0.28g, mp 155-158 ℃.Ultimate analysis: C ₁₇H ₂₃N ₅O ₃S, theoretical value: C, 54.09; H, 6.14; N, 18.55 measured values: C, 53.86; H, 6.13; N, 18.24.

Embodiment 22

N-(4-methoxy-benzyl) 5-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) pentane-1-sulphonamide

Use 4-methoxy-benzyl amine to replace methylamine to repeat the part I of embodiment 16 and the general method of J, obtain N-(4-methoxy-benzyl) 5-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) pentane-1-sulphonamide, mp 177-178 ℃.Ultimate analysis: C ₂₆H ₃₃N ₅O ₄S, theoretical value: C, 61.04; H, 6.50; N, 13.69.Measured value: C, 61.07; H, 6.74; N, 13.77.

Embodiment 23

5-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) pentane-1-sulphonamide

With the trifluoroacetic acid of N-(4-methoxy-benzyl) 5-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) pentane-1-sulphonamide (2.3g) (～20g) solution stirring is spent the night.With its part (～8mL) carry out concentrating under reduced pressure.Resistates distributes between 6M hydrochloric acid (9mL) and methylene dichloride (30mL).Water layer is cooled off in ice bath and under agitation adds 10% sodium hydroxide to pH13.The mixture stir about was regulated pH to 7 in 1 hour then.The throw out that obtains is passed through filtering separation,, pass through filtering separation from recrystallizing methanol, then 78 ℃ of high vacuum dry, obtain 5-(4-amino-2-ethoxyl methyl-1H-imidazo [4, the 5-c] quinoline-1-yl) pentane-1-sulphonamide of 0.5g, mp 176-178 ℃.Ultimate analysis: C ₁₈H ₂₅N ₅O ₃S, theoretical value: C, 55.22; H, 6.44; N, 17.89 measured values: C, 55.06; H, 6.42; N, 17.84.

Embodiment 24

4-(4-amino-2-ethoxyl methyl-6,7,8,9-tetrahydrochysene-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide

The trifluoroacetic acid solution of N-(4-methoxy-benzyl) 4-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide (0.6g) is stirred up to showing that by the LC/ mass spectroscopy all starting raw materials exhaust in envrionment temperature.Solution and platinum oxide (IV) are merged and hydrogenation on the Parr device, finish up to showing to react by the LC/ mass spectroscopy.Reaction mixture is passed through CELITE filtration adjuvant filtering layer.Filter cake concentrates with new trifluoroacetic acid rinsing and with filtrate decompression, obtains the trifluoroacetate of product, is oily matter.Use the general method of embodiment 23 that this material is converted into free alkali, sequentially from methyl alcohol recrystallization from water then, then 91 ℃ of following high vacuum dry, obtain 4-(4-amino-2-ethoxyl methyl-6,7,8,9-tetrahydrochysene-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide, mp 224-227 ℃.Ultimate analysis: C ₁₇H ₂₇N ₅O ₃S, theoretical value: C, 53.52; H, 7.13; N, 18.36 measured values: C, 53.36; H, 7.24; N, 18.06.

Embodiment 25

N, N-dimethyl 3-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl)-2,2-dimethylpropane-1-sulphonamide

Part A

(17.5mL, (20.14g, 96.5mmol is 1.0eq) in the suspension in methylene dichloride (300mL) 1.3eq) to be added drop-wise to 4-chloro-3-nitroquinoline with triethylamine.Add 3-amino-2, (10.96g 1.1eq), stirs 45 minutes concentrating under reduced pressure then with reaction mixture to 2-dimethyl propyl alcohol.Resistates and water (300mL) were pulled an oar 1 hour, by filtering separation, water (2 * 60mL) rinsings, dry under high vacuum then, obtain 2 of 20.7g, 2-dimethyl-3-[(3-nitroquinoline-4-yl) amino] propyl alcohol, be yellow solid.

Part B

With 2,2-dimethyl-3-[(3-nitroquinoline-4-yl) amino] propyl alcohol (1.45g) and 10% carbon carries the hydrogenation on the Parr device of the suspension of palladium in ethanol and analyzes up to TLC and show that reaction finishes.Reaction mixture is filtered by CELITE filtration adjuvant layer.Filter cake ethanol (3 * 10mL) rinsings.Filtrate decompression is concentrated.Be suspended in the toluene (150mL) resistates and concentrating under reduced pressure, obtain 3-[(3-quinolylamine-4-yl) amino]-2,2-dimethyl propyl alcohol.

Portion C

(564 μ L 1.05eq) are added drop-wise in pyridine (25mL) solution of the material that derives from part B (1.0eq) of cooling (0 ℃) with the oxyethyl group Acetyl Chloride 98Min..Progress by TLC monitoring reaction adds other oxyethyl group Acetyl Chloride 98Min. (0.6eq) and finishes with driving a reaction.The reaction mixture envrionment temperature of rising again is spent the night.Reaction mixture was heated 9 hours at 110 ℃ 80 ℃ of heating in 2 hours then.Reaction mixture is cooled to envrionment temperature concentrating under reduced pressure then.Resistates merges then by HPFC purifying (silica gel with the material that derives from another time operation, carry out 1L with the chloroform that contains 0-40% acetone (0.75% ethanol is stable), carry out the 1.8L wash-out with the chloroform that contains 40-60% acetone then), obtain 3-(the 2-ethoxyl methyl-1H-imidazo [4 of 1.66g, 5-c] quinoline-1-yl)-2,2-dimethyl propyl alcohol is colourless oily semisolid.

Part D

With toluene sulfonyl chloride (1.18g, 1.2eq) and 4-dimethylaminopyridine (13mg 0.02eq) sequentially joins 3-(2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl)-2, (1.61g, 5.14mmol is in pyridine 1.0eq) (6mL) solution for 2-dimethyl propyl alcohol.Reaction mixture was stirred 20 hours at ambient temperature, and (1 * 75mL) extracts to use ethyl acetate then with salt solution (75mL) cancellation.The extracting solution dried over mgso is filtered, then concentrating under reduced pressure.Resistates is dissolved in the methylene dichloride (20mL), with heptane (125mL) dilution, concentrating under reduced pressure, dry under high vacuum then, obtain the 3-(2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl)-2 of 2.12g, 2-dimethyl propyl p-toluenesulfonic esters is light brown oily thing.

Part E

(1.23g 5.0eq) joins in ethanol (22mL) solution of the material (1.0eq) that derives from part D with the sodium sulfhydrate hydrate.Be reflected at 75 ℃ of heating 30 hours, make it be cooled to envrionment temperature then and spend weekend.TLC analyzes the demonstration reaction and does not finish.Add other sodium sulfhydrate hydrate (3eq) and reaction mixture was heated other 48 hours.With the reaction mixture concentrating under reduced pressure.Resistates is suspended in and uses methylene dichloride (3 * 100mL) extractions in the water (100mL) then.The extracting solution that merges obtains the white foam of 1.23g with dried over mgso concentrating under reduced pressure then.This material is by HPFC purifying (silica gel, the chloroform that carries out 2 times of column volumes, the chloroform that contains 10-25%CMA carries out 7 times of column volumes, the chloroform that contains 25-35%CMA carries out 1.5 times of column volumes and contain 35%CMA with the chloroform that contains 0-10%CMA carries out 5 times of column volume wash-outs), obtain 3-(the 2-ethoxyl methyl-1H-imidazo [4 of 0.87g, 5-c] quinoline-1-yl)-2,2-dimethylpropane-1-mercaptan is clarifying oily matter.

Part F

Use the general method of embodiment 8 part G, with 3-(2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl)-2,2-dimethylpropane-1-mercaptan (0.75g) oxidation, obtain 3-(the 2-ethoxyl methyl-1H-imidazo [4 of 0.67g, 5-c] quinoline-1-yl)-2,2-dimethylpropane-1-SULPHURYL CHLORIDE is the yellow foam of oily.

Part G

Use the general method of embodiment 11 part A, will derive from material and the dimethylamine hydrochloride reaction of part F.Crude product is by HPFC purifying (silica gel, carry out 8 times of column volumes with the chloroform that contains 0-30%CMA, carry out 3 times of column volume wash-outs with the chloroform that contains 30%CMA then), obtain the N of 0.36g, N-dimethyl 3-(2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl)-2,2-dimethylpropane-1-sulphonamide is the canescence foam.

Section H

The general method of use embodiment 11 part B will derive from the material oxidation amination then of part G.With crude product purifying (silica gel carries out 15 times of column volumes with the chloroform that contains 0-30%CMA, carries out 2 times of column volume wash-outs with the chloroform that contains 30%CMA then), obtain the brown oil of 0.19g.Oily matter is dissolved in the ethanol (8mL), merges, stir 10 minutes brown oil of simmer down to stickiness then with 7M hydrochloric acid (65 μ L).The oily matter and the ethyl acetate of heat are ground, obtain solid, concentrate, grind, be cooled to envrionment temperature then with hot acetonitrile (6-7mL).The solid by filtration that obtains is separated, with acetonitrile (3 * 1mL) rinsings, and at 50 ℃ of dryings (0.10Torr (13Pa) 3 days, under 60 ℃ dry 16 hours then, obtain the N of 133mg, N-dimethyl 3-(4-amino-2-ethoxyl methyl-1H-imidazo [4 at 0.12 Torr (16Pa), 5-c] quinoline-1-yl)-2, the hydrochloride of 2-dimethylpropane-1-sulphonamide is brown powder, mp 193-195 ℃.Ultimate analysis: C ₂₀H ₂₉N ₅O ₃SHCl0.15H ₂O, theoretical value: C, 52.37; H, 6.66; N, 15.27 measured values: C, 52.07; H, 6.75; N, 15.08.

Embodiment 26

N, N-dimethyl 4-(4-amino-6,7-dimethyl-2-propyl group-1H-imidazo [4,5-c] pyridine-1-yl) butane-1-sulphonamide

Part A

Under nitrogen atmosphere, with triethylamine (38mL 2.0eq) disposablely joins 2,4-two chloro-5, (1.0eq) and N, (DMF is in mixture 450mL) for dinethylformamide for 30.0g, 136mmol for 6-dimethyl-3-nitropyridine.Reaction mixture was stirred 10 minutes, and (17.6mL 1.4eq) and with the reaction mixture stirring spends the night to add 4-amino-1-butanols.With the reaction mixture concentrating under reduced pressure, obtain crude product, be oily matter.With oily matter chloroform (500mL) and water/salt solution (1: 1, distribute between 50mL).Separate organic phase, and water/salt solution (1: 1, dried over mgso is used in 3 * 30mL) washings, filters, and concentrating under reduced pressure obtains orange solids then.With this material 40 ℃ of high vacuum dry then from the ethyl acetate/hexane recrystallization, obtain 4-(2-chloro-5, the 6-dimethyl-3-nitropyridine-1-yl) butane-1-alcohol of 23.0g.

Part B

Under nitrogen atmosphere, with 4-(2-chloro-5,6-dimethyl-3-nitropyridine-1-yl) butanols (24.5g, 89.5mmol, 1.0eq), sodiumazide (11.6g, 2.0eq), Cerium II Chloride (III) heptahydrate (16.7g, 0.5eq) and acetonitrile/water (9: 1.Mixture heating up 250mL) refluxes and spends the night.The reaction mixture filtered while hot and with filter cake with warm acetonitrile and DMF rinsing.Filtrate decompression is concentrated then 50 ℃ of following high vacuum dry 2 hours, obtains the thick 4-[(5 of 25g, 6-dimethyl-8-nitro tetrazolo [1,5-a] pyridine-7-yl) amino] butane-1-alcohol.

Portion C

Under nitrogen atmosphere, under agitation (9.8mL 1.5eq) is added drop-wise in the mixture of the material that derives from part B and chloroform (500mL) with thionyl chloride.Reaction mixture heated 3.5 hours under vigorous reflux, was cooled to envrionment temperature, water (200mL) dilution then.Separatory and with water (3 * 100mL) extract with chloroform.The organic layer water that merges (dried over mgso use in 3 * 50mL) washings, filters, and concentrating under reduced pressure, drying under high vacuum then obtains the thick N-(4-chlorobutyl)-5 of 30g, and 6-dimethyl-8-nitro tetrazolo [1,5-a] pyridine-7-amine is orange.

Part D

The material that will derive from portion C in pressurized vessel merges with catalyzer (5% carbon of 2.5g carries platinum) and ethyl acetate (500mL).Reaction mixture is placed hydrogen pressure ((30psi, (2.1 * 10 ⁵Pa)) following 2 days.HPLC analyzes the demonstration reaction and does not finish.Add more catalyzer (～1.3g) and reaction is continued, analyze up to HPLC and to show that reaction finishes.The reaction mixture filtration is washed with chloroform by CELITE filtration adjuvant layer and with filter cake.Filtrate decompression is concentrated, obtain the N of 20.0g ⁷-(4-chlorobutyl)-5,6-dimethyl tetrazolo [1,5-a] pyridine-7, the 8-diamines is pale solid.

Part E

Under nitrogen atmosphere, (1.62g is 0.375eq) with former butyric acid trimethyl (6.5mL with pyridine hydrochloride, 1.1.eq) sequentially join N7-(4-chlorobutyl)-5,6-dimethyl tetrazolo [1,5-a] pyridine-7, (10.0g, 37.2mmol is 1eq) in the suspension in toluene (250mL) for the 8-diamines.With reaction mixture reflux 1 hour, it was left standstill weekend at ambient temperature, then concentrating under reduced pressure.The white solid that obtains is distributed between chloroform (400mL) and saturated sodium bicarbonate aqueous solution (50mL).Separatory and with water (2 * 20mL) extract with chloroform.(3 * 25mL) wash the organic layer that merges with saturated sodium bicarbonate aqueous solution, use dried over mgso, filter, concentrating under reduced pressure, dry under high vacuum then, obtain the 7-(4-chlorobutyl)-5 of 11.75g, 6-dimethyl-8-propyl group-7H-imidazo [4,5-c] tetrazolo [1,5-a] pyridine, be pale solid.

Part F

With derive from part E material (1.0eq), thioacetic acid potassium (4.6g, 1.1eq) and the mixture of DMF (250mL) under nitrogen atmosphere, stir and spend the night.Distribute between chloroform (300mL) and water/salt solution (1: 1 100mL) with the reaction mixture concentrating under reduced pressure and with resistates.Separatory and with water (2 * 75mL) extract with chloroform.Organic layer water/the salt solution that merges (1: 1,3 * 50mL) washings, use dried over mgso, filter concentrating under reduced pressure, high vacuum dry under the heating of gentleness then, obtain 13.0g S-[4-(5,6-dimethyl-8-propyl group-7H-imidazo [4,5-c] tetrazolo [1,5-a] pyridine-7-yl) butyl] thioacetate, be brown solid.

Part G

With S-[4-(5,6-dimethyl-8-propyl group-7H-imidazo [4,5-c] tetrazolo [1,5-a] pyridine-7-yl) butyl] (methyl alcohol 1.0eq) (150mL) solution outgased about 10 minutes with nitrogen thioacetate for 6.5g, 18.0mmol.(10.3mL, 25 weight % in methyl alcohol, 2.5eq), stir 2 hours concentrating under reduced pressure then with solution at ambient temperature to drip sodium methylate in 5 minutes.Resistates is distributed between methylene dichloride (300mL) and water (50mL).Regulate pH to 7 by adding 1N hydrochloric acid.Separatory and with water (2 * 75mL) extract with methylene dichloride.The organic layer that merges is used dried over mgso with salt solution (50mL) washing, filters, and concentrating under reduced pressure obtains 4-(5,6-dimethyl-8-propyl group-7H-imidazo [4,5-c] tetrazolo [1,5-a] pyridine-7-yl) butane-1-mercaptan then, is yellow solid.

Section H

Under nitrogen atmosphere, the material (1.0eq) that derives from part G is cooled to 0 ℃ then with concentrated hydrochloric acid (30mL) and water (20mL) merging.Under vigorous stirring, in 10 minutes, add sodium chlorate (2.50g, water 1.3eq) (10mL) solution.Reaction mixture was used methylene dichloride (100mL) dilution in 2 hours then 0 ℃ of stirring.By slow adding 6M salt of wormwood (～30mL) regulate pH to 7.In adition process, form white depositions.Reaction mixture makes its envrionment temperature of rising again then with methylene dichloride (100mL) and water (100mL) dilution.Separate water layer, (2 * 50mL) extract to use methylene dichloride then.With the organic layer dried over mgso that merges, filter concentrating under reduced pressure then, obtain 4-(5,6-dimethyl-8-propyl group-7H-imidazo [4,5-c] tetrazolo [1, the 5-a] pyridine-7-yl) butane-1-SULPHURYL CHLORIDE of 2.6g, be yellow solid.

Part I

Under nitrogen atmosphere, (1.16g 2.1eq) joins in the suspension of material (1.0eq) in methylene dichloride (65mL) that derives from section H with dimethylamine hydrochloride.(2.81mL 2.5eq) and with reaction mixture stirred 2 hours at ambient temperature to drip 6M salt of wormwood.Add more dimethylamine hydrochloride (0.21eq) and 6M salt of wormwood (0.25eq) and reaction mixture was stirred 1 hour.Reaction mixture dilutes and separatory with methylene dichloride (150mL) and saturated sodium bicarbonate aqueous solution (75mL).(3 * 50mL) extract water with methylene dichloride.(dried over mgso is used in 2 * 50mL) washings to the organic layer that merges, and filters, and concentrating under reduced pressure obtains crude product then, is yellow foam with sodium bicarbonate aqueous solution.Crude product obtains the N of 0.8g by HPFC purifying (silica gel is with the chloroform wash-out that contains 2-30%CMA), and N-dimethyl 4-(5,6-dimethyl-8-propyl group-7H-imidazo [4,5-c] tetrazolo [1,5-a] pyridine-7-yl) butane-1-sulphonamide is white solid.

Part J

The material, platinum oxide (IV) that in pressurized vessel, will derive from part I (160mg) and trifluoroacetic acid (20mL) merge and place hydrogen pressure (50psi, 3.4 * 10 ⁵Pa) descended weekend.With the reaction mixture concentrating under reduced pressure.Resistates 1N hydrochloric acid (～10mL) dilution was stirred 1 hour in envrionment temperature then.Solution is cooled to 0 ℃, regulates pH to 7-8 by adding saturated sodium bicarbonate aqueous solution, (3 * 75mL) extract with chloroform with it then.The organic layer that merges sodium bicarbonate aqueous solution (dried over sodium sulfate is used in 3 * 40mL) washings, filters, and concentrating under reduced pressure, dry under high vacuum then, obtain crude product.Crude product is from the ethyl acetate/hexane recrystallization, pass through filtering separation, wash with ethyl acetate, dried overnight under high vacuum then obtains the N of 448mg, N-dimethyl 4-(4-amino-6,7-dimethyl-2-propyl group-1H-imidazo [4,5-c] pyridine-1-yl) butane-1-sulphonamide, be white powder, mp 127.0-128.0 ℃. ¹H NMR (300MHz, DMSO-d ₆) δ 5.59 (s, 2H), 4.24 (dd, J=7.2,6.4Hz, 2H), 3.09 (dd, J=7.2,6.8Hz, 2H), 2.81-2.68 (m, 8H), 2.37 (s, 3H), 2.30 (s, 3H), 1.86-1.67 (m, 6H), 1.00 (t, J=7.4Hz, 3H); MS (APCI) m/z 368 (M) ⁺Ultimate analysis: C ₁₇H ₂₉N ₅O ₂S, theoretical value: C, 55.56; H, 7.95; N, 19.06; Measured value: C, 55.35; H, 8.08; N, 19.02.

Embodiment 27

N-methyl 4-(4-amino-6,7-dimethyl-2-propyl group-1H-imidazo [4,5-c] pyridine-1-yl) butane-1-sulphonamide

Part A

Use the general method of embodiment 26 part I, with 4-(5,6-dimethyl-8-propyl group-7H-imidazo [4,5-c] tetrazolo [1,5-a] pyridine-7-yl) butane-1-SULPHURYL CHLORIDE (2.0g, 5.2mmol, 1.0eq) with methylamine hydrochloride (740mg, 2.1eq) reaction, obtain the N-methyl 4-(5 of 1.86g, 6-dimethyl-8-propyl group-7H-imidazo [4,5-c] tetrazolo [1,5-a] pyridine-7-yl) butane-1-sulphonamide.

Part B

In pressurized vessel, will derive from part A material, platinum oxide (IV) (～500mg) and trifluoroacetic acid (50mL) merge and place hydrogen pressure (50psi, 3.4 * 10 ⁵Pa) analyzing the demonstration reaction up to HPLC under finishes.With the reaction mixture filtration and with the filter cake methanol wash.Filtrate decompression concentrates.Resistates 1N hydrochloric acid (～10mL) dilution was stirred 1 hour in envrionment temperature then.Solution is cooled to 0 ℃ also regulates pH to 7-8 by adding saturated sodium bicarbonate aqueous solution.Form white depositions.Throw out is dissolved in the methyl alcohol with water rinse then by filtering separation, and methanol solution is filtered, and uses dilution with toluene, and concentrating under reduced pressure is dry under high vacuum then, obtains white solid.With solid and ethyl acetate and methyl alcohol grinding,, sequentially, dry under high vacuum then with ethyl acetate, acetonitrile, chloroform and ethyl acetate washing by filtering separation.Then this material and 1N sodium hydroxide (5mL) are merged supersound process 1 minute, and water (20mL) and chloroform (100mL) dilution.Separatory and with water (3 * 20mL) extract with chloroform.The organic layer that merges washs with 1N sodium hydroxide.By adding 1N hydrochloric acid the water layer that the merges pH 7 that neutralizes is used chloroform (3 * 30mL) anti-extractions then.The organic layer dried sodium sulfate that merges, filter, concentrating under reduced pressure 100 ℃ of following high vacuum dry 3 hours, sequentially grinds with ethyl acetate and methyl alcohol, dry under high vacuum then, obtain N-methyl 4-(4-amino-6,7-dimethyl-2-propyl group-1H-imidazo [4, the 5-c] pyridine-1-yl) butane-1-sulphonamide of 100mg, be white powder, mp164.0-166.0 ℃. ¹H NMR (300MHz, DMSO-d ₆) δ 6.88 (q, J=4.9Hz, 1H), 5.72 (s, 2H), 4.23 (dd, J=7.8,6.3Hz, 2H), 3.06 (dd, J=7.6,6.6Hz, 2H), 2.77 (t, J=7.4Hz, 2H), 2.56 (d, J=4.9Hz, 3H), 2.37 (s, 3H), 2.31 (s, 3H), 1.86-1.65 (m, 6H), 1.00 (t, J=7.4Hz, 3H); MS (APCI) m/z354 (M) ⁺Ultimate analysis: C ₁₆H ₂₇N ₅O ₂S, theoretical value: C, 54.37; H, 7.699; N, 19.81; Measured value: C, 54.14; H, 7.76; N, 19.62.

Embodiment 28

N, N-dimethyl 4-(4-amino-6,7-dimethyl-2-ethoxyl methyl-1H-imidazo [4,5-c] pyridine-1-yl) butane-1-sulphonamide

Part A

(3.93g 1.0eq) slowly joins the N of cooling (0 ℃) with the oxyethyl group Acetyl Chloride 98Min. ⁷-(4-chlorobutyl)-5,6-dimethyl tetrazolo [1,5-a] pyridine-7, (7.93g, 29.5mmol is 1.0eq) in the suspension in methylene dichloride (200mL) for the 8-diamines.The reaction mixture envrionment temperature of rising again is spent the night.HPLC analyzes the demonstration reaction and does not finish.Reaction mixture is cooled to 0 ℃, adds more oxyethyl group Acetyl Chloride 98Min. (0.4g), make rise again envrionment temperature and stir and to spend the night of reaction mixture then; Repeat this process.With reaction mixture with saturated sodium bicarbonate aqueous solution (～100mL) and methylene dichloride (100mL) dilute.Separatory and with water (3 * 50mL) extract with methylene dichloride.The organic layer that merges with sodium bicarbonate aqueous solution (dried over mgso use in 2 * 50mL) washings, filtration, concentrating under reduced pressure then obtains the crude product of 10.5g, is brown solid.This material and ethyl acetate/hexane are ground drying under high vacuum then, obtain 7-(4-chlorobutyl)-8-ethoxyl methyl-5 of 6.4g, 6-dimethyl-7H-imidazo [4,5-c] tetrazolo [1,5-a] pyridine is white solid.

Part B

Use the general method of embodiment 26 part F, make 7-(4-chlorobutyl)-8-ethoxyl methyl-5,6-dimethyl-7H-imidazo [4,5-c] tetrazolo [1,5-a] and pyridine (7.1g, 21.1mmol is 1.0eq) with thioacetic acid potassium (3.61g, 1.5eq) reaction, obtain S-[4-(8-ethoxyl methyl-5,6-dimethyl-7H-imidazo [4, the 5-c] tetrazolo [1 of 6.5g, 5-a] pyridine-7-yl) butyl] thioacetate, be brown solid.

Portion C

Use the general method of embodiment 26 part G, with S-[4-(8-ethoxyl methyl-5,6-dimethyl-7H-imidazo [4,5-c] tetrazolo [1,5-a] pyridine-7-yl) butyl] thioacetate (2.00g, 5.31mmol 1.0eq) hydrolysis obtains 4-(8-ethoxyl methyl-5,6-dimethyl-7H-imidazo [4,5-c] tetrazolo [1,5-a] pyridine-7-yl) butane-1-mercaptan, be yellow solid.

Part D

The general method of use embodiment 26 section H will derive from the material oxidation of portion C, obtain 4-(8-ethoxyl methyl-5,6-dimethyl-7H-imidazo [4,5-c] tetrazolo [1,5-a] pyridine-7-yl) butane-1-SULPHURYL CHLORIDE.

Part E

Use the general method of embodiment 26 part I, feasible material and dimethylamine hydrochloride reaction from part D.Crude product obtains the N of 1.1g, N-dimethyl 4-(8-ethoxyl methyl-5,6-dimethyl-7H-imidazo [4,5-c] tetrazolo [1,5-a] pyridine-7-yl) butane-1-sulphonamide by HPFC purifying (silica gel is with the chloroform wash-out that contains 2-30%CMA).

Part F

Use the general method of embodiment 26 part J, with N, N-dimethyl 4-(8-ethoxyl methyl-5,6-dimethyl-7H-imidazo [4,5-c] tetrazolo [1,5-a] pyridine-7-yl) butane-1-sulphonamide (0.21g, 0.51mmol, 1.0eq) reduction.Crude product and ethyl acetate ground and, obtain the N of 0.11g, N-dimethyl 4-(4-amino-6 100 ℃ of following high vacuum dry 3 hours, 7-dimethyl-2-ethoxyl methyl-1H-imidazo [4,5-c] pyridine-1-yl) butane-1-sulphonamide, be white powder, mp 158.0-160.0 ℃. ¹H NMR (300MHz, DMSO-d ₆) δ 5.77 (s, 2H), 4.65 (s, 2H), 4.31 (dd, J=8.1,7.1Hz, 2H), 3.52 (q, J=7.0Hz, 2H), 3.08 (dd, J=7.6,7.3Hz, 2H), 2.75 (s, 6H), 2.38 (s, 3H), 2.31 (s, 3H), 1.92-1.68 (m, 4H), 1.15 (t, J=7.0Hz, 3H); MS (APCI)/384 (M) ⁺Ultimate analysis: C ₁₇H ₂₉N ₅O ₃S0.33H ₂O, theoretical value: C, 52.43; H, 7.68; N, 17.98; Measured value: C, 52.34; H, 7.81; N, 18.11.

Embodiment 29

N, N-dimethyl 4-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] [1,5]-naphthyridine-1-yl) butane-1-sulphonamide

Part A

(38mL, (60g, 314mmol is in suspension 1.0eq) 1.3eq) to be added drop-wise to 4-hydroxyl-3-nitro [1,5]-naphthyridine with phosphoryl chloride in 70 minutes.Orange suspension stirred at ambient temperature be poured over frozen water (1.9L) in 5 hours then and go up and stirred 30 minutes.Solid by filtration is separated, and (3 * 200mL) washings are dissolved in the methylene dichloride (1.2L) water then.The solution dried over mgso is filtered, and concentrating under reduced pressure, obtains 4-chloro-3-nitro [1,5]-naphthyridine of 61.1g, is orange solids.

Part B

(6.4mL, (8.0g, 38.2mmol is 1.0eq) in the suspension in methylene dichloride 1.2eq) to join 4-chloro-3-nitro [1,5]-naphthyridine with triethylamine.With the solution that obtains be cooled to 5 ℃ and in 5 minutes, drip 4-amino-1-butanols (3.8mL, 1.1eq).Reaction mixture is stirred 3 hours at ambient temperature then with its usefulness saturated sodium bicarbonate aqueous solution (100mL) dilution.

Separatory and with water (2 * 50mL) extract with methylene dichloride.The organic layer dried over mgso that merges, filtration, concentrating under reduced pressure then obtains 4-[(3-nitro [1,5]-naphthyridine-4-yl of 9.94g) amino] butane-1-alcohol, be yellow solid.

Portion C

(3.0mL 1.1eq) is added drop-wise in methylene dichloride (190mL) solution of the material that derives from part B (1.0eq) of cooling (0 ℃) with thionyl chloride.In adition process, form white depositions, add other methylene dichloride (170mL) to promote stirring.Reaction mixture stirred to spend the night at ambient temperature use 50% saturated sodium bicarbonate (200mL) cancellation then.Separatory and with water (2 * 75mL) extract with methylene dichloride.The organic layer dried over mgso that merges, filtration, concentrating under reduced pressure then obtains N-(4-chlorobutyl)-3-nitro [1,5]-naphthyridine-4-amine of 10.6g, is yellow solid.

Part D

Catalyzer (5% carbon of 1.1g carries platinum) is joined in the suspension of material in ethyl acetate (190mL) that derives from portion C.Mixture is placed hydrogen pressure, and (30psi (2.1 * 10 ⁵Pa)) following 2 hours.Reaction mixture is filtered by CELITE filtration adjuvant layer.Filter cake ethyl acetate (50mL) rinsing.Filtrate decompression is concentrated, obtain N ⁴-(4-chlorobutyl) [1,5]-naphthyridine-3, the 4-diamines is thick yellow oil.

Part E

(4.5mL 1.1eq) is added drop-wise in methylene dichloride (180mL) solution of the material (1.0eq) that derives from part D with the oxyethyl group Acetyl Chloride 98Min. in 10 minutes.Reaction mixture was stirred 1 hour at ambient temperature,, obtains amino [1, the 5]-naphthyridine of N-[4-(4-chlorobutyl)-3-yl then with its concentrating under reduced pressure]-2-oxyethyl group acetamide hydrochloride.

Part F

The material that derives from part E is suspended in 3: 1 ethanol: in the water (200mL).(9.5mL 1.5eq) and with reaction mixture stirred for 2 weeks at ambient temperature, added other salt of wormwood after 1 week to add 6M salt of wormwood.The reaction mixture concentrating under reduced pressure also distributes resistates between methylene dichloride (100mL) and salt solution (100mL).Separatory also extracts water with methylene dichloride (50mL).The organic layer dried over mgso that merges, filtration, concentrating under reduced pressure then obtains 1-(4-chlorobutyl)-2-ethoxyl methyl-1H-imidazo [4,5-c] [1,5]-naphthyridine of 12.2g, is brown oil.

Part G

(4.75g is 1.1eq) in disposable DMF (150mL) solution that joins the material (1.0eq) that derives from part F for thioacetic acid potassium.Reaction mixture is stirred the concentrating under reduced pressure then that spends the night.Resistates is dissolved in the methylene dichloride (200mL), water (100mL) and salt solution (100mL) washing continuously, use dried over mgso, filter, concentrating under reduced pressure then obtains thick S-[4-(the 2-ethoxyl methyl-1H-imidazo [4 of 14.8g, 5-c] [1,5]-and naphthyridine-1-yl) butyl] thioacetate, be brown oil.

Section H

(1.5g, the substance dissolves that derives from part G 1.0eq) is in methyl alcohol (20mL) with a part.Solution is outgased with nitrogen gas stream, and (2.4mL, 25 weight % are in methyl alcohol, 2.5eq) to drip sodium methylate then in 3 minutes.Reaction mixture is stirred 1 hour concentrating under reduced pressure then at ambient temperature.Resistates distributes between methylene dichloride (70mL) and water (40mL).Regulate pH to 7 by adding 2M hydrochloric acid.Separatory also extracts water with methylene dichloride (30mL).The organic layer that merges with salt solution (40mL) washing, use dried over mgso, filtration, concentrating under reduced pressure then obtains 4-(2-ethoxyl methyl-1H-imidazo [4,5-c] [1, the 5]-naphthyridine-1-yl) butane-1-mercaptan of 1.36g, is brown solid.

Part I

(0.58g, water 1.3eq) (2mL) drips of solution is added in the solution of the material that derives from section H (1.0eq) in the mixture of concentrated hydrochloric acid (7mL) and water (5mL) of cooling (0 ℃) with sodium chlorate in 2 minutes.Reaction mixture was used methylene dichloride (50mL) dilution in 1 hour then 0 ℃ of stirring.Regulate pH to 5 by in 20 minutes, adding 6M salt of wormwood (8mL).Make the mixture envrionment temperature of rising again further use the dilution of methylene dichloride (50mL) and water (50mL) then.Separatory and with water (2 * 20mL) extract with methylene dichloride.The organic layer dried over mgso that merges, filtration, concentrating under reduced pressure then obtains 4-(2-ethoxyl methyl-1H-imidazo [4,5-c] [1, the 5]-naphthyridine-1-yl) butane-1-SULPHURYL CHLORIDE of 1.43g, is light yellow solid.

Part J

(0.64g, 2.1eq) (1.6mL 2.5eq) sequentially joins in methylene dichloride (18mL) solution of the material (1.0eq) that derives from part I with 6M salt of wormwood with dimethylamine hydrochloride.Reaction mixture stirred at ambient temperature used the dilution of methylene dichloride (40mL) and saturated sodium bicarbonate aqueous solution (40mL) in 1 hour then.Separatory and with water (2 * 20mL) extract with methylene dichloride.The organic layer dried over mgso that merges, filtration, concentrating under reduced pressure then obtains the orange solids of 1.06g.This material obtains the pure N of 0.48g by HPFC purifying (silica gel carries out the 1.2L wash-out with the chloroform that contains 0-30%CMA), N-dimethyl 4-(2-ethoxyl methyl-1H-imidazo [4,5-c] [1,5]-naphthyridine-1-yl) mixture of butane-1-sulphonamide and 0.40g.Mixture obtains the N of other 0.27g from methylene dichloride and hexane recrystallization, N-dimethyl 4-(2-ethoxyl methyl-1H-imidazo [4,5-c] [1,5]-naphthyridine-1-yl) butane-1-sulphonamide.

Partial K

With the 3-chloroperoxybenzoic acid (0.66g, 70%, 1.4eq) join N, N-dimethyl 4-(2-ethoxyl methyl-1H-imidazo [4,5-c] [1,5]-1,5-naphthyridine-1-yl) (0.75g, 1.92mmol is in chloroform 1.0eq) (10mL) solution for butane-1-sulphonamide.Reaction was stirred 3 hours at ambient temperature.Lcms analysis shows to react not to be finished, so add other 3-chloroperoxybenzoic acid (1.4eq).After other 2 hours of the restir, add more 3-chloroperoxybenzoic acid (0.42g) and continue and stirred other 1 hour.Reaction mixture is diluted with saturated sodium bicarbonate aqueous solution (75mL) and chloroform (75mL).Separatory and with organic phase with saturated sodium bicarbonate aqueous solution (75mL) washing.(2 * 30mL) extract the water layer that merges with methylene dichloride.The organic layer dried over mgso that merges, filtration, concentrating under reduced pressure then obtains the N of 1.27g, and N-dimethyl 4-(2-ethoxyl methyl-5-Oxy-1 H-imidazo [4,5-c] [1,5]-naphthyridine-1-yl) butane-1-sulphonamide is orange solids.

Partial L

(0.64mL, 15M 5.0eq) join in methyl alcohol (10mL) solution of the material that derives from Partial K (1.0eq) of cooling (0 ℃) with ammonium hydroxide.The dropping benzene sulfonyl chloride (0.51mL, 2.1eq).Reaction mixture is stirred 1 hour concentrating under reduced pressure then at 0 ℃.Resistates distributes between methylene dichloride (70mL) and saturated sodium bicarbonate aqueous solution (50mL).Separatory and with water (2 * 20mL) extract with methylene dichloride.The organic layer dried over mgso that merges, filtration, concentrating under reduced pressure then obtains the crude product of 1.22g, is orange solids.Twice (silica gel carries out the 1.3L wash-out with the chloroform that contains 0-25%CMA to this material, carries out the 600mL wash-out with the chloroform that contains 25-30%CMA by the HPFC purifying; Silica gel carries out the 960mL wash-out with the chloroform that contains 0-30%CMA), obtain the brown solid of 0.180g.This material is dry under high vacuum then from chloroform/hexane recrystallization, obtains the N of 100mg, N-dimethyl 4-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] [1,5]-naphthyridine-1-yl) butane-1-sulphonamide, be white powder, mp148-150 ℃. ¹H NMR (300MHz, DMSO-d ₆) δ 8.53 (dd, J=4.4,1.6Hz, 1H), 7.92 (dd, J=8.4,1.6Hz, 1H), 7.46 (dd, J=8.4,4.4Hz, 1H), 6.88 (br s, 2H), 4.87 (t, J=7.4Hz, 2H), 4.79 (s, 2H), 3.58 (q, J=7.0Hz, 2H), 3.09 (t, J=7.7Hz, 2H), 2.71 (s, 6H), 2.04 (m, 2H), 1.77 (m, 2H), 1.18 (t, J=7.0Hz, 3, H); MS (APCI) m/z 407 (M+1)+; Ultimate analysis: C ₁₈H ₂₆N ₆O ₃S, theoretical value: C, 53.18; H, 6.45; N, 20.67.Measured value: C, 52.83; H, 6.40; N, 20.99.

Embodiment 30

N, N-dimethyl 4-(4-amino-2-propyl group-1H-imidazo [4,5-c] [1,5]-naphthyridine-1-yl) butane-1-sulphonamide

Part A

With former butyric acid trimethyl (7.4mL, 1.3eq) and pyridine hydrochloride (0.20g 0.05eq) joins N ⁴-(4-chlorobutyl) [1,5]-naphthyridine-3 is in toluene (120mL) solution of 4-diamines (1.0eq).With reaction mixture reflux 2 hours, make it be cooled to envrionment temperature, then concentrating under reduced pressure.Resistates is dissolved in the methylene dichloride (120mL) also with saturated sodium bicarbonate aqueous solution (100mL) washing.(2 * 25mL) extract water lotion with methylene dichloride.The organic layer dried over mgso that merges, filtration, concentrating under reduced pressure then obtains 1-(4-chlorobutyl)-2-propyl group-1H-imidazo [4,5-c] [1,5]-naphthyridine of 10.8g, is yellow solid.

Part B

Use the general method of embodiment 29 part G, make 1-(4-chlorobutyl)-2-propyl group-1H-imidazo [4,5-c] [1,5]-1, the 5-naphthyridine (11.3g, 37.3mmol is 1.0eq) with thioacetic acid potassium (4.69g, 1.1eq) reaction, obtain thick S-[4-(2-propyl group-1H-imidazo [4,5-c] [1,5]-1 of 15.43g, 5-naphthyridine-1-yl) butyl] thioacetate, be brown oil.

Portion C

Use the general method of embodiment 29 section H, with S-[4-(2-propyl group-1H-imidazo [4,5-c] [1,5]-naphthyridine-1-yl) butyl] thioacetate (3.0g, 8.76mmol) hydrolysis, obtain 4-(2-propyl group-1H-imidazo [4,5-c] [1,5]-1 of 2.71g, 5-naphthyridine-1-yl) butane-1-mercaptan is brown oil.

Part D

Use the general method of embodiment 29 part I, will derive from the material oxidation of portion C, obtain 4-(2-propyl group-1H-imidazo [4,5-c] [1, the 5]-naphthyridine-1-yl) butane-1-SULPHURYL CHLORIDE of 2.15g, be light yellow solid.

Part E

Use the general method of embodiment 29 part J, feasible material (1.0eq) and dimethylamine hydrochloride (1.00g from part D, 2.1eq) reaction, obtain the N of 2.26g, N-dimethyl 4-(2-propyl group-1H-imidazo [4,5-c] [1,5]-1,5-naphthyridine-1-yl) butane-1-sulphonamide is yellow solid.

Part F

With the 3-chloroperoxybenzoic acid (1.98g, 70%, 1.5eq) join in chloroform (25mL) solution of the material (1.0eq) that derives from part E.To react and stir 1 hour at ambient temperature.Lcms analysis shows to react not to be finished.Add more 3-chloroperoxybenzoic acid (0.36g) and reaction mixture was stirred other 1 hour.Add ammonium hydroxide (5mL) repeatedly add on a small quantity subsequently toluene sulfonyl chloride (1.12g, 1.1eq).Reaction mixture is stirred filtration then in 1 hour at ambient temperature, to remove white solid.Filtrate is diluted with methylene dichloride (50mL) and saturated sodium bicarbonate aqueous solution (50mL).Separatory and with water (2 * 20mL) extract with methylene dichloride.The organic layer dried over mgso that merges, filtration, concentrating under reduced pressure then obtains the crude product of 3.03g, is orange solids.This material obtains the yellow solid of 1.36g by HPFC purifying (silica gel, the chloroform that carries out the 1.2L wash-out and contain 30%CMA with the chloroform that contains 0-30%CMA carries out the 450mL wash-out).This material then 80 ℃ of following high vacuum dry 18 hours, obtains the N of 0.747g, N-dimethyl 4-(4-amino-2-propyl group-1H-imidazo [4 from chloroform/hexane recrystallization, 5-c] [1,5]-naphthyridine-1-yl) butane-1-sulphonamide, be pale powder, mp162-163 ℃. ¹H NMR (300MHz, DMSO-d ₆) δ 8.51 (dd, J=4.3,1.6Hz, 1H), 7.91 (dd, J=8.4,1.6Hz, 1H), 7.43 (dd, J=8.4,4.3Hz, 1H), 6.74 (br s, 2H), 4.85 (t, J=7.2Hz, 2H), 3.10 (t, J=7.7Hz, 2H), 2.92 (t, J=7.5Hz, 2H), 2.70 (s, 6H), 1.95 (m, 2H), 1.87 (sextet, J=7.5Hz, 2H), 1.74 (m, 2H), 1.04 (t, J=7.4Hz, 3H); MS (APCI) m/z 391 (M+1) ⁺Ultimate analysis: C ₁₈H ₂₆N ₆O ₂S, theoretical value: C, 55.36; H, 6.71; N, 21.52.Measured value: C, 55.18; H, 6.98; N, 21.28.

Embodiment 31

4-(4-amino-6,7-dimethyl-2-propyl group-1H-imidazo [4,5-c] pyridine-1-yl) butane-1-sulphonamide

Part A

The preparation of 4-(5,6-dimethyl-8-propyl group-7H-imidazo [4,5-c] tetrazolo [1,5-a] pyridine-7-yl) butane-1-SULPHURYL CHLORIDE is described in part A-H of embodiment 26.Will be in 3 minutes in envrionment temperature to methoxy-benzyl amine (2.37mL, 18.17mmol, 2.2eq) be added drop-wise to 4-(5,6-dimethyl-8-propyl group-7H-imidazo [4,5-c] tetrazolo [1,5-a] pyridine-7-yl) (3.18g, 8.26mmol also stir in methylene dichloride 1eq) (80mL) solution and spend the night butane-1-SULPHURYL CHLORIDE.Reaction mixture is diluted and separatory with methylene dichloride (150mL) and water (50mL).(2 * 30mL) extract water layer with methylene dichloride.The organic layer that merges is water (3mL) and salt solution (20mL) washing sequentially, uses dried over mgso, filters and concentrating under reduced pressure.Thick reactant obtains N-(4-methoxy-benzyl) 4-(5 of 2.01g by HPFC purifying (silica gel is with the chloroform wash-out that contains 2-30%CMA), 6-dimethyl-8-propyl group-7H-imidazo [4,5-c] tetrazolo [1,5-a] pyridine-7-yl) butane-1-sulphonamide, be white foam.

Part B

With platinum oxide (IV) (340mg), trifluoroacetic acid (35mL) and N-(4-methoxy-benzyl) 4-(5,6-dimethyl-8-propyl group-7H-imidazo [4,5-c] tetrazolo [1,5-a] pyridine-7-yl) butane-1-sulphonamide (1.7g, 3.5mmol) be incorporated in the pressurized vessel and place hydrogen pressure (50psi, 3.4 * 10 ⁵Pa) analyzing the demonstration reaction up to HPFC under finishes.With the reaction mixture filtration and with the filter cake methanol wash.Filtrate decompression concentrates.Resistates 1N hydrochloric acid (～10mL) dilution was stirred 1 hour in envrionment temperature then.Mixture is regulated pH to 14 with chloroform (50mL) dilution and with 6N sodium hydroxide.Separatory and with water layer (2 * 30mL) extract, and are adjusted to pH10 with 1N hydrochloric acid, use chloroform (4 * 70mL) anti-extractions then with chloroform.The organic layer dried over sodium sulfate that merges, filter, concentrating under reduced pressure, grind with acetonitrile, filter and spend the night, obtain 4-(the 4-amino-6 of 0.352g 100 ℃ of following high vacuum dry 3 hours with at 80 ℃, 7-dimethyl-2-propyl group-1H-imidazo [4,5-c] pyridine-1-yl) butane-1-sulphonamide, be white powder, mp 167.0-169.0 ℃. ¹H NMR (300MHz, DMSO-d ₆) δ 6.78 (s, 2H), 5.57 (s, 2H), 4.26-4.18 (m, 2H), 3.08-2.99 (m, 2H), 2.77 (dd, J=7.7,7.3Hz, 2H), 2.37 (s, 3H), 2.30 (s, 3H), 1.86-1.72 (m, 6H), 1.00 (t, J=7.4Hz, 3H); MS (APCI) m/z 340 (M) ⁺Ultimate analysis: C ₁₅H ₂₅N ₅O ₂S0.2H ₂O, theoretical value C, 52.52; H, 7.46; N, 20.41; Measured value: C, 52.59; H, 7.68; N, 20.75.

Embodiment 32

N-methyl 4-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] [1,5]-naphthyridine-1-yl) butane-1-sulphonamide

Part A

The preparation of 4-(2-ethoxyl methyl-1H-imidazo [4,5-c] [1,5]-naphthyridine-1-yl) butane-1-SULPHURYL CHLORIDE is described in part A-I of embodiment 29.Repeat the general method of embodiment 29 part J, (0.726g 2.1eq) replaces dimethylamine hydrochloride to use methylamine hydrochloride.Do not need recrystallization, obtain N-methyl 4-(2-ethoxyl methyl-1H-imidazo [4,5-c] [1, the 5]-naphthyridine-1-yl) butane-1-sulphonamide of 1.16g.

Part B

With the 3-chloroperoxybenzoic acid (0.96g, 70%, (1.05g, 2.78mmol is in chloroform 1eq) (14mL) solution 2eq) to join N-methyl 4-(2-ethoxyl methyl-1H-imidazo [4,5-c] [1,5]-naphthyridine-1-yl) butane-1-sulphonamide.To react and stir 3 hours at ambient temperature, subsequently order add ammonium hydroxide (4mL) and toluene sulfonyl chloride (0.58g, 3.06mmol).To react stirring 1 hour and add other toluene sulfonyl chloride (0.20g).Reaction mixture dilutes with methylene dichloride (40mL) and saturated sodium bicarbonate aqueous solution.Separatory and with water layer with methylene dichloride (2 * 20mL) anti-extractions.The organic layer dried over mgso that merges is filtered and concentrating under reduced pressure, obtains orange solids.This material is further by HPFC purifying (silica gel, with the chloroform wash-out that contains 0-30%CMA), grind with acetonitrile and in vacuum drying oven 75 ℃ of dryings, obtain N-methyl 4-(the 4-amino-2-ethoxyl methyl-1H-imidazo [4 of 0.503g, 5-c] [1,5]-naphthyridine-1-yl) butane-1-sulphonamide, be white powder, mp 148-150 ℃.Ultimate analysis: C ₁₇H ₂₄N ₆O ₃S, theoretical value: C, 52.02; H, 6.16; N, 21.41.Measured value: C, 51.73; H, 6.41; N, 21.39.

Embodiment 33

N-methyl 4-(4-amino-2-propyl group-1H-imidazo [4,5-c] [1,5]-naphthyridine-1-yl) butane-1-sulphonamide

Part A

The preparation of 4-(2-propyl group-1H-imidazo [4,5-c] [1,5]-naphthyridine-1-yl) butane-1-SULPHURYL CHLORIDE is described in part A-D of embodiment 30.Repeat the general method of embodiment 29 part J, (0.92g 2.1eq) replaces dimethylamine hydrochloride, obtains N-methyl 4-(2-propyl group-1H-imidazo [4,5-c] [1, the 5]-naphthyridine-1-yl) butane-1-sulphonamide of 1.64g to use methylamine hydrochloride.By the column chromatography purifying or need not recrystallization and be used for following reaction.

Part B

With the 3-chloroperoxybenzoic acid (1.66g, 70%, (1.74g, 4.81mmol is in chloroform 1eq) (25mL) solution 2eq) to join N-methyl 4-(2-propyl group-1H-imidazo [4,5-c] [1,5]-naphthyridine-1-yl) butane-1-sulphonamide.To react and stir 1.5 hours at ambient temperature, subsequently order add ammonium hydroxide (5mL) and Tosyl chloride (1.01g, 5.29mmol).To react and stir 1 hour and use methylene dichloride (40mL) and saturated sodium bicarbonate aqueous solution dilution.Separatory and with water layer with methylene dichloride (2 * 20mL) anti-extractions.The organic layer dried over mgso that merges is filtered and concentrating under reduced pressure, obtains orange solids.This material is further by HPFC purifying (silica gel, with the chloroform wash-out that contains 0-30%CMA), with the acetonitrile grinding and 100 ℃ of following high vacuum dry, obtain N-methyl 4-(the 4-amino-2-propyl group-1H-imidazo [4 of 0.422g, 5-c] [1,5]-naphthyridine-1-yl) butane-1-sulphonamide, be pale solid, mp 174-175 ℃.Ultimate analysis: C ₁₇H ₂₄N ₆O ₂S, theoretical value: C, 54.24; H, 6.43; N, 22.32.Measured value: C, 54.02; H, 6.42; N, 22.22.

Embodiment 34

N-methyl 4-(4-amino-6,7-dimethyl-2-ethoxyl methyl-1H-imidazo [4,5-c] pyridine-1-yl) butane-1-sulphonamide

Part A

At ambient temperature with methylamine hydrochloride (0.85g, 12.5mmol) join 4-(8-ethoxyl methyl-5,6-dimethyl-7H-imidazo [4,5-c] tetrazolo [1,5-a] pyridine-7-yl) butane-1-SULPHURYL CHLORIDE (2.38g, 5.94mmol, as synthetic as described in embodiment 28 part A-D) and in the suspension in methylene dichloride (60mL).Drip subsequently 6M salt of wormwood (2.5mL) and will react the stirring spend the night.Reaction mixture dilutes and separatory with methylene dichloride (150mL) and saturated sodium bicarbonate aqueous solution.Water layer with methylene dichloride (3 * 50mL) instead extract and with the organic layer that merges with saturated sodium bicarbonate aqueous solution (2 * 50mL) washings, use dried over mgso, filter, and concentrating under reduced pressure, obtain N-methyl 4-(8-ethoxyl methyl-5,6-dimethyl-7H-imidazo [4, the 5-c] tetrazolo [1 of 1.87g, 5-a pyridine-7-yl) butane-1-sulphonamide is white foam.

Part B

With platinum oxide (IV) (400mg), trifluoroacetic acid (50mL) and N-methyl 4-(8-ethoxyl methyl-5,6-dimethyl-7H-imidazo [4,5-c] tetrazolo [1,5-a] pyridine-7-yl) butane-1-sulphonamide (1.87g, 4.73mmol) be incorporated in the pressurized vessel and place hydrogen pressure (50psi, 3.4 * 10 ⁵Pa) under, stirred weekend.HPLC analyzes the demonstration reaction and does not finish, and adds other platinum oxide (IV) (150mg).After 24 hours, with the reaction mixture filtration and with the filter cake methanol wash.Filtrate decompression concentrates.Resistates 1N hydrochloric acid (～5mL) dilution was stirred 1 hour in envrionment temperature then.Mixture is cooled to 0 ℃ also with chloroform (100mL) dilution, regulates pH to 14 with 6N sodium hydroxide.Separatory and with water layer (3 * 100mL) extract with chloroform.The organic layer dried over sodium sulfate that merges is filtered, and concentrating under reduced pressure, grinds with acetonitrile, filters and concentrates, and obtains white solid.This material is further by HPFC purifying (silica gel, with the chloroform wash-out that contains 15-40%CMA) and from the acetonitrile recrystallization, obtain N-methyl 4-(the 4-amino-6 of 0.592g, 7-dimethyl-2-ethoxyl methyl-1H-imidazo [4,5-c] pyridine-1-yl) butane-1-sulphonamide, be white powder, mp 194.5-196.0 ℃. ¹H NMR (300MHz, DMSO-d ₆) δ 6.89 (q, J=5.0Hz, 1H), 5.77 (s, 2H), 4.65 (s, 2H), 4.30 (dd, J=8.2,7.3Hz, 2H), 3.51 (q, J=7.0Hz, 2H), 3.05 (dd, J=7.7,7.3Hz, 2H), 2.56 (d, J=5.0Hz, 3H), 2.38 (s, 3H), 2.31 (s, 3H), 1.92-1.66 (m, 4H), 1.15 (t, J=7.0Hz, 3H); MS (APCI) m/z 370 (M) ⁺Ultimate analysis: C ₁₆H ₂₇N ₅O ₃S, theoretical value: C, 52.01; H, 7.37; N, 18.95; Measured value: C, 51.92; H, 7.45; N, 19.04.

Embodiment 35

4-(4-amino-2-ethoxyl methyl-6,7-dimethyl-1H-imidazo [4,5-c] pyridine-1-yl) butane-1-sulphonamide

Part A

General method according to embodiment 31, use 4-(8-ethoxyl methyl-5,6-dimethyl-7H-imidazo [4,5-c] tetrazolo [1,5-a] pyridine-7-yl) butane-1-SULPHURYL CHLORIDE (2.38g, 5.94mmol, as described in embodiment 28 part A-D, synthesize) replacement 4-(5,6-dimethyl-8-propyl group-7H-imidazo [4,5-c] tetrazolo [1,5-a] pyridine-7-yl) butane-1-SULPHURYL CHLORIDE.By replacing column chromatography to carry out purifying, obtain N-(4-methoxy-benzyl) 4-(8-ethoxyl methyl-5,6-dimethyl-7H-imidazo [4,5-c] tetrazolo [1, the 5-a] pyridine-7-yl) butane-1-sulphonamide of 1.73g with the ethyl acetate continuously grinding.

Part B

With platinum oxide (IV) (350mg), trifluoroacetic acid (35mL) and N-(4-methoxy-benzyl) 4-(8-ethoxyl methyl-5,6-dimethyl-7H-imidazo [4,5-c] tetrazolo [1,5-a] pyridine-7-yl) butane-1-sulphonamide (1.73g, 3.45mmol) be incorporated in the pressurized vessel and place hydrogen pressure (50psi, 3.4 * 10 ⁵Pa) analyzing the demonstration reaction up to HPLC under finishes.With the reaction mixture filtration and with the filter cake methanol wash.Filtrate decompression is concentrated.Resistates with 1N hydrochloric acid (～10mL) dilution stirred at ambient temperature then 1 hour.Mixture is cooled to 0 ℃ also with chloroform (100mL) dilution, regulates pH to 14 with 6N sodium hydroxide.Separatory also uses 1N hydrochloric acid to regulate water layer to pH 7, with chloroform (2 * 30mL) anti-extractions.The organic layer dried over sodium sulfate that merges is filtered, and concentrating under reduced pressure.Solid sequentially ground with acetonitrile and ethyl acetate and 80 ℃ of following high vacuum dry.After supersound process 3 minutes, 6N sodium hydroxide (5mL) and water (3mL) are joined in the solid, regulate the pH to 11 of mixture subsequently with 6N hydrochloric acid.Solution is cooled to 0 ℃, filters, wash with water, grind, obtain 4-(4-amino-2-ethoxyl methyl-6,7-dimethyl-1H-imidazo [4, the 5-c] pyridine-1-yl) butane-1-sulphonamide of 237mg, be white powder, mp200.0-201.5 ℃ with acetonitrile. ¹H NMR (300MHz, DMSO-d ₆) δ 6.79 (s, 2H), 5.77 (s, 2H), 4.66 (s, 2H), 4.30 (dd, J=8.0,6.4Hz, 2H), 3.51 (q, J=7.0Hz, 2H), 3.03 (dd, J=7.7,6.6Hz, 2H), 2.38 (s, 3H), 2.31 (s, 3H), 1.91-1.71 (m, 4H), 1.15 (t, J=7.0Hz, 3H); MS (APCI) m/z 356 (M) ⁺Ultimate analysis: C ₁₅H ₂₅N ₅O ₃S0.4H ₂O, theoretical value: C, 49.68; H, 7.17; N, 19.31; Measured value: C, 49.97; H, 7.38; N, 19.67.

Embodiment 36

3-[4-amino-2-(ethoxyl methyl)-1H-imidazo [4,5-c] quinoline-1-yl]-N, 2,2-trimethyl propane-1-sulphonamide

Part A

Use the general method of embodiment 11 part A, make 3-[2-(ethoxyl methyl)-1H-imidazo [4,5-c] quinoline-1-yl]-2,2-dimethylpropane-1-SULPHURYL CHLORIDE (2.33g, 5.88mmol is 1.0eq) with methylamine hydrochloride (834mg, 2.1eq) react, obtain the crude product of 2.0g.This material by the HPFC purifying (silica gel, the 0-100%B that is used in the chloroform carries out 8 times of column volume wash-outs, carries out 7 times of column volume wash-outs with B then, B is premixed 5: 95 methyl alcohol: chloroform), obtain the canescence foam of 1.5g.This material is by HPFC purifying (silica gel, the 0-10%B that is used in the ethyl acetate carries out 6 times of column volume wash-outs, use 10%B to carry out 6 times of column volume wash-outs then, B is 10% methyl alcohol in ethyl acetate), obtain 3-[2-(ethoxyl methyl)-1H-imidazo [4,5-c] quinoline-1-yl of 0.90g]-N, 2,2-trimethyl propane-1-sulphonamide is white foam.

Part B

Use the general method of embodiment 11 part B, will derive from the material oxidation amination then of part A.Crude product is sequentially ground with ethyl acetate and acetonitrile, obtains 3-[4-amino-2-(ethoxyl methyl)-1H-imidazo [4,5-c] quinoline-1-yl of 270mg]-N, 2,2-trimethyl propane-1-sulphonamide is brown powder, mp 161-163 ℃. ¹H NMR (300MHz, DMSO-d ₆): δ 8.38 (d, J=7.7Hz, 1H), 7.59 (dd, J=1.2,8.3Hz, 1H), 7.42 (m, 1H), 7.21 (m, 1H), 7.02 (q, J=5.0Hz, 1H), 6.61 (br s, 2H), 5.04-4.70 (m, 4H), 3.55 (br, 2H), 2.61 (dd, J=4.9Hz, 3H), 1.14 (t, J=7.0Hz, 3H), 1.03 (br s, 6H); MS (APCI) m/z 406 (M+H) ⁺Ultimate analysis: C ₁₉H ₂₇N ₅O ₃S, theoretical value: C, 56.28; H, 6.71; N, 17.27.Measured value: C, 56.24; H, 6.69; N, 17.06.

Embodiment 37

4-[4-amino-2-(ethoxyl methyl)-1H-imidazo [4,5-c] quinoline-1-yl]-N-sec.-propyl butane-1-sulphonamide

Part A

Use the general method of embodiment 11 part A, make 3-[2-(ethoxyl methyl)-1H-imidazo [4,5-c] quinoline-1-yl] butane-1-SULPHURYL CHLORIDE (4.1g, 10.7mmol, 1.0eq) with Isopropylamine (0.70g, 11.8mmol, 1.1eq) react, obtain the crude product of 4.2g.This material obtains 2-(ethoxyl methyl)-1H-imidazo [4,5-c] quinoline-1-yl by HPFC purifying (silica gel carries out 7 times of column volume wash-outs with the chloroform that contains 17%CMA)]-N-sec.-propyl butane-1-sulphonamide.

Part B

Use the general method of embodiment 11 part B, will derive from the material oxidation amination then of part A.Crude product is carried out purifying from ethyl alcohol recrystallization subsequently by grinding with acetonitrile, obtain the 176mg product.Filtrate concentrated and with resistates by HPFC purifying (silica gel carries out 8 times of column volume wash-outs with the chloroform that contains 0-20%CMA, carries out 9 times of column volume wash-outs with the chloroform that contains 20%CMA then), obtain the light yellow oil of 0.36g.This material and ethanol (15mL) are ground.The solid by filtration that obtains is separated, and (2 * 2mL) rinsings are then 80 ℃ of following high vacuum dry with ethanol, obtain 4-[4-amino-2-(ethoxyl methyl)-1H-imidazo [4 of 214mg, 5-c] quinoline-1-yl]-N-sec.-propyl butane-1-sulphonamide, be white powder, mp146-147 ℃. ¹H NMR (300MHz, DMSO-d ₆): δ 8.05 (d, J=7.6Hz, 1H), 7.62 (dd, J=1.1,8.3Hz, 1H), 7.45 (m, 1H), 7.26 (m, 1H), 6.99 (d, J=7.6Hz, 1H), 6.58 (br s, 2H), 4.78 (s, 2H), 4.60 (m, 2H), 3.57 (q, J=7.0Hz, 2H), 3.38 (m, 1H), 3.05 (m, 2H), 1.98 (m, 2H), 1.84 (m, 2H), 1.17 (t, J=7.0Hz, 3H), 1.09 (d, J=6.5Hz, 6H); MS (APCI) m/z 420 (M+H) ⁺Ultimate analysis: C ₂₀H ₂₉N ₅O ₃S, theoretical value: C, 57.26; H, 6.97; N, 16.69.Measured value: C, 57.15; H, 6.96; N, 16.77.

Embodiment 38

5-[4-amino-2-(ethoxyl methyl)-6,7,8,9-tetrahydrochysene-1H-imidazo [4,5-c] quinoline beautiful jade-1-yl] pentane-1-sulphonamide

The general method that uses embodiment 18 is with 5-[4-amino-2-(ethoxyl methyl)-1H-imidazo [4,5-c] quinoline-1-yl] pentane-1-sulphonamide (1.2g) reduction.Crude product is placed the stable weight that has 1.2g under the high vacuum up to colourless oily matter.Oily matter and water (10mL) merged and with 10% sodium hydroxide adjusting pH to pH 12.Mixture is stirred filtration then in 1 hour.With 6M hydrochloric acid filtrate is adjusted to pH 7.5.The throw out that obtains is by filtering separation, and is dry then from recrystallizing methanol, obtains white solid.This substance dissolves stirred in 12M hydrochloric acid (5mL) then spend the night.Mixture is cooled off in ice bath then by slowly adding 6M salt of wormwood adjusting pH to pH 8.The suspension stirring that obtains was also regulated pH to pH 12 with 10% sodium hydroxide in 2 hours.After other 2 hours of the restir, mixture is filtered.Filtrate decompression is concentrated.Resistates spends the night 78 ℃ of following vacuum-dryings then from recrystallizing methanol, obtains the white solid of about 0.17g.This material makes it be cooled to envrionment temperature with the hot water making beating then.Solid by filtration is separated, water (2 * 1mL) rinsings, dry air then 110 ℃ of following high vacuum dry 15 minutes, obtains 5-[4-amino-2-(ethoxyl methyl)-6 of 178mg, 7,8,9-tetrahydrochysene-1H-imidazo [4,5-c] quinoline-1-yl] pentane-1-sulphonamide, be white powder, mp 203-205 ℃. ¹HNMR (300MHz, DMSO-d ₆): δ 6.73 (s, 2H), 5.80 (s, 2H), 4.64 (s, 2H), 4.24 (m, 2H), 3.50 (q, J=7.0Hz, 2H), 2.98 (m, 4H), 2.66 (m, 2H), 1.77 (m, 8H), 1.47 (m, 2H), 1.14 (t, J=7.0Hz, 3H); MS (APCI) m/z 396 (M+H) ⁺Ultimate analysis: C ₁₈H ₂₉N ₅O ₃S, theoretical value: C, 54.66; H, 7.39; N, 17.71.Measured value: C, 54.59; H, 7.65; N, 17.88.

Embodiment 39

N-methyl 4-(4-amino-2-ethyl-6,7,8,9-tetrahydrochysene-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide

The general method that uses embodiment 18 is with N-methyl 4-(4-amino-2-ethyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide (420mg) reduction.Reaction mixture filters by CELITE filtration adjuvant layer then with chloroform (5mL) and methyl alcohol (10mL) dilution.Filter cake methyl alcohol (2 * 2mL) rinsings.Filtrate decompression concentrates.With resistates and methylene dichloride (50mL) with saturated sodium bicarbonate aqueous solution (about 20mL) merges and with mixture vigorous stirring 30 minutes.Separate organic layer, use dried over mgso, concentrating under reduced pressure then obtains the crude product of 0.51g, is white solid.Take out the 50mg part.Remaining material and concentrated hydrochloric acid (about 10mL) are merged, obtain muddy solution.Dripping 6M salt of wormwood under cooling, to be lower than 35-40 ℃ with holding temperature be about 10-11 up to pH.With mixture stir about 10 minutes.The throw out that obtains is passed through filtering separation, and (3 * 4mL) rinsings are also dry under high vacuum, obtain the white solid of 338mg for water.This material obtains colourless oily matter by HPFC purifying (silica gel, the methyl alcohol with 10/90/15 times of column volumes of chloroform wash-out).With methylene dichloride oily matter is transferred in the bottle, the part evaporating solvent obtains white solid.By filtering separation, (2 * 1mL) rinsings are also dry under high vacuum, obtain the white crystalline solid of 202mg with methylene dichloride with this material.With this substance dissolves in warm methyl alcohol (about 9mL), concentrating under reduced pressure, dry under high vacuum then, obtain colourless oily matter.Oily matter is dissolved in 1/1 the methanol/ethyl acetate (about 8mL), concentrating under reduced pressure, then 75 ℃ of following high vacuum dry, obtain N-methyl 4-(4-amino-2-ethyl-6,7,8 of 138mg, 9-tetrahydrochysene-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-sulphonamide, be white powder, mp 166-170 ℃. ¹H NMR (300MHz, DMSO-d ₆): δ 6.88 (q, J=5.0Hz, 1H), 5.81 (br s, 2H), 4.20 (m, 2H), 3.06 (m, 2H), 2.94 (m, 2H), 2.82 (q, J=7.5Hz, 2H), 2.66 (m, 2H), 2.56 (d, J=5.0Hz, 3H), 1.76 (m, 8H), 1.32 (t, J=7.4Hz, 3H); MS (APCI) m/z 366 (M+H) ⁺Ultimate analysis: C ₁₇H ₂₇N ₅O ₂S0.50H ₂O, theoretical value C, 54.52; H, 7.54; N, 18.70.Measured value: C, 54.82; H, 7.71; N, 18.58.

Embodiment 40

4-[4-amino-2-(ethoxyl methyl)-1H-imidazo [4,5-c] quinoline-1-yl]-N-(pyridine-2-yl) butane-1-sulphonamide

Part A

Use the general method of embodiment 8 part I,, obtain the crude product of 26.8g, be brown solid 1-(4-chlorobutyl)-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline (21.2g) oxidation amination then.This material and ethyl acetate (100mL) are ground.The pale solid that obtains is by filtering separation, and (3 * 30mL) rinsings are also dry under high vacuum, obtain 1-(4-chlorobutyl)-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-4-amine of 15.18g with ethyl acetate.

Part B

Use the general method of embodiment 8 part E, make 1-(4-chlorobutyl)-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-4-amine (2.00g, 6.02mmol) and thioacetic acid potassium (824mg, 7.23mmol) reaction, obtain S-[4-(4-amino-2-ethoxyl methyl-1H-imidazo [4, the 5-c] quinoline-1-yl) butyl of 2.23g] thioacetate, be yellow powder.

Portion C

The general method of use embodiment 8 part F will derive from the material hydrolysis of part B.Crude product obtains 4-(4-amino-2-ethoxyl methyl-IH-imidazo [4, the 5-c] quinoline-1-yl) butane-1-mercaptan of 1.43g by hurried chromatography purification (5 * 15cm silicagel column is with the chloroform gradient elution that contains 10 to 20%CMA).

Part D

The general method that uses embodiment 8 part G is with 4-(4-amino-2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl) butane-1-mercaptan (380mg) oxidation, obtain 4-(the 4-amino-2-ethoxyl methyl-1H-imidazo [4 of 280mg, 5-c] quinoline-1-yl) butane-1-SULPHURYL CHLORIDE, be brown foam.

Part E

(265mg 4eq) joins in the material (1eq) that derives from part D, adds pyridine (3.5mL) subsequently rapidly with solid 2-aminopyridine.The solution that obtains is stirred 1 hour concentrating under reduced pressure then at ambient temperature.Resistates dilutes with methyl alcohol (40mL), and concentrating under reduced pressure is dry under high vacuum then.Resistates is suspended in warm 1/1 the ethanol/methylene, be adsorbed on the silica gel, (carry out 15 times of column volume wash-outs by the HPFC purifying then with the chloroform that contains 0 to 35%CMA, carry out 8 times of column volumes with the chloroform that contains 35%CMA then and carry out gradient elution), obtain the light yellow solid of 79mg.This material is analyzed up to 1H NMR 75-100 ℃ of following high vacuum dry then from ethyl alcohol recrystallization and is shown that ethanol is removed, obtain 4-[4-amino-2-(ethoxyl methyl)-1H-imidazo [4 of 62mg, 5-c] quinoline-1-yl]-N-(pyridine-2-yl) butane-1-sulphonamide, be buff powder, mp 197-200 ℃. ¹H NMR (300MHz, DMSO-d ₆): δ 10.89 (br s, 1H), 8.15 (d, J=5.4Hz, 1H), 8.04 (d, J=7.8Hz, 1H), 7.71 (ddd, J=1.9,7.3,8.5Hz, 1H), 7.62 (dd, J=1.1,8.3Hz, 1H), 7.45 (m, 1H), 7.25 (m, 1H), 6.99 (m, 2H), 6.63 (br s, 2H), 4.76 (s, 2H), 4.59 (m, 2H), 3.51 (m, 4H), 1.94 (m, 4H), 1.11 (t, J=7.0Hz, 3H); MS (APCI) m/z 455 (M+H) ⁺Ultimate analysis, C ₂₂H ₂₆N ₆O ₃S, theoretical value: C, 58.13; H, 5.77; N, 18.49.Measured value: C, 57.95; H, 5.71; N, 18.28.

Embodiment 41

3-[4-amino-2-(ethoxyl methyl)-1H-imidazo [4,5-c] quinoline-1-yl]-N-(4-methoxy-benzyl)-2,2-dimethylpropane-1-sulphonamide

Part A

(1.96mL 2.1eq) joins 3-(2-ethoxyl methyl-1H-imidazo [4,5-c] quinoline-1-yl)-2, and (2.83g is in methylene dichloride 1.0eq) (36mL) solution for 2-dimethylpropane-1-SULPHURYL CHLORIDE with 4-methoxy-benzyl amine.The suspension that obtains was used methylene dichloride (100mL) dilution and water (40mL) washing in 1 hour then in the envrionment temperature stirring.Organic layer obtains the crude product of 3.3g with dried over mgso and concentrating under reduced pressure, is oily matter.This material is by HPFC purifying (silica gel, carry out 8 times of column volume wash-outs with the chloroform that contains 0-20%CMA, carry out 3 times of column volume wash-outs with the chloroform that contains 20%CMA then), obtain 3-[2-(ethoxyl methyl)-1H-imidazo [4 of 1.63g, 5-c] quinoline-1-yl]-N-(4-methoxy-benzyl)-2,2-dimethylpropane-1-sulphonamide is light yellow foam.

Part B

Use the general method of embodiment 8 part I, will derive from the material oxidation amination then of part A, obtain the crude product of 1.87g, be the brown foam.This material obtains the brown foam of 1.36g by HPFC purifying (silica gel carries out 7 times of column volume wash-outs with the chloroform that contains 0-20%CMA, carries out 5 times of column volume wash-outs with the chloroform that contains 20%CMA then).This material and methyl alcohol (10mL) are ground, pass through filtering separation, with methyl alcohol (3 * 7mL) rinsings, dry under high vacuum then, obtain 3-[4-amino-2-(ethoxyl methyl)-1H-imidazo [4,5-c] quinoline-1-yl of 993mg]-N-(4-methoxy-benzyl)-2,2-dimethylpropane-1-sulphonamide, be white powder, mp203-205 ℃. ¹H NMR (300MHz, DMSO-d ₆): δ 8.36 (d, J=8.5Hz, 1H), 7.61 (m, 2H), 7.42 (m, 1H), 7.23 (m, 3H), 6.92 (m, 2H), 6.61 (br s, 2H), 4.68 (br m, 4H), 4.09 (d, J=6.0Hz, 2H), 3.75 (s, 3H), 3.55 (br, 2H), 1.14 (t, J=7.0Hz, 3H), 1.03 (s, 6H); MS (APCI) m/z 512 (M+H) ⁺Ultimate analysis C ₂₆H ₃₃N ₅O ₄S, theoretical value: C, 61.04; H, 6.50; N, 13.69.Measured value: C, 60.87; H, 6.60; N, 13.68.

Embodiment 42

3-[4-amino-2-(ethoxyl methyl)-1H-imidazo [4,5-c] quinoline-1-yl]-2,2-dimethylpropane-1-sulphonamide

With trifluoroacetic acid (8mL) and methyl-phenoxide (213 μ L, 1.2eq) sequentially join solid 3-[4-amino-2-(ethoxyl methyl)-1H-imidazo [4,5-c] quinoline-1-yl]-N-(4-methoxy-benzyl)-2,2-dimethylpropane-1-sulphonamide (834mg, 1.63mmol, 1.0eq) in.The solution that obtains was stirred 22 hours at ambient temperature, then concentrating under reduced pressure.Resistates is distributed between methylene dichloride (50mL) and saturated sodium bicarbonate aqueous solution (about 35mL).Separate water layer and (1 * 40mL) extracts then with the chloroform that contains 10% methyl alcohol (4 * 25mL) extractions with chloroform with water layer.The organic layer dried over mgso that merges, concentrating under reduced pressure then obtains the light yellow semisolid of 1.15g.This substance dissolves in the ethyl acetate that contains 10% methyl alcohol, leaves standstill it and filtered a small amount of insoluble substance that forms to remove in 1 hour then in the process of leaving standstill.Filtrate decompression is concentrated dry under high vacuum then.Resistates and methyl alcohol (about 5mL) grind, by filtering separation, and with methyl alcohol (4 * 2mL) rinsings obtain the yellow solid of 475mg.This material makes it be cooled to envrionment temperature with the chloroform that contains 5% methyl alcohol (about 3-4mL) making beating of heat, and by filtering separation, (3 * 1mL) rinsings, drying under high vacuum then obtain the light yellow solid of 395mg with the chloroform that contains 5% methyl alcohol.Repeat this process, obtain 3-[4-amino-2-(ethoxyl methyl)-1H-imidazo [4,5-c] quinoline-1-yl of 352mg]-2,2-dimethylpropane-1-sulphonamide is buff powder, mp 229-231 ℃. ¹H NMR (300MHz, DMSO-d ₆): δ 8.36 (d, J=8.0Hz, 1H), 7.59 (dd, J=1.1,8.3Hz, 1H), 7.42 (m, 1H), 7.21 (m, 1H), 7.02 (br s, 2H), 6.61 (br s, 2H), 4.70 (m, 4H), 3.55 (br, 2H), 1.14 (t, J=7.0Hz, 3H), 1.05 (s, 6H); MS (EI) m/z 392 (M+H) ⁺Ultimate analysis: C ₁₈H ₂₅N ₅O ₃S, theoretical value: C, 55.22; H, 6.44; N, 17.89.Measured value: C, 55.02; H, 6.64; N, 18.08.

Embodiment 43

3-(4-amino-2-methyl-6,7,8,9-tetrahydrochysene-1H-imidazo [4,5-c] quinoline-1-yl)-2,2-dimethylpropane-1-sulphonamide

Part A

With toluene sulfonyl chloride (4.67g, 1.2eq) and 4-dimethylaminopyridine (46mg 0.02eq) sequentially joins 2,2-dimethyl-3-[(3-nitroquinoline-4-yl) amino] propyl alcohol (5.19g, 18.8mmol, 1.0eq) in the suspension in pyridine (35mL).Reaction mixture stirs in envrionment temperature and spends the night, then concentrating under reduced pressure.Resistates washs with chloroform (300mL) dilution and water (60mL).Water lotion extracts with methylene dichloride (75mL).The organic layer that merges obtains 2 of 7.88g, 2-dimethyl-3-[(3-nitroquinoline-4-yl with dried over mgso concentrating under reduced pressure then) amino] the propyl group p-toluenesulfonic esters, be yellow solid.

Part B

With 2,2-dimethyl-3-[(3-nitroquinoline-4-yl) amino] and the propyl group p-toluenesulfonic esters (5.37g, 12.5mmol), the 10% carbon mixture that carries palladium (530mg) and acetonitrile places hydrogen pressure (50psi, 3.4 * 10 on the Parr device ⁵Pa) following 6 hours.Reaction mixture filters by CELITE filtration adjuvant layer, and filter cake is colourless up to washing lotion with the acetonitrile rinsing.Filtrate decompression concentrates, and obtains thick 3-[(3-quinolylamine-4-yl of 4.50g) amino]-2,2-dimethyl propyl p-toluenesulfonic esters is orange.

Portion C

With trimethyl orthoacetate (1.72mL, 1.2eq) and pyridine hydrochloride (130mg 0.1eq) sequentially joins in the suspension of material (1eq) in toluene (111mL) that derives from part B.Reaction mixture 100 ℃ of heating 1 hour, is cooled to envrionment temperature and spends the night, itself and the material that derives from another time operation are merged concentrating under reduced pressure then, obtain the crude product of 5.50g, be brown foam.This material is by HPFC purifying (silica gel, carry out 7 times of column volume wash-outs with the chloroform that contains 0 to 20%CMA, carry out 5 times of column volume gradient elutions with the chloroform that contains 20%CMA then), obtain 3-(the 2-methyl isophthalic acid H-imidazo [4 of 3.94g, 5-c] quinoline-1-yl)-2,2-dimethyl propyl p-toluenesulfonic esters is white foam.

Part D

(155mg 2.0eq) joins 3-(2-methyl isophthalic acid H-imidazo [4,5-c] quinoline-1-yl)-2, and (338mg, 0.80mmol is in n-propyl alcohol 1.0eq) (4.0mL) solution for 2-dimethyl propyl p-toluenesulfonic esters with potassium sulfocyanate.With reaction mixture EMRYS OPTIMIZER microwave synthesizer (derive from Biotage, Inc, Charlottesville, Virginia, USA) in 190 ℃ the heating 20 minutes.Repeat this reaction.With the reaction mixture concentrating under reduced pressure that merges.Resistates distributes between chloroform (100mL) and water (75mL).Organic layer with dried over mgso and concentrating under reduced pressure, obtains the oily matter of 0.50g with salt solution (50mL) washing.Oily matter is by HPFC purifying (silica gel, carry out 8 times of column volume wash-outs with the chloroform that contains 0 to 20%CMA, carry out 4 times of column volume gradient elutions with the chloroform that contains 20%CMA then), obtain 3-(the 2-methyl isophthalic acid H-imidazo [4 of 390mg, 5-c] quinoline-1-yl)-2,2-dimethyl propyl thiocyanic ester are clarifying oily matter.

Part E

(95mg 2.0eq) joins in ethanol (12mL) solution of the material that derives from part D (1.0eq) of cooling (0 ℃) with sodium borohydride.Make the reaction mixture envrionment temperature of rising again.After 3 hours, will react with hydrochloric acid (about 1mL, 7M) cancellation, stirring several minutes, concentrating under reduced pressure then.Resistates is dissolved in the methylene dichloride (125mL), adds entry (75mL) then.With saturated sodium bicarbonate with mixture alkalization (pH about 7).Separate organic layer, with dried over mgso and concentrating under reduced pressure, obtain the 3-(2-methyl isophthalic acid H-imidazo [4,5-c] quinoline-1-yl)-2 of 330mg, 2-dimethylpropane-1-mercaptan is oily matter.

Part F

With benzyl trimethyl ammonium chloride (663mg, 3.4eq) and trichloroisocyanuric acid (268mg, 1.1eq) methylene dichloride (5mL) solution stirred at ambient temperature 45 minutes, (47 μ L are in methylene dichloride 2.5eq) (6mL) solution to be added drop-wise to the material that derives from part E (1.0eq) of cooling (0 ℃) and water then in about 2 minutes.After 45 minutes, (0.89mL 6.5eq), makes rise again envrionment temperature and stirring 2 hours of reaction mixture then to add 4-methoxy-benzyl amine.Reaction mixture is with methylene dichloride (125mL) dilution, with washing water (2 * 200mL), use dried over mgso, concentrating under reduced pressure then obtains the crude product of 0.67g, is oily matter.Oily matter is by HPFC purifying (silica gel, carry out 8 times of column volume wash-outs with the chloroform that contains 0 to 20%CMA, carry out 4 times of column volume gradient elutions with the chloroform that contains 20%CMA then) and merge with the material that derives from another time operation, obtain N-(4-methoxy-benzyl) 3-(the 2-methyl isophthalic acid H-imidazo [4 of 757mg, 5-c] quinoline-1-yl)-2,2-dimethylpropane-1-sulphonamide is white foam.

Part G

(490mg, 1.2eq is based on 70% concentration) joins in chloroform (16mL) solution of the material (1.0eq) that derives from part F with the 3-chloroperoxybenzoic acid.Reaction mixture stirred at ambient temperature merged with dense ammonium hydroxide (4mL) then in 40 minutes.In several minutes, repeatedly add on a small quantity toluene sulfonyl chloride (379mg, 1.2eq).Chloroform (100mL) dilution and water (50mL) washing were used in the reaction mixture stirring in 1 hour then.Water layer extracts with methylene dichloride (30mL).The organic layer that merges obtains the crude product of 0.89g with dried over mgso and concentrating under reduced pressure, is brown foam.This material is by HPFC purifying (silica gel, carry out 8 times of column volume wash-outs with the chloroform that contains 0 to 30%CMA, carry out 8 times of column volume gradient elutions with the chloroform that contains 30%CMA then), obtain 3-(the 4-amino-2-methyl-1H-imidazo [4 of 500mg, 5-c] quinoline-1-yl)-N-(4-methoxy-benzyl)-2,2-dimethylpropane-1-sulphonamide is brown/orange powder.

Section H

The substance dissolves that derives from part G was stirred 4.5 hours in trifluoroacetic acid (11mL) and in envrionment temperature.Add platinum oxide (IV) and (500mg) and with mixture place hydrogen pressure (50psi, 3.4 * 10 on the Parr device ⁵Pa) following 20 hours.Reaction mixture is filtered by CELITE filtration adjuvant layer.Filter cake use continuously trifluoroacetic acid (2 * 8mL), methyl alcohol (3 * 15mL) and methyl alcohol/chloroform (2 * 15mL) rinsings of 1/1.Filtrate decompression is concentrated.Resistates between methylene dichloride (150mL) and water (75mL), distribute and with the pH regulator of water layer to about 8-9.Separatory, water layer is with methylene dichloride (3 * 50mL) and contain the methylene dichloride of 10% methyl alcohol (2 * 50mL) extract.The organic layer that merges obtains the crude product of 0.44g with dried over mgso and concentrating under reduced pressure, is brown semisolid.This material is by HPFC purifying (silica gel carries out 5 times of column volume wash-outs with the chloroform that contains 20 to 50%CMA, carries out 6 times of column volume gradient elutions with the chloroform that contains 50%CMA then), and the white that obtains 180mg is semi-solid.This material is from Virahol (about 8mL) crystallization of heat, and by filtering separation, (3 * 2mL) rinsings are also dry under high vacuum, obtain the white solid of 131mg with Virahol.With the methyl alcohol of this substance dissolves in heat, methanol solution is concentrated and solid by filtration is separated, use ethanol repeats this process and the solid that obtains was descended dried high vacuum dry 48 hours at 100 ℃, obtains 3-(the 4-amino-2-methyl-6,7 of about 125mg, 8,9-tetrahydrochysene-1H-imidazo [4,5-c] quinoline-1-yl)-2,2-dimethylpropane-1-sulphonamide, be pale solid, mp242-243 ℃ (decomposition). ¹H NMR (300MHz, DMSO-d ₆): δ 6.97 (s, 2H), 5.71 (s, 2H), 4.38 (br, 2H), 3.15 (br, 2H), 2.88 (br, 2H), 2.66 (br, 2H), 1.74 (br, 4H), 1.01 (s, 6H); MS (EI) m/z 352 (M+H) ⁺Ultimate analysis: C ₁₆H ₂₅N ₅O ₂S0.10C ₃H ₈O0.22H ₂O, theoretical value: C, 54.17; H, 7.32; N, 19.38.Measured value: C, 54.01; H, 7.16; N, 19.44.

Exemplary compounds

Some exemplary compounds comprises what some were described in the above-described embodiments, has structure and the following R of following formula I c, IIc, IIIa and IVa ₁, R ₁', X ' and R ₂Substituting group, the wherein concrete compound of every line display in the table.

R ₁	R ₁’	X’	R ₂
R ₁	R ₁’	X’	R ₂	Hydrogen	Hydrogen	-(CH ₂) ₂-	Methyl
Hydrogen	Hydrogen	-(CH ₂) ₂-	Ethyl	Hydrogen	Hydrogen	-(CH ₂) ₂-	Methyl
Hydrogen	Hydrogen	-(CH ₂) ₂-	Ethyl	Hydrogen	Hydrogen	-(CH ₂) ₂-	N-propyl
Hydrogen	Hydrogen	-(CH ₂) ₂-	Normal-butyl	Hydrogen	Hydrogen	-(CH ₂) ₂-	N-propyl
Hydrogen	Hydrogen	-(CH ₂) ₂-	Normal-butyl	Hydrogen	Hydrogen	-(CH ₂) ₂-	Ethoxyl methyl
Hydrogen	Hydrogen	-(CH ₂) ₂-	The 2-methoxy ethyl	Hydrogen	Hydrogen	-(CH ₂) ₂-	Ethoxyl methyl
Hydrogen	Hydrogen	-(CH ₂) ₂-	The 2-methoxy ethyl	Hydrogen	Hydrogen	-(CH ₂) ₂-	Hydroxymethyl
Hydrogen	Hydrogen	-(CH ₂) ₂-	The 2-hydroxyethyl	Hydrogen	Hydrogen	-(CH ₂) ₂-	Hydroxymethyl
Hydrogen	Hydrogen	-(CH ₂) ₂-	The 2-hydroxyethyl	Hydrogen	Hydrogen	-(CH ₂) ₃-	Methyl
Hydrogen	Hydrogen	-(CH ₂) ₃-	Ethyl	Hydrogen	Hydrogen	-(CH ₂) ₃-	Methyl
Hydrogen	Hydrogen	-(CH ₂) ₃-	Ethyl	Hydrogen	Hydrogen	-(CH ₂) ₃-	N-propyl
Hydrogen	Hydrogen	-(CH ₂) ₃-	Normal-butyl	Hydrogen	Hydrogen	-(CH ₂) ₃-	N-propyl
Hydrogen	Hydrogen	-(CH ₂) ₃-	Normal-butyl	Hydrogen	Hydrogen	-(CH ₂) ₃-	Ethoxyl methyl
Hydrogen	Hydrogen	-(CH ₂) ₃-	The 2-methoxy ethyl	Hydrogen	Hydrogen	-(CH ₂) ₃-	Ethoxyl methyl
Hydrogen	Hydrogen	-(CH ₂) ₃-	The 2-methoxy ethyl	Hydrogen	Hydrogen	-(CH ₂) ₃-	Hydroxymethyl
Hydrogen	Hydrogen	-(CH ₂) ₃-	The 2-hydroxyethyl	Hydrogen	Hydrogen	-(CH ₂) ₃-	Hydroxymethyl
Hydrogen	Hydrogen	-(CH ₂) ₃-	The 2-hydroxyethyl	Hydrogen	Hydrogen	-(CH ₂) ₄-	Methyl
Hydrogen	Hydrogen	-(CH ₂) ₄-	Ethyl	Hydrogen	Hydrogen	-(CH ₂) ₄-	Methyl
Hydrogen	Hydrogen	-(CH ₂) ₄-	Ethyl	Hydrogen	Hydrogen	-(CH ₂) ₄-	N-propyl
Hydrogen	Hydrogen	-(CH ₂) ₄-	Normal-butyl	Hydrogen	Hydrogen	-(CH ₂) ₄-	N-propyl
Hydrogen	Hydrogen	-(CH ₂) ₄-	Normal-butyl	Hydrogen	Hydrogen	-(CH ₂) ₄-	Ethoxyl methyl
Hydrogen	Hydrogen	-(CH ₂) ₄-	The 2-methoxy ethyl	Hydrogen	Hydrogen	-(CH ₂) ₄-	Ethoxyl methyl
Hydrogen	Hydrogen	-(CH ₂) ₄-	The 2-methoxy ethyl	Hydrogen	Hydrogen	-(CH ₂) ₄-	Hydroxymethyl
Hydrogen	Hydrogen	-(CH ₂) ₄-	The 2-hydroxyethyl	Hydrogen	Hydrogen	-(CH ₂) ₄-	Hydroxymethyl
Hydrogen	Hydrogen	-(CH ₂) ₄-	The 2-hydroxyethyl	Hydrogen	Hydrogen	-(CH ₂) ₅-	Methyl
Hydrogen	Hydrogen	-(CH ₂) ₅-	Ethyl	Hydrogen	Hydrogen	-(CH ₂) ₅-	Methyl
Hydrogen	Hydrogen	-(CH ₂) ₅-	Ethyl	Hydrogen	Hydrogen	-(CH ₂) ₅-	N-propyl
Hydrogen	Hydrogen	-(CH ₂) ₅-	Normal-butyl	Hydrogen	Hydrogen	-(CH ₂) ₅-	N-propyl

Hydrogen	Hydrogen	-(CH ₂) ₅-	Ethoxyl methyl
Hydrogen	Hydrogen	-(CH ₂) ₅-	Ethoxyl methyl	Hydrogen	Hydrogen	-(CH ₂) ₅-	The 2-methoxy ethyl
Hydrogen	Hydrogen	-(CH ₂) ₅-	Hydroxymethyl	Hydrogen	Hydrogen	-(CH ₂) ₅-	The 2-methoxy ethyl
Hydrogen	Hydrogen	-(CH ₂) ₅-	Hydroxymethyl	Hydrogen	Hydrogen	-(CH ₂) ₅-	The 2-hydroxyethyl
Hydrogen	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Methyl	Hydrogen	Hydrogen	-(CH ₂) ₅-	The 2-hydroxyethyl
Hydrogen	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Methyl	Hydrogen	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Ethyl
Hydrogen	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	N-propyl	Hydrogen	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Ethyl
Hydrogen	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	N-propyl	Hydrogen	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Normal-butyl
Hydrogen	Hydrogen	-CH ₂C(CH ₃) ₂CH	Ethoxyl methyl	Hydrogen	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Normal-butyl
Hydrogen	Hydrogen	-CH ₂C(CH ₃) ₂CH	Ethoxyl methyl	Hydrogen	Hydrogen	-CH ₂C(CH ₃)2CH ₂-	The 2-methoxy ethyl
Hydrogen	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Hydroxymethyl	Hydrogen	Hydrogen	-CH ₂C(CH ₃)2CH ₂-	The 2-methoxy ethyl
Hydrogen	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Hydroxymethyl	Hydrogen	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	The 2-hydroxyethyl
Sec.-propyl	Hydrogen	-(CH ₂) ₂-	Methyl	Hydrogen	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	The 2-hydroxyethyl
Sec.-propyl	Hydrogen	-(CH ₂) ₂-	Methyl	Sec.-propyl	Hydrogen	-(CH ₂) ₂-	Ethyl
Sec.-propyl	Hydrogen	-(CH ₂) ₂-	N-propyl	Sec.-propyl	Hydrogen	-(CH ₂) ₂-	Ethyl
Sec.-propyl	Hydrogen	-(CH ₂) ₂-	N-propyl	Sec.-propyl	Hydrogen	-(CH ₂) ₂-	Normal-butyl
Sec.-propyl	Hydrogen	-(CH ₂) ₂-	Ethoxyl methyl	Sec.-propyl	Hydrogen	-(CH ₂) ₂-	Normal-butyl
Sec.-propyl	Hydrogen	-(CH ₂) ₂-	Ethoxyl methyl	Sec.-propyl	Hydrogen	-(CH ₂) ₂-	The 2-methoxy ethyl
Sec.-propyl	Hydrogen	-(CH ₂) ₂-	Hydroxymethyl	Sec.-propyl	Hydrogen	-(CH ₂) ₂-	The 2-methoxy ethyl
Sec.-propyl	Hydrogen	-(CH ₂) ₂-	Hydroxymethyl	Sec.-propyl	Hydrogen	-(CH ₂) ₂-	The 2-hydroxyethyl
Sec.-propyl	Hydrogen	-(CH ₂) ₃-	Methyl	Sec.-propyl	Hydrogen	-(CH ₂) ₂-	The 2-hydroxyethyl
Sec.-propyl	Hydrogen	-(CH ₂) ₃-	Methyl	Sec.-propyl	Hydrogen	-(CH ₂) ₃-	Ethyl
Sec.-propyl	Hydrogen	-(CH ₂) ₃-	N-propyl	Sec.-propyl	Hydrogen	-(CH ₂) ₃-	Ethyl
Sec.-propyl	Hydrogen	-(CH ₂) ₃-	N-propyl	Sec.-propyl	Hydrogen	-(CH ₂) ₃-	Normal-butyl
Sec.-propyl	Hydrogen	-(CH ₂) ₃-	Ethoxyl methyl	Sec.-propyl	Hydrogen	-(CH ₂) ₃-	Normal-butyl
Sec.-propyl	Hydrogen	-(CH ₂) ₃-	Ethoxyl methyl	Sec.-propyl	Hydrogen	-(CH ₂) ₃-	The 2-methoxy ethyl
Sec.-propyl	Hydrogen	-(CH ₂) ₃-	Hydroxymethyl	Sec.-propyl	Hydrogen	-(CH ₂) ₃-	The 2-methoxy ethyl
Sec.-propyl	Hydrogen	-(CH ₂) ₃-	Hydroxymethyl	Sec.-propyl	Hydrogen	-(CH ₂) ₃-	The 2-hydroxyethyl
Sec.-propyl	Hydrogen	-(CH ₂) ₄-	Methyl	Sec.-propyl	Hydrogen	-(CH ₂) ₃-	The 2-hydroxyethyl

Sec.-propyl	Hydrogen	-(CH ₂) ₄-	Ethyl
Sec.-propyl	Hydrogen	-(CH ₂) ₄-	Ethyl	Sec.-propyl	Hydrogen	-(CH2)4-	N-propyl
Sec.-propyl	Hydrogen	-(CH ₂) ₄-	Normal-butyl	Sec.-propyl	Hydrogen	-(CH2)4-	N-propyl
Sec.-propyl	Hydrogen	-(CH ₂) ₄-	Normal-butyl	Sec.-propyl	Hydrogen	-(CH ₂) ₄-	Ethoxyl methyl
Sec.-propyl	Hydrogen	-(CH ₂) ₄-	The 2-methoxy ethyl	Sec.-propyl	Hydrogen	-(CH ₂) ₄-	Ethoxyl methyl
Sec.-propyl	Hydrogen	-(CH ₂) ₄-	The 2-methoxy ethyl	Sec.-propyl	Hydrogen	-(CH ₂) ₄-	Hydroxymethyl
Sec.-propyl	Hydrogen	-(CH ₂) ₄-	The 2-hydroxyethyl	Sec.-propyl	Hydrogen	-(CH ₂) ₄-	Hydroxymethyl
Sec.-propyl	Hydrogen	-(CH ₂) ₄-	The 2-hydroxyethyl	Sec.-propyl	Hydrogen	-(CH ₂) ₅-	Methyl
Sec.-propyl	Hydrogen	-(CH ₂) ₅-	Ethyl	Sec.-propyl	Hydrogen	-(CH ₂) ₅-	Methyl
Sec.-propyl	Hydrogen	-(CH ₂) ₅-	Ethyl	Sec.-propyl	Hydrogen	-(CH ₂) ₅-	N-propyl
Sec.-propyl	Hydrogen	-(CH ₂) ₅-	Normal-butyl	Sec.-propyl	Hydrogen	-(CH ₂) ₅-	N-propyl
Sec.-propyl	Hydrogen	-(CH ₂) ₅-	Normal-butyl	Sec.-propyl	Hydrogen	-(CH ₂) ₅-	Ethoxyl methyl
Sec.-propyl	Hydrogen	-(CH ₂) ₅-	The 2-methoxy ethyl	Sec.-propyl	Hydrogen	-(CH ₂) ₅-	Ethoxyl methyl
Sec.-propyl	Hydrogen	-(CH ₂) ₅-	The 2-methoxy ethyl	Sec.-propyl	Hydrogen	-(CH ₂) ₅-	Hydroxymethyl
Sec.-propyl	Hydrogen	-(CH ₂) ₅-	The 2-hydroxyethyl	Sec.-propyl	Hydrogen	-(CH ₂) ₅-	Hydroxymethyl
Sec.-propyl	Hydrogen	-(CH ₂) ₅-	The 2-hydroxyethyl	Sec.-propyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Methyl
Sec.-propyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Ethyl	Sec.-propyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Methyl
Sec.-propyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Ethyl	Sec.-propyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	N-propyl
Sec.-propyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Normal-butyl	Sec.-propyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	N-propyl
Sec.-propyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Normal-butyl	Sec.-propyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Ethoxyl methyl
Sec.-propyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	The 2-methoxy ethyl	Sec.-propyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Ethoxyl methyl
Sec.-propyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	The 2-methoxy ethyl	Sec.-propyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Hydroxymethyl
Sec.-propyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	The 2-hydroxyethyl	Sec.-propyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Hydroxymethyl
Sec.-propyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	The 2-hydroxyethyl	Methyl	Hydrogen	-(CH ₂) ₂-	Methyl
Methyl	Hydrogen	-(CH ₂) ₂-	Ethyl	Methyl	Hydrogen	-(CH ₂) ₂-	Methyl
Methyl	Hydrogen	-(CH ₂) ₂-	Ethyl	Methyl	Hydrogen	-(CH ₂) ₂-	N-propyl
Methyl	Hydrogen	-(CH ₂) ₂-	Normal-butyl	Methyl	Hydrogen	-(CH ₂) ₂-	N-propyl
Methyl	Hydrogen	-(CH ₂) ₂-	Normal-butyl	Methyl	Hydrogen	-(CH ₂) ₂-	Ethoxyl methyl
Methyl	Hydrogen	-(CH ₂) ₂-	The 2-methoxy ethyl	Methyl	Hydrogen	-(CH ₂) ₂-	Ethoxyl methyl

Methyl	Hydrogen	-(CH ₂) ₂-	Hydroxymethyl
Methyl	Hydrogen	-(CH ₂) ₂-	Hydroxymethyl	Methyl	Hydrogen	-(CH ₂) ₂-	The 2-hydroxyethyl
Methyl	Hydrogen	-(CH ₂) ₃-	Methyl	Methyl	Hydrogen	-(CH ₂) ₂-	The 2-hydroxyethyl
Methyl	Hydrogen	-(CH ₂) ₃-	Methyl	Methyl	Hydrogen	-(CH ₂) ₃-	Ethyl
Methyl	Hydrogen	-(CH ₂) ₃-	N-propyl	Methyl	Hydrogen	-(CH ₂) ₃-	Ethyl
Methyl	Hydrogen	-(CH ₂) ₃-	N-propyl	Methyl	Hydrogen	-(CH ₂) ₃-	Normal-butyl
Methyl	Hydrogen	-(CH ₂) ₃-	Ethoxyl methyl	Methyl	Hydrogen	-(CH ₂) ₃-	Normal-butyl
Methyl	Hydrogen	-(CH ₂) ₃-	Ethoxyl methyl	Methyl	Hydrogen	-(CH ₂) ₃-	The 2-methoxy ethyl
Methyl	Hydrogen	-(CH ₂) ₃-	Hydroxymethyl	Methyl	Hydrogen	-(CH ₂) ₃-	The 2-methoxy ethyl
Methyl	Hydrogen	-(CH ₂) ₃-	Hydroxymethyl	Methyl	Hydrogen	-(CH ₂) ₃-	The 2-hydroxyethyl
Methyl	Hydrogen	-(CH ₂) ₄-	Methyl	Methyl	Hydrogen	-(CH ₂) ₃-	The 2-hydroxyethyl
Methyl	Hydrogen	-(CH ₂) ₄-	Methyl	Methyl	Hydrogen	-(CH ₂) ₄-	Ethyl
Methyl	Hydrogen	-(CH ₂) ₄-	N-propyl	Methyl	Hydrogen	-(CH ₂) ₄-	Ethyl
Methyl	Hydrogen	-(CH ₂) ₄-	N-propyl	Methyl	Hydrogen	-(CH ₂) ₄-	Normal-butyl
Methyl	Hydrogen	-(CH ₂) ₄-	Ethoxyl methyl	Methyl	Hydrogen	-(CH ₂) ₄-	Normal-butyl
Methyl	Hydrogen	-(CH ₂) ₄-	Ethoxyl methyl	Methyl	Hydrogen	(CH ₂) ₄-	The 2-methoxy ethyl
Methyl	Hydrogen	-(CH ₂) ₄-	Hydroxymethyl	Methyl	Hydrogen	(CH ₂) ₄-	The 2-methoxy ethyl
Methyl	Hydrogen	-(CH ₂) ₄-	Hydroxymethyl	Methyl	Hydrogen	-(CH ₂) ₄-	The 2-hydroxyethyl
Methyl	Hydrogen	-(CH ₂) ₅-	Methyl	Methyl	Hydrogen	-(CH ₂) ₄-	The 2-hydroxyethyl
Methyl	Hydrogen	-(CH ₂) ₅-	Methyl	Methyl	Hydrogen	-(CH ₂) ₅-	Ethyl
Methyl	Hydrogen	-(CH ₂) ₅-	N-propyl	Methyl	Hydrogen	-(CH ₂) ₅-	Ethyl
Methyl	Hydrogen	-(CH ₂) ₅-	N-propyl	Methyl	Hydrogen	-(CH ₂) ₅-	Normal-butyl
Methyl	Hydrogen	-(CH ₂) ₅-	Ethoxyl methyl	Methyl	Hydrogen	-(CH ₂) ₅-	Normal-butyl
Methyl	Hydrogen	-(CH ₂) ₅-	Ethoxyl methyl	Methyl	Hydrogen	-(CH ₂) ₅-	The 2-methoxy ethyl
Methyl	Hydrogen	-(CH ₂) ₅-	Hydroxymethyl	Methyl	Hydrogen	-(CH ₂) ₅-	The 2-methoxy ethyl
Methyl	Hydrogen	-(CH ₂) ₅-	Hydroxymethyl	Methyl	Hydrogen	-(CH ₂) ₅-	The 2-hydroxyethyl
Methyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Methyl	Methyl	Hydrogen	-(CH ₂) ₅-	The 2-hydroxyethyl
Methyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Methyl	Methyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Ethyl
Methyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	N-propyl	Methyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Ethyl

Methyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Normal-butyl
Methyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Normal-butyl	Methyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Ethoxyl methyl
Methyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	The 2-methoxy ethyl	Methyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Ethoxyl methyl
Methyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	The 2-methoxy ethyl	Methyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Hydroxymethyl
Methyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	The 2-hydroxyethyl	Methyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	Hydroxymethyl
Methyl	Hydrogen	-CH ₂C(CH ₃) ₂CH ₂-	The 2-hydroxyethyl	Methyl	Methyl	-(CH ₂) ₂-	Methyl
Methyl	Methyl	-(CH ₂) ₂-	Ethyl	Methyl	Methyl	-(CH ₂) ₂-	Methyl
Methyl	Methyl	-(CH ₂) ₂-	Ethyl	Methyl	Methyl	-(CH ₂) ₂-	N-propyl
Methyl	Methyl	-(CH ₂) ₂-	Normal-butyl	Methyl	Methyl	-(CH ₂) ₂-	N-propyl
Methyl	Methyl	-(CH ₂) ₂-	Normal-butyl	Methyl	Methyl	-(CH ₂) ₂-	Ethoxyl methyl
Methyl	Methyl	-(CH ₂) ₂-	The 2-methoxy ethyl	Methyl	Methyl	-(CH ₂) ₂-	Ethoxyl methyl
Methyl	Methyl	-(CH ₂) ₂-	The 2-methoxy ethyl	Methyl	Methyl	-(CH ₂) ₂-	Hydroxymethyl
Methyl	Methyl	-(CH ₂) ₂-	The 2-hydroxyethyl	Methyl	Methyl	-(CH ₂) ₂-	Hydroxymethyl
Methyl	Methyl	-(CH ₂) ₂-	The 2-hydroxyethyl	Methyl	Methyl	-(CH ₂) ₃-	Methyl
Methyl	Methyl	-(CH ₂) ₃-	Ethyl	Methyl	Methyl	-(CH ₂) ₃-	Methyl
Methyl	Methyl	-(CH ₂) ₃-	Ethyl	Methyl	Methyl	-(CH ₂) ₃-	N-propyl
Methyl	Methyl	-(CH ₂) ₃-	Normal-butyl	Methyl	Methyl	-(CH ₂) ₃-	N-propyl
Methyl	Methyl	-(CH ₂) ₃-	Normal-butyl	Methyl	Methyl	-(CH ₂) ₃-	Ethoxyl methyl
Methyl	Methyl	-(CH ₂) ₃-	The 2-methoxy ethyl	Methyl	Methyl	-(CH ₂) ₃-	Ethoxyl methyl
Methyl	Methyl	-(CH ₂) ₃-	The 2-methoxy ethyl	Methyl	Methyl	-(CH ₂) ₃-	Hydroxymethyl
Methyl	Methyl	-(CH ₂) ₃-	The 2-hydroxyethyl	Methyl	Methyl	-(CH ₂) ₃-	Hydroxymethyl
Methyl	Methyl	-(CH ₂) ₃-	The 2-hydroxyethyl	Methyl	Methyl	-(CH ₂) ₄-	Methyl
Methyl	Methyl	-(CH ₂) ₄-	Ethyl	Methyl	Methyl	-(CH ₂) ₄-	Methyl
Methyl	Methyl	-(CH ₂) ₄-	Ethyl	Methyl	Methyl	-(CH ₂) ₄-	N-propyl
Methyl	Methyl	-(CH ₂) ₄-	Normal-butyl	Methyl	Methyl	-(CH ₂) ₄-	N-propyl
Methyl	Methyl	-(CH ₂) ₄-	Normal-butyl	Methyl	Methyl	-(CH ₂) ₄-	Ethoxyl methyl
Methyl	Methyl	-(CH ₂) ₄-	The 2-methoxy ethyl	Methyl	Methyl	-(CH ₂) ₄-	Ethoxyl methyl
Methyl	Methyl	-(CH ₂) ₄-	The 2-methoxy ethyl	Methyl	Methyl	-(CH ₂) ₄-	Hydroxymethyl
Methyl	Methyl	-(CH ₂) ₄-	The 2-hydroxyethyl	Methyl	Methyl	-(CH ₂) ₄-	Hydroxymethyl

Methyl	Methyl	-(CH ₂) ₅-	Methyl
Methyl	Methyl	-(CH ₂) ₅-	Methyl	Methyl	Methyl	-(CH ₂) ₅-	Ethyl
Methyl	Methyl	-(CH ₂) ₅-	N-propyl	Methyl	Methyl	-(CH ₂) ₅-	Ethyl
Methyl	Methyl	-(CH ₂) ₅-	N-propyl	Methyl	Methyl	-(CH ₂) ₅-	Normal-butyl
Methyl	Methyl	-(CH ₂) ₅-	Ethoxyl methyl	Methyl	Methyl	-(CH ₂) ₅-	Normal-butyl
Methyl	Methyl	-(CH ₂) ₅-	Ethoxyl methyl	Methyl	Methyl	-(CH ₂) ₅-	The 2-methoxy ethyl
Methyl	Methyl	-(CH ₂) ₅-	Hydroxymethyl	Methyl	Methyl	-(CH ₂) ₅-	The 2-methoxy ethyl
Methyl	Methyl	-(CH ₂) ₅-	Hydroxymethyl	Methyl	Methyl	-(CH ₂) ₅-	The 2-hydroxyethyl
Methyl	Methyl	-CH ₂C(CH ₃) ₂CH ₂-	Methyl	Methyl	Methyl	-(CH ₂) ₅-	The 2-hydroxyethyl
Methyl	Methyl	-CH ₂C(CH ₃) ₂CH ₂-	Methyl	Methyl	Methyl	-CH ₂C(CH ₃) ₂CH ₂-	Ethyl
Methyl	Methyl	-CH ₂C(CH ₃) ₂CH ₂-	N-propyl	Methyl	Methyl	-CH ₂C(CH ₃) ₂CH ₂-	Ethyl
Methyl	Methyl	-CH ₂C(CH ₃) ₂CH ₂-	N-propyl	Methyl	Methyl	-CH ₂C(CH ₃) ₂CH ₂-	Normal-butyl
Methyl	Methyl	-CH ₂C(CH ₃) ₂CH ₂-	Ethoxyl methyl	Methyl	Methyl	-CH ₂C(CH ₃) ₂CH ₂-	Normal-butyl
Methyl	Methyl	-CH ₂C(CH ₃) ₂CH ₂-	Ethoxyl methyl	Methyl	Methyl	-CH ₂C(CH ₃) ₂CH ₂-	The 2-methoxy ethyl
Methyl	Methyl	-CH ₂C(CH ₃) ₂CH ₂-	Hydroxymethyl	Methyl	Methyl	-CH ₂C(CH ₃) ₂CH ₂-	The 2-methoxy ethyl
Methyl	Methyl	-CH ₂C(CH ₃) ₂CH ₂-	Hydroxymethyl	Methyl	Methyl	-CH ₂C(CH ₃) ₂CH ₂-	The 2-hydroxyethyl
Morpholine		-(CH ₂) ₂-	Methyl	Methyl	Methyl	-CH ₂C(CH ₃) ₂CH ₂-	The 2-hydroxyethyl
Morpholine		-(CH ₂) ₂-	Methyl	Morpholine		-(CH ₂) ₂-	Ethyl
Morpholine		-(CH ₂) ₂-	N-propyl	Morpholine		-(CH ₂) ₂-	Ethyl
Morpholine		-(CH ₂) ₂-	N-propyl	Morpholine		-(CH ₂) ₂-	Normal-butyl
Morpholine		-(CH ₂) ₂-	Ethoxyl methyl	Morpholine		-(CH ₂) ₂-	Normal-butyl
Morpholine		-(CH ₂) ₂-	Ethoxyl methyl	Morpholine		-(CH ₂) ₂-	The 2-methoxy ethyl
Morpholine		-(CH ₂) ₂-	Hydroxymethyl	Morpholine		-(CH ₂) ₂-	The 2-methoxy ethyl
Morpholine		-(CH ₂) ₂-	Hydroxymethyl	Morpholine		-(CH ₂) ₂-	The 2-hydroxyethyl
Morpholine		-(CH ₂) ₃-	Methyl	Morpholine		-(CH ₂) ₂-	The 2-hydroxyethyl
Morpholine		-(CH ₂) ₃-	Methyl	Morpholine		-(CH ₂) ₃-	Ethyl
Morpholine		-(CH ₂) ₃-	N-propyl	Morpholine		-(CH ₂) ₃-	Ethyl
Morpholine		-(CH ₂) ₃-	N-propyl	Morpholine		-(CH ₂) ₃-	Normal-butyl
Morpholine		-(CH ₂) ₃-	Ethoxyl methyl	Morpholine		-(CH ₂) ₃-	Normal-butyl

Morpholine	-(CH ₂) ₃-	The 2-methoxy ethyl
Morpholine	-(CH ₂) ₃-	The 2-methoxy ethyl	Morpholine	-(CH ₂) ₃-	Hydroxymethyl
Morpholine	-(CH ₂) ₃-	The 2-hydroxyethyl	Morpholine	-(CH ₂) ₃-	Hydroxymethyl
Morpholine	-(CH ₂) ₃-	The 2-hydroxyethyl	Morpholine	-(CH ₂) ₄-	Methyl
Morpholine	-(CH ₂) ₄-	Ethyl	Morpholine	-(CH ₂) ₄-	Methyl
Morpholine	-(CH ₂) ₄-	Ethyl	Morpholine	-(CH ₂) ₄-	N-propyl
Morpholine	-(CH ₂) ₄-	Normal-butyl	Morpholine	-(CH ₂) ₄-	N-propyl
Morpholine	-(CH ₂) ₄-	Normal-butyl	Morpholine	-(CH ₂) ₄-	Ethoxyl methyl
Morpholine	-(CH ₂) ₄-	The 2-methoxy ethyl	Morpholine	-(CH ₂) ₄-	Ethoxyl methyl
Morpholine	-(CH ₂) ₄-	The 2-methoxy ethyl	Morpholine	-(CH ₂) ₄-	Hydroxymethyl
Morpholine	-(CH ₂) ₄-	The 2-hydroxyethyl	Morpholine	-(CH ₂) ₄-	Hydroxymethyl
Morpholine	-(CH ₂) ₄-	The 2-hydroxyethyl	Morpholine	-(CH ₂) ₅-	Methyl
Morpholine	-(CH ₂) ₅-	Ethyl	Morpholine	-(CH ₂) ₅-	Methyl
Morpholine	-(CH ₂) ₅-	Ethyl	Morpholine	-(CH ₂) ₅-	N-propyl
Morpholine	-(CH ₂) ₅-	Normal-butyl	Morpholine	-(CH ₂) ₅-	N-propyl
Morpholine	-(CH ₂) ₅-	Normal-butyl	Morpholine	-(CH ₂) ₅-	Ethoxyl methyl
Morpholine	-(CH ₂) ₅-	The 2-methoxy ethyl	Morpholine	-(CH ₂) ₅-	Ethoxyl methyl
Morpholine	-(CH ₂) ₅-	The 2-methoxy ethyl	Morpholine	-(CH ₂) ₅-	Hydroxymethyl
Morpholine	-(CH ₂) ₅-	The 2-hydroxyethyl	Morpholine	-(CH ₂) ₅-	Hydroxymethyl
Morpholine	-(CH ₂) ₅-	The 2-hydroxyethyl	Morpholine	-CH ₂C(CH ₃) ₂CH ₂-	Methyl
Morpholine	-CH ₂C(CH ₃) ₂CH ₂-	Ethyl	Morpholine	-CH ₂C(CH ₃) ₂CH ₂-	Methyl
Morpholine	-CH ₂C(CH ₃) ₂CH ₂-	Ethyl	Morpholine	-CH ₂C(CH ₃) ₂CH ₂-	N-propyl
Morpholine	-CH ₂C(CH ₃) ₂CH ₂-	Normal-butyl	Morpholine	-CH ₂C(CH ₃) ₂CH ₂-	N-propyl
Morpholine	-CH ₂C(CH ₃) ₂CH ₂-	Normal-butyl	Morpholine	-CH ₂C(CH ₃) ₂CH ₂-	Ethoxyl methyl
Morpholine	-CH ₂C(CH ₃) ₂CH ₂-	The 2-methoxy ethyl	Morpholine	-CH ₂C(CH ₃) ₂CH ₂-	Ethoxyl methyl

Cytokine induction in the human cell

Have been found that compound of the present invention is regulated the cytokine biosynthesizing by the generation of inducing interferon α and/or tumor necrosis factor alpha when using method check as described below.

Use external human blood cell's system evaluation cytokine induction.Active based on people such as Testerman at " Cytokine Induction by the Immunomodulators Imiquimod andS-27609 ", Journal ofLeukocyte Biology, 58, that describes among the 365-372 (September, 1995) enters the Interferon, rabbit in the substratum and the measurement of tumour necrosis factor (α) (being respectively IFN and TNF) to secretion.

Cultivate the preparation of the hemocyte of usefulness

Collect whole blood by venipuncture to EDTA vacuum (vacutainer) pipe from the human donor of health.Use HISTOPAQUE-1077 by density gradient centrifugation from separation of whole blood peripheral blood lymphocytes (PBMC).Blood Dulbecco ' s phosphate buffered saline (PBS) (DPBS) or Hank ' s balanced salt solution (HBSS) were diluted with 1: 1.The PBMC layer collected and with DPBS or HBSS washed twice, and with 4 * 10 ⁶Cell/mL is suspended in the RPMI perfect medium once more.With PBMC suspension join the flat sterile tissue culture plate in 48 holes that comprise equivalent RPMI perfect medium (containing test compound) (Costar, Cambridge, MA or Becton Dickinson Labware, Lincoln Park, NJ) in.

Compound

With compound dissolution in dimethyl sulfoxide (DMSO) (DMSO).DMSO concentration should not surpass 1% the ultimate density be used for joining culture hole.Compound is tested with the concentration of 30-0.014 μ M usually.

Cultivate

The solution of test compound is joined in first hole that comprises the RPMI perfect medium with 60 μ M, and in the hole, make a series of three times of dilutions.Then PBMC suspension is joined in the hole with equivalent, make test compound concentration be in required scope (30-0.014 μ M).The ultimate density of PBMC suspension is 2 * 10 ⁶Cell/mL.Plate is covered with the aseptic plastic lid, leniently mix, under 5% carbon dioxide atmosphere, cultivated 18 to 24 hours then at 37 ℃.

Separate

After cultivating, with plate under 4 ℃ with centrifugal 10 minutes of 1000rpm (about 200xg).

Transfer in the aseptic polypropylene test tube with the aseptic polypropylene transfer pipet not celliferous culture supernatants of taking-up and with it.Before analyzing, sample is remained on-30 to-70 ℃.Sample is by elisa assay Interferon, rabbit (α) and by ELISA or IGEN analysis of experiments tumour necrosis factor (α).

The elisa assay of Interferon, rabbit (α) and tumour necrosis factor (α)

Use derives from PBL Biomedical Laboratories, New Brunswick, and the Human Multi-Species test kit of NJ is measured Interferon, rabbit (α) concentration by ELISA.The result is expressed as pg/mL.

Use derives from Biosource International, Camarillo, and the ELISA kit measurement tumour necrosis factor (α) of CA is concentration (TNF).Perhaps, by ORIGEN M-Series immunoassay and deriving from International, Gaithersburg, reading is measured TNF concentration on the IGEN M-8 analyzer of MD.Immunoassay is used and to be derived from Biosource International, and Camarillo, the people TNF of CA catch and to detect antibody right.The result is expressed as pg/mL.

The patent that this paper quotes, patent document and disclosed complete disclosing are all incorporated into this paper as a reference in full, are incorporated into this paper respectively as each.Multiple change of the present invention and variation will become apparent to those skilled in the art that it does not depart from the scope of the present invention and spirit.Should be appreciated that the present invention is not subjected to exemplary that this paper proposes and the excessive restriction of embodiment, and this embodiment and embodiment exist as an example just, scope of the present invention only is subjected to the restriction of the claim of this paper.

Claims

1. the compound of formula (I):

Wherein:

R ₁And R ₁' be independently selected from:

Hydrogen,

Alkyl,

Thiazolinyl,

Aryl,

Aryl alkylene,

Heteroaryl,

The heteroaryl alkylidene group,

Heterocyclic radical,

The heterocyclic radical alkylidene group and

Be selected from alkyl, thiazolinyl, aryl, aryl alkylene, heteroaryl, heteroaryl alkylidene group, heterocyclic radical or the heterocyclic radical alkylidene groups that following substituting group replaces by one or more:

Hydroxyl,

Alkyl,

Haloalkyl,

Hydroxyalkyl,

Alkoxyl group,

Halogenated alkoxy,

Halogen,

Cyano group,

Nitro,

Aryl sulfonyl,

Alkyl sulphonyl and

-N(R ₉) ₂，

A and b are 1 to 6 integer independently, and condition is a+b≤7;

W be selected from key ,-C (O)-and-S (O) ₂-;

R ₆Be selected from=O and=S;

R ₉Be selected from hydrogen and alkyl;

R " be hydrogen or non-interfering substituting group;

R _AAnd R _BBe independently selected from:

Hydrogen,

Halogen,

Alkyl,

Thiazolinyl,

Alkoxyl group,

The alkyl sulfenyl and

-N(R ₉) ₂；

Or R _AAnd R _BForm unsubstituted altogether or by one or more R _aThe fused-aryl ring that group replaces, or form unsubstituted or by one or more R _c5 to 7 yuan of saturated rings of condensed that group replaces;

R _aBe selected from:

Fluorine,

Alkyl,

Haloalkyl,

Alkoxyl group and

-N(R ₉) ₂；

R _bBe selected from:

Halogen,

Hydroxyl,

Alkyl,

Thiazolinyl,

Haloalkyl,

Alkoxyl group and

-N (R ₉) ₂With

R _cBe selected from:

Halogen,

Hydroxyl,

Alkyl,

Thiazolinyl,

Haloalkyl,

Alkoxyl group,

The alkyl sulfenyl and

-N(R ₉) ₂；

Or its pharmacologically acceptable salt.

2. the compound of formula (Ia):

Wherein:

R ₁And R ₁' be independently selected from:

Hydrogen,

Alkyl,

Thiazolinyl,

Aryl,

Aryl alkylene,

Heteroaryl,

The heteroaryl alkylidene group,

Heterocyclic radical,

The heterocyclic radical alkylidene group and

Hydroxyl,

Alkyl,

Haloalkyl,

Hydroxyalkyl,

Alkoxyl group,

Halogenated alkoxy,

Halogen,

Cyano group,

Nitro,

Aryl sulfonyl,

Alkyl sulphonyl and

-N(R ₉) ₂，

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

R ₅Be selected from:

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

W be selected from key ,-C (O)-and-S (O) ₂-;

A and b are 1 to 6 integer independently, and condition is a+b≤7;

R _AAnd R _BBe independently selected from:

Hydrogen,

Halogen,

Alkyl,

Thiazolinyl,

Alkoxyl group,

The alkyl sulfenyl and

-N(R ₉) ₂；

R _aBe selected from:

Fluorine,

Alkyl,

Haloalkyl,

Alkoxyl group and

-N(R ₉) ₂；

R _bBe selected from:

Halogen,

Hydroxyl,

Alkyl,

Thiazolinyl,

Haloalkyl,

Alkoxyl group and

-N (R ₉) ₂With

R _cBe selected from:

Halogen,

Hydroxyl,

Alkyl,

Thiazolinyl,

Haloalkyl,

Alkoxyl group,

The alkyl sulfenyl and

-N(R ₉) ₂；

Or its pharmacologically acceptable salt.

3. the compound of formula (Ib):

Wherein:

R ₁And R ₁' be independently selected from:

Hydrogen,

Alkyl,

Thiazolinyl,

Aryl,

Aryl alkylene,

Heteroaryl,

The heteroaryl alkylidene group,

Heterocyclic radical,

The heterocyclic radical alkylidene group and

Hydroxyl,

Alkyl,

Haloalkyl,

Hydroxyalkyl,

Alkoxyl group,

Halogenated alkoxy,

Halogen,

Cyano group,

Nitro,

Aryl sulfonyl,

Alkyl sulphonyl and

-N(R ₉) ₂，

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

R ₅Be selected from:

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

W be selected from key ,-C (O)-and-S (O) ₂-;

A and b are 1 to 6 integer independently, and condition is a+b≤7;

And R _{A '}And R _{B '}Be independently selected from:

Hydrogen,

Halogen,

Alkyl,

Thiazolinyl,

Alkoxyl group,

The alkyl sulfenyl and

-N(R ₉) ₂；

Or its pharmacologically acceptable salt.

4. the compound of formula (II):

Wherein:

R ₁And R ₁' be independently selected from:

Hydrogen,

Alkyl,

Thiazolinyl,

Aryl,

Aryl alkylene,

Heteroaryl,

The heteroaryl alkylidene group,

Heterocyclic radical,

The heterocyclic radical alkylidene group and

Hydroxyl,

Alkyl,

Haloalkyl,

Hydroxyalkyl,

Alkoxyl group,

Halogenated alkoxy,

Halogen,

Cyano group,

Nitro,

Aryl sulfonyl,

Alkyl sulphonyl and

-N(R ₉) ₂，

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

R ₅Be selected from:

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

W be selected from key ,-C (O)-and-S (O) ₂-;

A and b are 1 to 6 integer independently, and condition is a+b≤7;

N is 0 to 4;

Or its pharmacologically acceptable salt.

5. the compound of formula (IIa):

Wherein:

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

R ₅Be selected from:

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

W be selected from key ,-C (O)-and-S (O) ₂-;

A and b are 1 to 6 integer independently, and condition is a+b≤7;

N is 0 to 4;

Or its pharmacologically acceptable salt.

6. the compound of formula (III):

Wherein:

R ₁And R ₁' be independently selected from:

Hydrogen,

Alkyl,

Thiazolinyl,

Aryl,

Aryl alkylene,

Heteroaryl,

The heteroaryl alkylidene group,

Heterocyclic radical,

The heterocyclic radical alkylidene group and

Hydroxyl,

Alkyl,

Haloalkyl,

Hydroxyalkyl,

Alkoxyl group,

Halogenated alkoxy,

Halogen,

Cyano group,

Nitro,

Aryl sulfonyl,

Alkyl sulphonyl and

-N(R ₉) ₂，

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

R ₅Be selected from:

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

W be selected from key ,-C (O)-and-S (O) ₂-;

A and b are 1 to 6 integer independently, and condition is a+b≤7;

N is 0 to 4;

Or its pharmacologically acceptable salt.

7. be selected from formula (IV), (V), (VI) and compound (VII):

Wherein:

R ₁And R ₁' be independently selected from:

Hydrogen,

Alkyl,

Thiazolinyl,

Aryl,

Aryl alkylene,

Heteroaryl,

The heteroaryl alkylidene group,

Heterocyclic radical,

The heterocyclic radical alkylidene group and

Hydroxyl,

Alkyl,

Haloalkyl,

Hydroxyalkyl,

Alkoxyl group,

Halogenated alkoxy,

Halogen,

Cyano group,

Nitro,

Aryl sulfonyl,

Alkyl sulphonyl and

-N(R ₉) ₂，

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

R ₅Be selected from:

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

W be selected from key ,-C (O)-and-S (O) ₂-;

A and b are 1 to 6 integer independently, and condition is a+b≤7;

M is 0 to 3;

Or its pharmacologically acceptable salt.

8. be selected from following formula (VIII), (IX), (X) and compound (XI):

Wherein:

R ₁And R ₁' be independently selected from:

Hydrogen,

Alkyl,

Thiazolinyl,

Aryl,

Aryl alkylene,

Heteroaryl,

The heteroaryl alkylidene group,

Heterocyclic radical,

The heterocyclic radical alkylidene group and

Hydroxyl,

Alkyl,

Haloalkyl,

Hydroxyalkyl,

Alkoxyl group,

Halogenated alkoxy,

Halogen,

Cyano group,

Nitro,

Aryl sulfonyl,

Alkyl sulphonyl and

-N(R ₉) ₂，

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

R ₅Be selected from:

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

W be selected from key ,-C (O)-and-S (O) ₂-;

A and b are 1 to 6 integer independently, and condition is a+b≤7;

M is 0 to 3;

Or its pharmacologically acceptable salt.

9. claim 1 or 2 compound or salt, wherein R _AAnd R _BBe independently selected from hydrogen and C _1-4Alkyl.

10. the compound of claim 3 or salt, wherein R _{A '}And R _{B '}Be independently selected from hydrogen and C _1-4Alkyl.

11. the compound of claim 7 or 8 or salt, wherein m is 0.

12. each compound or salt in the claim 4,5 or 6, wherein n is 0.

13. claim 1 to 4,6 to 11 or be subordinated in the claim 12 of claim 4 or 6 each compound or salt, wherein R ₁And R ₁' be independently selected from:

Hydrogen,

Alkyl,

Thiazolinyl,

Aryl,

Aryl alkylene,

Heteroaryl,

The heteroaryl alkylidene group,

Heterocyclic radical,

The heterocyclic radical alkylidene group and

Hydroxyl,

Alkyl,

Haloalkyl,

Hydroxyalkyl,

Alkoxyl group,

Halogenated alkoxy,

Halogen,

Cyano group,

Nitro,

Aryl sulfonyl,

Alkyl sulphonyl and

-N(R ₉) ₂。

14. the compound of claim 13 or salt, wherein R ₁' be hydrogen or alkyl, R ₁Be selected from hydrogen, alkyl, aryl, substituted aryl, aryl alkylene, substituted aryl alkylidene group and heteroaryl.

15. the compound of claim 13 or salt, wherein R ₁' be hydrogen or methyl, R ₁Be selected from hydrogen, methyl, ethyl, propyl group, butyl, cyclohexyl, phenyl, 4-p-methoxy-phenyl, benzyl, 4-methoxy-benzyl, 2-pyridyl, 3-pyridyl, 4-chloro-phenyl-and 4-fluorophenyl.

16. the compound of claim 15 or salt, wherein R ₁And R ₁' all be hydrogen.

17. claim 1 to 4,6 to 11 or be subordinated in the claim 12 of claim 4 or 6 each compound or salt, wherein R ₁And R ₁' be combined together to form the ring shown in the following formula:

Wherein A ' be selected from-O-,-CH ₂-,-N (R ₄)-and-N (Q-R ₄)-.

18. the compound of claim 17 or salt, wherein R ₁And R ₁' be combined together to form the morpholine ring.

19. claim 2 to 8, be subordinated to the claim 9 of claim 2, claim 10 to 12, or be subordinated in the claim 13 to 18 of claim 2 to 4, claim 6 to 11 or claim 12 each compound or salt, described claim 12 is subordinated to claim 4 or 6, wherein R ₂Be selected from hydrogen, alkyl, alkoxyl group alkylidene group, hydroxy alkylidene and-X-R ₄With-X-Y-R ₄, wherein X is C _1-2Alkyl; Y is-S (O) _0-2-,-S (O) ₂-N (R ₈)-,-C (R ₆)-,-C (R ₆)-O-,-O-C (R ₆)-,-O-C (O)-O-,-N (R ₈)-Q-,-C (R ₆)-N (R ₈)-,-O-C (R ₆)-N (R ₈)-or-C (R ₆)-N (OR ₉)-; And R ₄Be alkyl.

20. the compound of claim 19 or salt, wherein R ₂Be selected from hydrogen, C _1-4Alkyl, C _1-4Alkyl-O-C _1-4Alkylidene group and HO-C _1-3Alkylidene group.

21. the compound of claim 20 or salt, wherein R ₂Be selected from hydrogen, methyl, ethyl, n-propyl, normal-butyl, hydroxymethyl, 2-hydroxyethyl, ethoxyl methyl and 2-methoxy ethyl.

22. each compound or salt in the claim 1 to 21, wherein X ' is (CH ₂) _2-4-O-(CH ₂) _2-4-.

23. each compound or salt in the claim 1 to 21, wherein X ' is-(CH ₂) _1-7-.

24. each compound or salt in the claim 1 to 21, wherein X ' is-(CH ₂)-C (CH ₃) ₂-.

25. pharmaceutical composition, it comprises in the claim 1 to 24 with the treatment significant quantity of pharmaceutically acceptable carrier combination each compound or salt.

26. the biosynthetic method of cytokine in the induced animal, it comprises each the compound or the pharmaceutical composition of salt or claim 25 in the claim 1 to 24 of animals administer significant quantity.

27. treatment has the method for the virus disease in the animal that needs, it comprises each the compound or the pharmaceutical composition of salt or claim 25 in the claim 1 to 24 of animals administer treatment significant quantity.

28. treatment has the method for the tumorigenesis disease in the animal that needs, it comprises each the compound or the pharmaceutical composition of salt or claim 25 in the claim 1 to 24 of animals administer treatment significant quantity.

29. the compound of formula (XII):

Wherein:

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

R ₅Be selected from:

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

W be selected from key ,-C (O)-and-S (O) ₂-;

A and b are 1 to 6 integer independently, and condition is a+b≤7;

N is 0 to 4;

Or its pharmacologically acceptable salt.

30. the compound of formula (XIII):

Wherein:

R ₁And R ₁' be independently selected from:

Hydrogen,

Alkyl,

Thiazolinyl,

Aryl,

Aryl alkylene,

Heteroaryl,

The heteroaryl alkylidene group,

Heterocyclic radical,

The heterocyclic radical alkylidene group and

Hydroxyl,

Alkyl,

Haloalkyl,

Hydroxyalkyl,

Alkoxyl group,

Halogenated alkoxy,

Halogen,

Cyano group,

Nitro,

Aryl sulfonyl,

Alkyl sulphonyl and

-N(R ₉) ₂，

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

R ₅Be selected from:

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

W be selected from key ,-C (O)-and-S (O) ₂-;

A and b are 1 to 6 integer independently, and condition is a+b≤7;

N is 0 to 4;

Or its pharmacologically acceptable salt.

31. the compound of formula (XIV):

Wherein:

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

R ₅Be selected from:

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

W be selected from key ,-C (O)-and-S (O) ₂-;

A and b are 1 to 6 integer independently, and condition is a+b≤7;

M is 0 to 3;

Or its pharmacologically acceptable salt.

32. the compound of formula (XV):

Wherein:

R ₁And R ₁' be independently selected from:

Hydrogen,

Alkyl,

Thiazolinyl,

Aryl,

Aryl alkylene,

Heteroaryl,

The heteroaryl alkylidene group,

Heterocyclic radical,

The heterocyclic radical alkylidene group and

Hydroxyl,

Alkyl,

Haloalkyl,

Hydroxyalkyl,

Alkoxyl group,

Halogenated alkoxy,

Halogen,

Cyano group,

Nitro,

Aryl sulfonyl,

Alkyl sulphonyl and

-N(R ₉) ₂，

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

R ₅Be selected from:

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

W be selected from key ,-C (O)-and-S (O) ₂-;

A and b are 1 to 6 integer independently, and condition is a+b≤7;

M is 0 to 3;

Or its pharmacologically acceptable salt.

33. the compound of formula (XVI):

Wherein:

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

R ₅Be selected from:

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

W be selected from key ,-C (O)-and-S (O) ₂-;

A and b are 1 to 6 integer independently, and condition is a+b≤7;

Or its pharmacologically acceptable salt.

34. the compound of formula (XVII):

Wherein:

R ₁And R ₁' be independently selected from:

Hydrogen,

Alkyl,

Thiazolinyl,

Aryl,

Aryl alkylene,

Heteroaryl,

The heteroaryl alkylidene group,

Heterocyclic radical,

The heterocyclic radical alkylidene group and

Hydroxyl,

Alkyl,

Haloalkyl,

Hydroxyalkyl,

Alkoxyl group,

Halogenated alkoxy,

Halogen,

Cyano group,

Nitro,

Aryl sulfonyl,

Alkyl sulphonyl and

-N(R ₉) ₂，

R ₂Be selected from:

-R ₄，

-X-R ₄，

-X-Y-R ₄And

-X-R ₅；

Y is selected from:

-O-，

-S(O) _0-2-，

-S(O) ₂-N(R ₈)-，

-C(R ₆)-，

-C(R ₆)-O-，

-O-C(R ₆)-，

-O-C(O)-O-，

-N(R ₈)-Q-，

-C(R ₆)-N(R ₈)-，

-O-C(R ₆)-N(R ₈)-，

-C(R ₆)-N(OR ₉)-，

R ₅Be selected from:

R ₆Be selected from=O and=S;

R ₇Be C _2-7Alkylidene group;

R ₉Be selected from hydrogen and alkyl;

R ₁₀Be C _3-8Alkylidene group;

A is selected from-O-,-C (O)-,-CH ₂-,-S (O) _0-2-and-N (R ₄)-;

W be selected from key ,-C (O)-and-S (O) ₂-;

A and b are 1 to 6 integer independently, and condition is a+b≤7;

Or its pharmacologically acceptable salt.