CN101384593A - 3-deazapurine derivatives as tlr7 modulators - Google Patents
3-deazapurine derivatives as tlr7 modulators Download PDFInfo
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- CN101384593A CN101384593A CNA2007800056096A CN200780005609A CN101384593A CN 101384593 A CN101384593 A CN 101384593A CN A2007800056096 A CNA2007800056096 A CN A2007800056096A CN 200780005609 A CN200780005609 A CN 200780005609A CN 101384593 A CN101384593 A CN 101384593A
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Abstract
The present invention relates to immune response modifiers of Formula (I), which act selectively through agonism, of Toll-Like Receptors (TLRs), uses thereof, processes for the preparation thereof, intermediates used in the preparation thereof and compositions containing said inhibitors. These inhibitors have utility in a variety of therapeutic areas including the treatment of infectious disease such as Hepatitis (e.g. HCV, HBV), genetically related viral infection and cancer.
Description
Technical field
The present invention relates to a kind of 3-deazapurine (3-deazapurine) derivative.The invention still further relates to this 3-deazapurine derivatives the preparation method, be used to prepare this 3-deazapurine derivatives intermediate, contain the purposes of pharmaceutical composition and this 3-deazapurine derivatives of this 3-deazapurine derivatives.
Background technology
Toll sample acceptor (TLR) is main transmembrane protein, it is characterized by the extracellular and is rich in leucine and cytoplasmic tail, and this cytoplasmic tail contains the conserved regions that is called Toll/IL-1 acceptor (TIR) structural domain.They are mainly gone up at immunocyte (for example dendritic cell, T lymphocyte, scavenger cell, monocyte and natural killer cell) and express, and it has vital role in innate immune system.(it is summarized referring to for example Ulevitch, R.J., Nature Reviews:Immunology for a group is bonded to the pattern recognition acceptor of pathogenic agent associated molecular pattern for they, 4,512-520,2004, and, Akira, S., Takeda, K., and Kaisho, T., AnnualRev.Immunol., 21,335-376,2003).Their title derives from the homologous sequence of drosophila melanogaster (Drosophila melanogaster) the gene Toll that finds in fruit bat, the Toll gene is not subjected to have in the fungal infection vital role (Hoffmann, J.A. the protection fruit bat; Nature; 426,33-38,2003).In Mammals, identify 11 kinds of TLR, and in other vertebrates, also found other nonmammalian TLR.All TLR, in the specificity that on identification pathogenicity bo organism, exists or the process of a group-specific molecule determiner, as if all work as homodimer or heterodimer, above-mentioned molecule determiner comprises bacterial cell surface lipopolysaccharides, lipoprotein, bacterial flagellin, from the DNA and the viral RNA of bacterium and virus.Cell response relates to the activation of one or more transcription factors to the TLR activatory, causes generation and the secretion of cytokine and costimulatory molecules such as Interferon, rabbit, TNF-α, interleukin, MIP-1 and MCP-1, and the intrusion of pathogenic agent is killed and removed in their effect.
Therefore, just needing to provide a kind of TLR7 conditioning agent, especially agonist.Preferably, this compounds should have more than one in the following characteristic: they answer selectivity and TLR7 receptors bind; Gastrointestinal absorption is good; Metabolic stability and have favourable pharmacokinetic properties; Show side effect hardly and be easy to preparation.
Summary of the invention
The inventor has found a series of 3-deazapurine derivatives, it is the conditioning agent of TLR7 acceptor, especially agonist, the various treatments field that it is applied to relate to the adjusting of TLR7 acceptor, especially agonism comprises the disease that treatment virus infection (such as HCV or HBV), cancer and tumour and T2 helper (TH2) mediate.
According to a first aspect of the invention, provide the compound of formula (I),
Or the pharmacy acceptable salt of this compound or solvate, wherein
(a) Y is a chemical bond, and R
3Be selected from aryl, (C
1-C
6) alkyl and-(C
1-C
4) alkylidene group-O-(C
1-C
4) alkyl; Or
(b) Y is (C
1-4) alkylidene group, and R
3Be selected from aryl, (C
3-C
7) cycloalkyl and 3-10 unit heterocyclic radical;
Z is oxygen or does not exist;
R
1Be selected from H, halogen, OH, CN, (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
6) alkoxyl group ,-NHSO
2R
6,-NR
6R
7,-C (O) R
6,-CO
2R
6,-C (O) NR
6R
7,-C (O) NR
6SO
2R
8, aryl and 3-10 unit heterocyclic radical;
R
2Be selected from H, halogen, OH, (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
6) alkoxyl group ,-NR
6R
7,-CO
2R
6,-C (O) NR
6R
7,-C (O) NR
6SO
2R
8And 3-10 unit heterocyclic radical; Or
R
1With R
2Can be connected to form (C
2-C
5) the alkylidene group connection, this connection is chosen wantonly and is comprised 1 or 2 heteroatoms that is selected from independently of one another among N, O and the S;
R
5Do not exist and R
4Be selected from H, (C
3-C
7) cycloalkyl, aryl ,-(CH
2) aryl ,-C (O) R
9,-CO
2R
9,-(C
1-C
6) alkylidene group-O-C (O) R
9,-(C
1-C
6) alkylidene group-O-CO
2R
9) ,-C (O) NR
9R
10,-(C
1-C
6) alkylidene group-O-C (O) NR
9R
10And-(C
1-C
6) alkylidene group-O-P (O) (OH)
2Or
R
4Do not exist and R
5Be selected from R
9,-C (O) R
9,-CO
2R
9,-(C
1-C
6) alkylidene group-O-C (O) R
9,-(C
1-C
6) alkylidene group-O-CO
2R
9,-C (O) NR
9R
10,-(C
1-C
6) alkylidene group-O-C (O) NR
9R
10And-(C
1-C
6) alkylidene group-O-P (O) (OH)
2
R
6And R
7Be selected from H, (C independently of one another
1-C
6) alkyl, (C
3-C
7) cycloalkyl and-(C
1-C
6) alkylidene group (C
3-C
7) cycloalkyl; Or R
6And R
7Form 3-6 unit saturated heterocyclic with the nitrogen that they connected, this heterocycle is chosen wantonly and is contained 1 or 2 heteroatoms that is selected among N, O and the S in addition;
R
8Be selected from (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl and phenyl;
R
9And R
10Be selected from H, (C independently of one another
1-C
6) alkyl, (C
3-C
7) cycloalkyl, aryl ,-(CH
2) aryl and 3-10 unit heterocyclic radical; Or
R
9And R
10Form 3-10 unit heterocyclic radical with the nitrogen that they connected;
R
11And R
12Be independently selected from H and (C
1-C
6) alkyl; Or R
11And R
12Form 3-6 unit saturated heterocyclyl with the N that is connected, this heterocyclic radical is chosen wantonly and is contained 1 or 2 heteroatoms that is selected among N, O and the S in addition;
This alkyl, cycloalkyl, alkoxyl group, aryl and heterocyclic radical are optional to be independently selected from following atom or group replacement by one or more: halogen, OH, oxo, CF
3, CN, (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
6) alkoxyl group ,-(C
1-C
6) alkylidene group-O-(C
1-C
6) alkyl ,-(C
1-C
6) alkylidene group-OH ,-NR
11R
12,-(C
1-C
6) alkylidene group-NR
11R
12, aryl and 3-10 unit heterocyclic radical;
Its condition is, if R
1And R
2Be H and Z and R
5Do not exist, then:
(a) work as Y-R
3During for ethyl, R
4It is not methyl; And
(b) work as Y-R
3During for methyl, R
4Be not H or methyl.
Except as otherwise noted, otherwise alkyl and alkoxyl group can be the straight or branched group and contain 1-6 carbon atom, and preferred 1-4 carbon atom.Examples of alkyl comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, amyl group and hexyl.The alkoxyl group example comprises methoxyl group, oxyethyl group, isopropoxy and n-butoxy.
Cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and norbornane base.
Halogen means fluorine, chlorine, bromine or iodine, and is preferably fluorine or chlorine.
Aryl comprises phenyl, naphthyl, anthryl and phenanthryl, and is preferably phenyl.
Except as otherwise noted, otherwise that heterocycle can be is saturated, fractional saturation or aromatic heterocycle, and contains one or more and be independently selected from heteroatoms among N, O and the S.For example, heterocycle can be that 5-6 unit is saturated, fractional saturation or aromatic heterocycle.The example of saturated heterocyclic group is: tetrahydrofuran base, pyrrolidyl, pyrrolinyl, imidazolidyl, imidazolinyl, dioxolanyl, dihydro pyranyl, THP trtrahydropyranyl, piperidyl, pyrazolinyl, alkyl dioxin, morpholinyl, dithiane base, thio-morpholinyl, piperazinyl, azepine leather base, oxygen azepine leather base and sulphur azepine leather base.The example of aromatics monocyclic heterocyclic group is: pyrryl, furyl, thienyl, pyrazolyl, imidazolyl isoxazolyl oxazolyl, isothiazolyl, thiazolyl, triazolyl is (such as 1,2,3-triazolyl and 1,2, the 4-triazolyl) oxadiazole base is (such as 1-oxa--2, the 3-di azoly, 1-oxa--2, the 4-di azoly, 1-oxa--2,5 di azolies and 1-oxa--3, the 4-di azoly), thiadiazolyl group (such as 1-thia-2, the 3-di azoly, 1-thia-2, the 4-di azoly, 1-thia-2,5-di azoly and 1-thia-3, the 4-di azoly), tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl and triazinyl.The example of bicyclic aromatic heterocyclic group is: benzofuryl, benzothienyl, indyl, benzimidazolyl-, indazolyl, benzotriazole base, quinolyl and isoquinolyl.
Optional when substituting group in a large number when a plurality of substituting groups, selected group can be identical or different.
In a scheme, Z is an oxygen, so that form the N-oxide compound.
In another program of the present invention, Z does not exist.
In another scheme of the present invention, R
1Be selected from
(a)H；
(b)CN；
(c) halogen;
(d) optional (C that is replaced by 1-3 halogen atom
1-C
6) alkyl;
(e) tetrahydrofuran oxygen base;
(f) contained (C that 1-3 the first saturated heterocyclyl of heteroatomic 3-6 that is independently selected among N, O and the S replaces
1-C
6) alkyl, wherein this heterocyclic radical is optional is independently selected from CF by 1-3
3, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group and-(C
1-C
6) alkylidene group-O-(C
1-C
6) group in the alkyl replaces;
(g)-(C
1-C
4) alkylidene group-O-(C
1-C
6) alkyl;
(h)-(C
1-C
4) alkylidene group-N (H)-(C
1-C
4) alkylidene group-O-(C
1-C
4) alkyl;
(i) optional by the (C of OH or cyclopropyl replacement
1-C
6) alkoxyl group;
(j) (C
3-C
7) cycloalkyl;
(k)-(C
1-C
4) alkylidene group (C
3-C
7) cycloalkyl;
(1)-C(O)NR
6R
7；
(m)-CO
2R
6；
(n)-C(O)R
6；
(o) 5 yuan of aromatic heterocyclic radicals, it comprises (i) 1-4 nitrogen-atoms or (ii) 1-2 nitrogen-atoms and 1 Sauerstoffatom or sulphur atom or (iii) 1 Sauerstoffatom or sulphur atom; Perhaps 6 yuan of aromatic heterocyclic radicals, it comprises 1-3 nitrogen-atoms, and these 5 and 6 yuan of aromatic heterocyclic radicals are optional to be independently selected from halogen, OH, CF by 1-3
3, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group ,-(C
1-C
6) alkylidene group-O-(C
1-C
6) alkyl ,-(C
1-C
6) alkylidene group-OH ,-NR
11R
12And-(C
1-C
6) alkylidene group-NR
11R
12In atom or group replace;
(p) the optional phenyl that is replaced by 1-3 halogen atom;
(q)-NR
6R
7；
(r)-NH-(C
1-C
4) alkylidene group-O-(C
1-C
6) alkyl;
(s) or R
1With R
2Can be connected to form (C
2-C
5) the alkylidene group connection;
Wherein
R
6, R
7, R
11And R
12Define as first aspect present invention.
In another program, R
1Be selected from
(a)H；
(b)CN；
(c) halogen
(d) optional (C that is replaced by 1-3 halogen atom
1-C
6) alkyl;
(e) tetrahydrofuran oxygen base;
(f) chosen wantonly (the C that is replaced by 1 or 2 methyl substituted morpholinyl, piperazinyl or pyrrolidyl
1-C
6) alkyl;
(h)-(C
1-C
4) alkylidene group-N (H)-(C
1-C
4) alkylidene group-O-(C
1-C
4) alkyl;
(i) optional by the (C of OH or cyclopropyl replacement
1-C
6) alkoxyl group;
(j) (C
3-C
7) cycloalkyl;
(k)-(C
1-C
4) alkylidene group (C
3-C
7) cycloalkyl;
(l)-C(O)NR
6R
7；
(m)-CO
2R
6；
(n)-C(O)R
6；
(o) comprise (i) 1-4 nitrogen-atoms or (ii) 1-2 nitrogen-atoms and 1 Sauerstoffatom or sulphur atom or (iii) 5 yuan of aromatic heterocyclic radicals of 1 Sauerstoffatom or sulphur atom; 6 yuan of aromatic heterocyclic radicals that perhaps comprise 1-3 nitrogen-atoms, these 5 and 6 yuan of aromatic heterocyclic radicals are optional to be independently selected from halogen, OH, CF by 1-3
3, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group ,-(C
1-C
6) alkylidene group-O-(C
1-C
6) alkyl ,-(C
1-C
6) alkylidene group-OH ,-NR
11R
12And-(C
1-C
6) alkylidene group-NR
11R
12In atom or group replace;
(p) the optional phenyl that is replaced by 1-3 halogen atom;
(q)-NR
6R
7；
(r)-NH-(C
1-C
4) alkylidene group-O-(C
1-C
6) alkyl;
Wherein
R
6, R
7, R
11And R
12Define as first aspect present invention.
In another scheme, R
1Be selected from the optional (C that is replaced by 1-3 halogen atom
1-C
4) alkyl; (C
3-C
7) cycloalkyl; Or it is optional by individual halogen, OH, the CF of being independently selected from of 1-3
3, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group ,-(C
1-C
6) alkylidene group-O-(C
1-C
6) alkyl and-NH (C
1-C
6) the 5-6 unit aromatic heterocyclic radical that replaces of atom in the alkyl or group.
In another scheme, R
1Be selected from the methyl or the ethyl that are replaced by 1-3 fluorine atom; Cyclopropyl;-(C
1-C
2) alkylidene group-O-(C
1-C
2) alkyl; Optional by the (C of OH or cyclopropyl replacement
1-C
4) alkoxyl group;-COCH
3-CH
2OCH
3And-CO
2CH
3
In another scheme, R
1Be cyclopropyl or CF
3
In another scheme, R
1Be 5 yuan of aromatic heterocyclic radicals, it comprises: (i) 1-4 nitrogen-atoms or (ii) 1-2 nitrogen-atoms and 1 Sauerstoffatom or sulphur atom or (iii) 1 Sauerstoffatom or sulphur atom, these 5 yuan of aromatic heterocyclic radicals are optional to be independently selected from halogen, OH, CF by 1-3
3, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group ,-(C
1-C
3) alkylidene group-O-(C
1-C
4) alkyl ,-(C
1-C
4) alkylidene group-OH ,-R
11R
12And-(C
1-C
3) alkylidene group-NR
11R
12In atom or group replace R wherein
11And R
12Described in first aspect present invention, define.
In another scheme, R
1Be selected from imidazolyl, oxazolyl, oxadiazole base, triazolyl, pyrazolyl and thiazolyl, these groups are all optional can be independently selected from halogen, OH, CF by 1-3
3, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group ,-(C
1-C
3) alkylidene group-O-(C
1-C
4) alkyl ,-(C
1-C
4) alkylidene group-OH and-(C
1-C
3) alkylidene group-NR
11R
12In atom or group replace R wherein
11And R
12Define as first aspect present invention.
In another scheme, R
1Being selected from not, Bei replaces De oxazolyl, triazolyl, pyrazolyl and thiazolyl.
In another scheme, R
1The Wei oxazolyl.
In another scheme, R
2Be selected from
(a)H；
(b) halogen;
(c) optional (C that is replaced by 1-3 halogen atom
1-C
6) alkyl;
(d) tetrahydrofuran oxygen base;
(e) contained (C that 1-3 the first saturated heterocyclyl of heteroatomic 3-6 that is independently selected among N, O and the S replaces
1-C
6) alkyl, wherein this heterocyclic radical is optional is independently selected from CF by 1-3
3, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group and-(C
1-C
6) alkylidene group-O-(C
1-C
6) group in the alkyl replaces;
(f)-(C
1-C
4) alkylidene group-O-(C
1-C
6) alkyl;
(g)-(C
1-C
4) alkylidene group-N (H)-(C
1-C
4) alkylidene group-O-(C
1-C
4) alkyl;
(h) optional by the (C of OH or cyclopropyl replacement
1-C
6) alkoxyl group;
(i) (C
3-C
7) cycloalkyl;
(j)-(C
1-C
4) alkylidene group (C
3-C
7) cycloalkyl;
(k)-C(O)NR
6R
7；
(1)-CO
2R
6；
(m)-C(O)R
6；
(n) comprise (i) 1-4 nitrogen-atoms or (ii) 1-2 nitrogen-atoms and 1 Sauerstoffatom or sulphur atom or (iii) 5 yuan of aromatic heterocyclic radicals of 1 Sauerstoffatom or sulphur atom; 6 yuan of aromatic heterocyclic radicals that perhaps comprise 1-3 nitrogen-atoms, these 5 and 6 yuan of aromatic heterocyclic radicals are optional to be independently selected from halogen, OH, CF by 1-3
3, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group ,-(C
1-C
6) alkylidene group-O-(C
1-C
6) alkyl ,-(C
1-C
6) alkylidene group-OH ,-NR
11R
12And-(C
1-C
6) alkylidene group-NR
11R
12In atom or group replace;
(o) the optional phenyl that is replaced by 1-3 halogen atom;
(p)-NR
6R
7；
(q)-NH-(C
1-C
4) alkylidene group-O-(C
1-C
6) alkyl;
Wherein
R
6, R
7, R
11And R
12Define as first aspect present invention.
In another scheme, R
2Be H or methyl.
In another scheme, R
2Be H.
In another scheme, Y is a methylene radical; And R
3Be aryl or 5-6 unit heterocyclic radical, this heterocyclic radical contains 1-3 heteroatoms that is independently selected among N, O and the S, and this aryl and heterocyclic radical are optional to be independently selected from following atom or group replacement by 1-3: halogen, OH, oxo, CF
3, CN, (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
6) alkoxyl group ,-(C
1-C
6) alkylidene group-O-(C
1-C
6) alkyl ,-NH (C
1-C
6) alkyl ,-N ((C
1-C
6) alkyl)
2, aryl and 3-10 unit heterocyclic radical.
In another scheme, Y is a methylene radical; And R
3Be selected from: aryl comprises (i) 1-4 nitrogen-atoms or (ii) 1-2 nitrogen-atoms and 1 Sauerstoffatom or sulphur atom or (iii) 5 yuan of aromatic heterocyclic radicals of 1 Sauerstoffatom or sulphur atom, and comprises 6 yuan of aromatic heterocyclic radicals of 1-3 nitrogen-atoms; This aryl and aromatic heterocycle are optional to be independently selected from following atom or group replacement by 1-3: halogen, OH, oxo, CF
3, CN, (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
6) alkoxyl group ,-(C
1-C
6) alkylidene group-O-(C
1-C
6) alkyl ,-(C
1-C
6) alkylidene group-OH ,-NR
11R
12,-(C
1-C
6) alkylidene group-NR
11R
12, aryl and 3-10 unit heterocyclic radical, wherein R
11And R
12Define as first aspect present invention.
In another scheme, Y is a methylene radical; And R
3Be selected from phenyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl, its each optionally be independently selected from halogen, (C by 1-3
1-4) alkyl, (C
1-C
4) alkoxyl group and CF
3In atom or group replace.
In another scheme, Y is a methylene radical; And R
3Be selected from phenyl, pyridin-3-yl and 6-methyl-pyridin-3-yl.
In another scheme,
Y is a methylene radical;
R
1Be selected from: by (the C of 1-3 halogen atom replacement
1-C
4) alkyl; (C
3-C
7) cycloalkyl; And the optional 5-6 unit aromatic heterocyclic radical that is replaced by 1-3 group that is independently selected from the following group: halogen, OH, CF
3, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group ,-(C
1-C
6) alkylidene group-O-(C
1-C
6) alkyl and-NH (C
1-C
6) alkyl;
R
2Be H;
R
3Be phenyl or 3-pyridyl, its each optionally can be independently selected from halogen, (C by 1-3
1-4) alkyl and CF
3In atom or group replace;
R
4Be H; And
R
5Do not exist.
In another scheme,
Y is a methylene radical;
R
1Be selected from CF
3, cyclopropyl is Ji oxazolyl;
R
2Be H;
R
3Be selected from phenyl, pyridin-3-yl and 6-methyl-pyridin-3-yl.
R
4Be H; And
R
5Do not exist.
In another scheme, R
5Do not exist; And
R
4Be selected from-(C
1-C
6) alkylidene group-O-C (O) R
9,-(C
1-C
6) alkylidene group-O-CO
2R
9,-(C
1-C
6) alkylidene group-O-C (O) NR
9R
10And-(C
1-C
6) alkylidene group-O-P (O) (OH)
2, wherein Y, Z, R
1, R
2, R
3, R
9And R
10Define as first aspect present invention, to produce compound as shown in the formula (Ia):
In another scheme, R
4Be H and R
5Do not exist.
In another scheme, R
4Do not exist; And
R
5Be selected from-(C
1-C
6) alkylidene group-O-C (O) R
9,-(C
1-C
6) alkylidene group-O-CO
2R
9,-(C
1-C
6) alkylidene group-O-C (O) NR
9R
10And-(C
1-C
6) alkylidene group-O-P (O) (OH)
2, wherein Y, R
1, R
2, R
3, R
9And R
10As hereinbefore defined, to produce compound as shown in the formula (Ib):
Embodiments of the invention form another scheme of the present invention.
Preferred compound of the present invention is those compounds of embodiment 1-4,12,15-18,26,27,36-38,40-54,60,70,76,78,82,83,86,92-94,96-98 and 100-102 and the pharmacy acceptable salt or the solvate of tautomer and this compound or its tautomer thereof.
Preferred compound is selected from:
4-amino-1-benzyl-6-cyclopropyl-1,3-dihydro-imidazol-is [4,5-c] pyridin-2-ones (embodiment 1) also;
4-amino-1-benzyl-6-oxazole-2-base-1,3-dihydro-imidazol-is [4,5-c] pyridin-2-ones (embodiment 12) also;
4-amino-1-benzyl-6-Trifluoromethyl-1,3-dihydro-imidazol-is [4,5-c] pyridin-2-ones (embodiment 15) also;
And the pharmacy acceptable salt or the solvate of tautomer and this compound or its tautomer.
In another program of the present invention, provide the compound of formula (Ic)
Wherein
Y is a methylene radical;
R
1And R
2Be selected from H, halogen, OH, (C independently of one another
1-C
6) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
6) alkoxyl group ,-NR
6R
7,-CO
2R
6,-C (O) NR
6R
7,-C (O) NR
6SO
2R
8, aryl and 3-10 unit heterocyclic radical; Perhaps
R
1With R
2Can be connected to form (C
2-C
5) the alkylidene group connection, this connection is chosen wantonly and is comprised 1 or 2 heteroatoms that is selected from independently of one another among N, O and the S;
R
3Be selected from (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl, aryl and 3-10 unit heterocyclic radical;
R
4Be selected from R
9,-C (O) R
9,-CO
2R
9And-C (O) NR
9R
10, and R
5Do not exist; Perhaps
R
5Be selected from R
9,-C (O) R
9,-CO
2R
9And-C (O) NR
9R
10, and R
4Do not exist;
R
6And R
7Be selected from H and (C independently of one another
1-C
6) alkyl;
R
8Be selected from (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl and phenyl;
R
9And R
10Be selected from H, (C independently of one another
1-C
6) alkyl, (C
3-C
7) cycloalkyl, aryl ,-(CH
2) aryl and 3-10 unit heterocyclic radical; Perhaps
R
9And R
10Form 3-10 unit heterocyclic radical with the nitrogen that they connected;
This alkyl, cycloalkyl, alkoxyl group, aryl and heterocyclic radical are optional to be independently selected from following group replacement by one or more: halogen, OH, oxo, CF
3, CN, (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
6) alkoxyl group, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, NH (C
1-C
6) alkyl, N ((C
1-C
6) alkyl)
2, aryl and 3-10 unit heterocyclic radical;
Or the pharmacy acceptable salt of this compound or solvate;
Its condition is, if R
1And R
2Be H and z and R
5Do not exist, then
(a) if Y-R
3Be ethyl, R
4It is not methyl; Or
(b) if Y-R
3Be methyl, R
4Be not H or methyl.
Another scheme of the present invention comprises the compound of formula (Ic), wherein R
4Be selected from R
9,-C (O) R
9,-CO
2R
9And-C (O) NR
9R
10R
5Do not exist; And Y, R
1, R
2, R
3, R
9And R
10Define as a second aspect of the present invention, with the compound of the formula (Ia) shown in the generation as mentioned.
Another scheme of the present invention comprises the compound of formula (Ic), wherein
Y is a methylene radical;
R
1And R
2Be selected from H, (C independently of one another
1-C
6) alkyl, (C
3-C
7) cycloalkyl ,-CO
2H ,-CO
2(C
1-C
6) alkyl and-C (O) NH (C
1-C
6) alkylidene group (C
3-C
7) cycloalkyl; Or R
1With R
2Can be connected to form (C
2-C
5) the alkylidene group connection;
R
3Be phenyl, it is chosen wantonly by one or more and is independently selected from following group replacement: halogen, OH, CF
3, CN, (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
6) alkoxyl group, NH (C
1-C
6) alkyl and N ((C
1-C
6) alkyl)
2
R
5Do not exist; And
R
4Be H.
The another scheme of a second aspect of the present invention comprises the compound of formula (Ic), wherein
Y is a methylene radical;
R
1And R
2Be selected from H, (C independently of one another
1-C
6) alkyl, (C
3-C
7) cycloalkyl ,-CO
2H ,-CO
2(C
1-C
6) alkyl and-C (O) NH (C
1-C
6) alkylidene group (C
3-C
7) cycloalkyl; Or R
1With R
2Can be connected to form (C
2-C
5) the alkylidene group connection;
R
3Be phenyl, it is chosen wantonly and is independently selected from halogen and CF by one or more
3In group replace;
R
5Do not exist; And
R
4Be H.
The another scheme of a second aspect of the present invention comprises the compound of formula (Ic), wherein R
5Be selected from R
9,-C (O) R
9,-CO
2R
9And-C (O) NR
9R
10R
4Do not exist; And Y, R
1, R
2And R
3As hereinbefore defined, with the compound of the formula (Ib) shown in producing as mentioned.
The another scheme of a second aspect of the present invention comprises the compound of formula (Ic), wherein R
1And R
2Be selected from H, (C independently of one another
1-C
6) alkyl, (C
3-C
7) cycloalkyl ,-CO
2R
6,-C (O) NR
6R
7And-C (O) NR
6SO
2R
8Or R
1With R
2Can be connected to form (C
2-C
5) the alkylidene group connection, this connection is chosen wantonly and is contained 1 or 2 heteroatoms that is selected from independently of one another among N, O and the S.
The another scheme of a second aspect of the present invention comprises the compound of formula (Ic), wherein R
1And R
2Be selected from H, (C independently of one another
1-C
6) alkyl, (C
3-C
7) cycloalkyl ,-CO
2H ,-CO
2(C
1-C
6) alkyl and-C (O) NH (C
1-C
6) alkylidene group (C
3-C
7) cycloalkyl; Or R
1With R
2Can be connected to form (C
2-C
5) the alkylidene group connection.
The another scheme of a second aspect of the present invention comprises the compound of formula (Ic), wherein R
1And R
2Be selected from H, (C independently of one another
1-C
3) alkyl, cyclopropyl ,-CO
2H ,-CO
2CH
3And-C (O) NH (CH
2) cyclopropyl; Or R
1With R
2Can be connected to form C
5-alkylidene group connects.
The another scheme of a second aspect of the present invention comprises the compound of formula (Ic), wherein R
1Be selected from H, methyl, n-propyl, sec.-propyl, cyclopropyl ,-CO
2H ,-CO
2CH
3And-C (O) NH (CH
2) cyclopropyl; And R
2Be selected from H and methyl; Or R
1With R
2Can be connected to form C
5-alkylidene group connects.
The another scheme of a second aspect of the present invention comprises the compound of formula (Ic), wherein R
3Be aryl, it is chosen wantonly by one or more and is independently selected from following group replacement: halogen, OH, oxo, CF
3, CN, (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
6) alkoxyl group, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, NH (C
1-C
6) alkyl, N ((C
1-C
6) alkyl)
2, aryl and 3-10 unit heterocyclic radical.
The another scheme of a second aspect of the present invention comprises the compound of formula (Ic), wherein R
3Be phenyl, it is chosen wantonly by one or more and is independently selected from following group replacement: halogen, OH, CF
3, CN, (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
6) alkoxyl group, NH (C
1-C
6) alkyl and N ((C
1-C
6) alkyl)
2Yet more preferably R
3Be independently selected from halogen and CF for optional by one or more
3In the phenyl that replaces of group.
The another scheme of a second aspect of the present invention comprises the compound of formula (Ic), wherein R
3Be selected from 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl and 3-trifluoromethyl.
Except as otherwise noted, otherwise compound of the present invention comprises formula (I), (Ia), (Ib) and compound (Ic).
It should be understood that the present invention contains all combinations of the aforesaid of the present invention concrete scheme consistent with the definition of formula (I) compound.
In a third aspect of the present invention, provide the method for a kind of preparation formula (Ic) compound
Wherein, in various Ia, XVIII, XVIIIa, XIX, XIXa, XXa, XXb, XIV, XV, LIV and LXIII, Y-R
3Such as claim 14 definition, R
1Such as claim 2 definition, R
2Such as claim 10 definition, PG
1And PG
2Be nitrogen protective material and R
13Be (C
1-6) alkyl;
This method comprises:
(a) make the reaction of formula (XVIII) or compound (XVIIIa) and carbonyl supplying agent
Forming corresponding formula (XIX) or (XIXa) compound,
Then with formula (XIX) or compound deprotection (XIXa); Or
(b) compound of reduction-type (XXa)
To form the compound of formula (XXb)
Make the cyclisation of formula (XXb) compound by handling then with protonic acid; Or
(c) compound of reduction-type (XIV)
To form the compound of formula (XV)
In the presence of carbonyl moiety, make the compound cyclisation of formula (XV) then; Or
(e) in the presence of the diphenylphosphine acyl azide, make the cyclisation of formula (LIV) compound for corresponding formula (XIXA) compound above then, with the amino protecting group deprotection
Perhaps
(f) make the compound hydrolysis of formula (LXIII)
In as fourth aspect present invention, the intermediate of formula XVIII, XVIIIa, XIX, XIXa, XXa, XXb, XIV, XV, LIV and LXIII is provided,
Y-R wherein
3Such as claim 14 definition, R
1Such as claim 2 definition, R
2Such as claim 10 definition, PG
1And PG
2Be nitrogen protective material and R
3Be (C
1-6) alkyl.
The pharmacy acceptable salt of formula (I) compound comprises its acid salt and alkali salt.
The acid salt that is fit to is formed by the acid that can form nontoxic salt.Example comprises second hydrochloric acid, adipate, aspartate, benzoate, benzene sulfonate, bicarbonate/carbonate, hydrosulfate/vitriol, borate, d-camphorsulfonic acid salt, Citrate trianion, cyclamate, ethanedisulphonate, esilate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzic acid salt, hydrochloride/muriate, hydrobromate/bromide, hydriodate/iodide, isethionate, lactic acid salt, oxysuccinic acid, maleate, malonate, mesylate, Methylsulfate, naphthoate, the 2-naphthalenesulfonate, nicotinate, nitrate, Orotate, oxalate, palmitate, embonate, phosphate/phosphor acid monohydric salt/dihydrogen phosphate, pyroglutamate, sugar lime, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and hydroxynaphthoate (xinofoate salts).
The alkali salt that is fit to is formed by the bases that can form nontoxic salt.Example comprises aluminium salt, arginic acid salt, benzyl star salt (benzathine), calcium salt, choline salt, diethyl amine salt, diethanolamine salt, glycinate, lysine salt, magnesium salts, meglumine salt (meglumine), ethanolamine salt (olamine), sylvite, sodium salt, tromethamine salt (tromethamine) and zinc salt.
Also can form half salt of acids and bases, for example, Hemisulphate and half calcium salt.
The summary of the salt that is fit to can be referring to the ＂ Handbook ofPharmaceutical Salts:Properties of Stahl and Wermuth, Selection, andUse ＂ (Wiley-VCH, Weinheim, Germany, 2002).
The pharmacy acceptable salt of formula (I) compound can prepare by in following three kinds of methods more than one:
(i) make formula (I) compound and required acid or alkali reaction;
(ii) use required acid or alkali that the unstable protection base of acid or alkali is removed from the suitable precursor of formula (I) compound; Or
(iii) by with acid that is fit to or alkali reaction or utilize the ion exchange column that is fit to, a kind of salt of formula (I) compound is converted into another kind of salt.
Three reactions are all carried out in solution usually.Prepared salt is precipitable separates out the river and is filtered collection and maybe can reclaims by evaporating solvent.The degree of ionization of gained salt can not wait (from complete ionization to ionization hardly).
Compound of the present invention also can exist with non-solvent form and solvation form.Term " solvate " is used for describing the molecular complex that comprises compound of the present invention and one or more pharmaceutically acceptable solvent molecules (for example ethanol) in this article.When described solvent adopts term " hydrate " during for water be.
Generally acknowledged categorizing system to organic hydrate is that definition separates site (definesisolated site) definition separation site, passage or metallic ion coordination hydrate at present, referring to K.R.Morris's
Polymorphism in Pharmaceutical Solids(H.g.Brittain chief editor, Marcel Dekker, 1995), during this article is incorporated herein as a reference.By in separating the site hydrate, inserting organic molecule water molecules is separated, mutually not directly contact.In channel water compound (channel hydrates), water molecules is in the lattice passage, this itself and other water molecules next-door neighbour.In the metallic ion coordination hydrate, water molecules and metal ion bonding.
When solvent or water were combined closely, title complex had the clear and definite stoichiometry that does not rely on humidity.Yet, when solvent or water in passage solvate and hygroscopic compound when faint, the content of water/solvent will depend on humidity and drying conditions.At this moment, nonstoichiometry method is a normal content.
Compound of the present invention can exist so that successive is solid-state, and its scope is from amorphous fully crystallization extremely fully.Term " amorphous " is meant that material lacks the state of long-range order on molecular level, and according to the different physical propertys that present solid or liquid of temperature.Common these materials are the X-ray diffractogram of indicating characteristic not, although show solid property, more becomes often to be described as liquid.Solid property then is the change of state to the feature that characteristics of liquids changes after being heated, and generally is (second order) (" glass transition ") of two-stage.Term " crystallization " is meant that material has the solid-state of regular orderly internal structure, the X-ray diffractogram that has definite kurtosis of its indicating characteristic at molecular level.When fully being heated, these materials also can show the characteristic of liquid, but the feature of the variation from solid-state to liquid state is phase transformation, generally is (" fusing point ") of one-level.
Compound of the present invention can also exist with polycomponent mixture (except that salt and solvate), and its Chinese traditional medicine and at least a other component exist with stoichiometry or non-stoichiometric consumption.Such mixture comprises clatraten (medicine-oikocryst inclusion complex) and eutectic.The latter is normally defined the crystalline composites of neutral molecule composition, and it is bonded together mutually by non-covalent, but also can be the mixture of neutral molecule and salt.Eutectic can be by fusion-crystallization, recrystallization or each component is ground by physical property ground prepares together from solvent, referring to the ChemCommun of 0.Almarsson and M.J.Zaworotko,
17, 1889-1896 (2004), during this article is incorporated herein as a reference.About the summary of polycomponent mixture, referring to the J PharmSci of Haleblian,
64(8), 1269-1288 (in August, 1975), during this article is incorporated herein as a reference.
Be in conditions suitable following time, compound of the present invention also can exist with mesomorphic state (intermediate phase or liquid crystal).Mesomorphic state is the intermediate state between real crystalline state and real liquid state (melt or solution).Because of the caused mesomorphism of temperature variation is called as the ＂ mesomorphism of ＂ thermic, add the caused mesomorphism of second kind of composition (as water or other solvent) and be called as the molten ＂ mesomorphism that causes of ＂.Have and form the molten compound that causes intermediate phase trend and be called as " amphipathic molecule ", it is by having ion (as-COO
-Na
+,-COO
-K
+Or-SO
3 -Na
+) or nonionic (as-N
-N
+(CH
3)
3) the molecular composition of polar head-group.Additional information please refer to the Crystals and the Polarizing Microscope of N.H.Hartshorne and A.Stuart, the 4th edition (EdwardArnold, 1970), during this article is incorporated herein as a reference.
The compound that hereinafter relates to formula (I) includes its salt, solvate, polycomponent mixture and liquid crystal, with and solvate, polycomponent mixture and the liquid crystal of salt.
Formula (I) compound of definition during compound of the present invention comprises as mentioned comprises as its all polymorphic form of hereinafter definition and the compound isotopically labelled of crystal habit, its prodrug and isomer (comprising optical isomer, geometrical isomer and tautomer) and formula (I).
As mentioned above, the so-called ＂ prodrug ＂ of formula (I) compound is also included within the scope of the present invention.Therefore, itself have very little or some derivatives of formula (I) compound of not having a pharmacologically active in delivering medicine to body or on the body time, for example can change into and have required active formula (I) compound by the hydrolytic scission effect.These derivatives are called " prodrug ".Can be about the further data that prodrug is used referring to ＂ Pro-drugs as Novel Delivery Systems ＂ the 14th volume, ACS Symposium Series (T.Higuchi and W.Stella) and ＂ BioreVersible Carriers in Drug Design ＂, Pergamon Press, 1987 (E.B.Roche compiles, American Pharmaceutical Association).
Prodrug of the present invention for example can be replaced by some part well known by persons skilled in the art by the appropriate functional group that will exist in formula (I) compound and be used as " precursor portions " (described in ＂ Design of Prodrugs ＂ (Elsevier, 1985) of H.Bundgaard) and be prepared.
Some examples of prodrug of the present invention comprise
When (i) its Chinese style (I) compound contained carboxylic acid functional, its ester, for example the hydrogen in the carboxylic acid functional of its Chinese style (I) compound was substituted by (C
1-C
8) compound of alkyl; And
When (ii) its Chinese style (I) compound contained primary amine groups or secondary amine functional group, its amide group, for example as the case may be, 1 or 2 hydrogen in the amidine functional group of its Chinese style (I) compound was substituted by (C
1-C
10) compound of alkyloyl.
Substituent further example according to the example of above-mentioned example and other prodrug type can be referring to above-mentioned reference.In addition, some compounds of formula (I) itself can serve as the prodrug of other compound of formula (I).
Particularly, R of the present invention
4Be H and R as defined herein and not
5Do not exist formula (I) compound of (that is the compound of formula (Ia)) to change into R through metabolism or solvolysis
4Be H and R
5Non-existent formula (I) compound.In addition, R of the present invention
4Do not exist and R
5Formula (I) compound that is H (that is formula (Ib) compound) as defined herein and not can change into R through metabolism or solvolysis
4Do not exist and R
5Formula (I) compound for H.
The metabolite of formula (I) compound is also included within the scope of the present invention,, gives the compound that forms in vivo behind the medicine that is.Some examples of metabolite according to the invention comprise
(i) when formula (I) when compound contains methyl, be its hydroxymethyl derivative (CH
3--CH
2OH);
(ii) when formula (I) when compound contains alkoxyl group, for its hydroxy derivatives (OR-〉-OH);
(iii) when formula (I) compound contains uncle's amino, be its secondary amino group derivative (NR
1R
2--NHR
1Or-NHR
2);
(iv), be its primary amino derivative (NHR when formula (I) when compound contains secondary amino group
1--NH
2);
(v) when formula (I) when compound contains phenyl moiety, for its phenol derivatives (Ph 〉-PhOH);
(vi), be its carboxylic acid derivative (CONH when formula (I) when compound contains amide group
2--COOH).
Formula (I) compound that contains one or more unsymmetrical carbon can be used as two or more steric isomer existence.When formula (I) compound contains thiazolinyl or alkenylene, can be cis/trans (or Z/E) geometrical isomer.When constitutional isomer can be with low energy barrier change, tautomerism (" tautomerism ") can take place.The proton tautomerism form can be taked in the formula of ketone group (I) compound for example containing, or in the compound that contains the aromatics part, so-called valence tautomerism form can be taked.This shows that the simplification compound can present the isomery more than a type.
Dotted line in the act formula (I) is that example describes, wherein R
4For formula (Ia) compound of H is R wherein
5Tautomer for formula (Ib) compound of H:
The mixture of more than one of all steric isomers, geometrical isomer and the tautomeric form (comprising the compound that presents the isomery more than a type) of formula (I) compound and they includes within the scope of the invention.The present invention comprises that also wherein counterion is the acid salt class of optically active (for example d-lactic acid salt or l-Methionin) or racemize (for example dl-tartrate or dl-arginine).
The cis/trans isomer can separate by well known to a person skilled in the art routine techniques (for example chromatography and Steppecd crystallization).
The routine techniques that is used to prepare/separate single enantiomer comprises synthetic or for example use chiral hplc (HPLC) resolution of racemic compound (or salt or derivative with racemic compound) by the optical purity precursor chirality that is fit to.
Perhaps, can make racemic compound (or racemize precursor) and optically active compound (for example, the alcohol that is fit to; Or alkali or acid (when formula (I) compound contains acidity or basic moiety) are such as 1-phenylethylamine or tartrate) reaction.The gained non-enantiomer mixture can separate by chromatography and/or Steppecd crystallization, and in the diastereomer 1 or 2 can be converted into corresponding pure enantiomer by well known to a person skilled in the art method.
Chipal compounds of the present invention (and chiral precurser) can use chromatography (being typically the HPLC method), have on the inhomogeneous resin of moving phase, obtaining with the form that is rich in enantiomer, this moving phase is made up of hydrocarbon, and this hydrocarbon is generally heptane or the hexane that contains 0-50 volume % (2-20 volume % usually) Virahol and 0-5 volume % alkylamine (common 0.1% diethylamine).Concentrate eluant is to produce enriched mixture.
The present invention includes all crystal formations of formula (I) compound, comprise its racemic compound and racemic mixture (conglomerates).The stereoisomerism racemic mixture can separate by routine techniques well known by persons skilled in the art, for example referring to the ＂ Stereochemistry of Organic Compounds ＂ (Wiley, New York, 1994) of E.L.Eliel and S.H.Wilen.
The present invention includes all pharmaceutically acceptable compound isotopically labelleds of formula (I), wherein one or more atom is replaced with and has the same atoms number but atomic mass or total mass number are different from the atom that occurring in nature occupies preferred atomic mass or total mass number.
The isotopic example that is fit to be included in the The compounds of this invention comprises: hydrogen isotope, such as
2H reaches
3H; Carbon isotope, such as
11C,
13C reaches
14C; Chlorine isotope, such as
36Cl; Fluorine isotope, such as
18F; Iodine isotope, such as
123I reaches
125I; Nitrogen isotope, such as
13N reaches
15N; Oxygen isotope, such as
15O,
17O reaches
18O; Phosphorus isotope, such as
32P; And sulfur isotope, such as
35S.
Some compound isotopically labelleds of formula (I) (for example, being associated with radioisotopic those compounds) can be used in medicine and/or the research of substrate tissue distribution.The radio isotope tritium (that is,
3H) and carbon 14 (that is,
14C) owing to it is easy to merge and easy this purpose that is particularly useful for of detection method.
Through heavy isotope (such as deuterium, promptly
2When H) replacing, produce certain treatment advantage (for example, the transformation period prolongs or the required dosage minimizing in the body) because of metabolic stability is bigger, therefore more preferred in some cases.
Through the positron radiation isotropic substance (such as
11C,
18F,
15O reaches
13When N) replacing, can be used in positron emission fault (PET) research with investigation substrate acceptor occupancy.
The compound isotopically labelled of formula (I) usually can be by well known to a person skilled in the art routine techniques preparation, or adopt the isotope labeling reagent that is fit to substitute used in the past non-marked reagent, by with the embodiment of this paper and the same method preparation of those methods described in the preparation example.
Pharmacy acceptable solvent thing of the present invention comprises that wherein the crystallization solvent can be by isotropic substance (for example, D
2O, d
6-acetone, d
6-those solvates of DMSO) replacing.
Also be included in the scope of the present invention just like hereinafter defined intermediate compound, its all salt, solvate and mixture, and as mentioned to all solvates and the mixture of defined its salt of formula (I) compound.The present invention includes all polymorphic forms and the crystal habit thereof of above-mentioned substance type.
When preparation formula of the present invention (I) compound, to those skilled in the art, customaryly select that the intermediate forms of best features combination can be provided is conspicuous in order to prepare purpose.These features comprise fusing point, solubleness, workability and the output of intermediate forms, and the simplification of the separable purified product that is produced thus.
Be intended to can be used as crystallized product or amorphous products administration, or can exist with solid-state continuum (from amorphous fully crystallization extremely fully) as the compound of the present invention of medicine.It for example can be by obtaining their solid packing, powder or form membrane such as methods such as precipitation, crystallization, lyophilize, spraying drying or evaporation dryings.Also can use microwave drying or radio-frequency drying for this reason.
They can be individually dosed or with one or more other compound Combined Preparation of the present invention or with one or more other medicines (perhaps making up arbitrarily) Combined Preparation as it.Usually, they will be as the administration with the preparation of one or more pharmaceutically acceptable excipient composition.Term ＂ vehicle ＂ is used to describe any composition except that The compounds of this invention in this article.Select vehicle to depend on following factor to a great extent: such as specific administration mode, vehicle to the influence of solvability and stability and formulation character etc.
Pharmaceutical composition that is applicable to the The compounds of this invention conveying and preparation method thereof is conspicuous for those skilled in the art.This based composition and preparation method thereof can be referring to for example ＂ Remington ' s Pharmaceutical Sciences ＂, the 19th edition (Mack PublishingCompany, 1995).
The administering mode that is fit to comprises oral administration, parenteral administration, topical, suction/intranasal administration, rectum/vagina administration and through eye/through the ear administration.
Compound Orally-administrable of the present invention.Oral administration can comprise to be swallowed, so that compound enters gi tract; Maybe can adopt and suck or sublingual administration, so that compound directly enters blood flow from the oral cavity.The preparation that is applicable to oral administration comprises: solid preparation, and such as tablet, the capsule that contains particulate, liquid or powder, lozenge (comprising filling liquid), masticatory, multiparticulates and nanoparticle, gel, sosoloid, liposome, film, pill (ovum shape body), sprays, liquid preparation and oral cavity/mucous membrane adhesion paster.
Liquid preparation comprises suspension, solution, syrup and elixir.The weighting agent that this class preparation can be used as in soft capsule or the hard capsule uses, and comprises supporting agent (for example, water, ethanol, polyoxyethylene glycol, propylene glycol, methylcellulose gum or suitable oil) and one or more emulsifying agents and/or suspending agent usually.Liquid preparation also can be by for example preparing solid compatibility again in anther sac.
Compound of the present invention also can be used for quick-dissolving agent, speed collapses agent, such as Liang and Chen in Expert Opinion in Therapeutic Patents, 11 (6), those formulations described in the 981-986 (2001).
For Tabules, according to dosage, medicine can account for this formulation 1 weight % to 80 weight %, be preferably 5 weight % to 60 weight % of formulation.Except that medicine, tablet also contains disintegrating agent usually.The example of disintegrating agent comprises hydroxypropylcellulose, starch, pregelatinized Starch and the sodiun alginate that primojel, Xylo-Mucine, calcium carboxymethylcellulose, croscarmellose sodium, polyvinylpolypyrrolidone, polyvinylpyrrolidone, methylcellulose gum, Microcrystalline Cellulose, low-carbon alkyl replace.Usually, disintegrating agent account for this formulation 1 weight % to 25 weight %, be preferably 5 weight % to 20 weight % of formulation.
Tackiness agent generally is used to make tablet formulation have tackiness.The tackiness agent that is fit to comprises Microcrystalline Cellulose, gelatin, sugar, polyoxyethylene glycol, natural and synthetic gum, polyvinylpyrrolidone, pregelatinized Starch, hydroxypropylcellulose and HPMC.Tablet also can contain thinner, such as lactose (monohydrate, spray-dried monohydrate, lactose hydrous and analogue), N.F,USP MANNITOL, Xylitol, dextrose, sucrose, sorbyl alcohol, Microcrystalline Cellulose, starch and dicalcium phosphate dihydrate.
Optional tensio-active agent (such as sodium lauryl sulphate and Polysorbate 80) and the glidant (such as silicon-dioxide and talcum powder) of also can comprising of tablet.When containing these materials, tensio-active agent can account for 0.2 weight % to 5 weight % of tablet, and glidant can account for 0.2 weight % to 1 weight % of tablet.
Tablet generally also contains lubricant, such as the mixture of Magnesium Stearate, calcium stearate, Zinic stearas, sodium stearyl fumarate and Magnesium Stearate and sodium lauryl sulphate.Lubricant accounts for 0.25 weight % to 10 weight % of tablet usually, preferably accounts for 0.5 weight % to 3 weight %.Other possible composition comprises antioxidant, tinting material, seasonings, sanitas and odor mask.
Illustrative tablet contain about at the most 80 weight % medicines, about 10 weight % to about 90 weight % tackiness agents, about 0 weight % to about 85 weight % thinners, about 2 weight % to about 10 weight % disintegrating agents and about 0.25 weight % to about 10 weight % lubricants.Tablet batch mixing directly compressible or form tablet by the cylinder compressing tablet.Perhaps, the part of tablet batch mixing or a part of batch mixing can be carried out wet method, dry method or melt granulation before compressing tablet, fusion is condensed or extrude.Final preparation can comprise one or more layers, can be dressing or dressing not; Even can the tunica envelope.The argumentation of the preparation of tablet is referring to the ＂ Pharmaceutical DosageForms:Tablets ＂ of H.Lieberman and L.Lachman, and the 1st rolls up (Marcel Dekker, New York, 1980).
But consume film for the per os that people or animal doctor use and be generally the water-soluble film formulation or the hydroexpansivity thin-film dosage form of easily scratching, its rapidly dissolvable or mucosal adhesive and comprise compound, film-forming polymer, tackiness agent, solvent, wetting Agent for Printing Inks, softening agent, stablizer or emulsifying agent, viscosity improver and the solvent of formula (I) usually.Some components in the said preparation have more than one function.
Formula (I) compound can be water-soluble or insoluble.Water-soluble cpds comprises 1 weight % to 80 weight % usually, is more typically the solute of 20 weight % to 50 weight %.Insoluble chemical compound can constitute the larger proportion of composition, is at most 88 weight % of solute usually.Perhaps, formula (I) compound can be the form of many particles microballon.
Film-forming polymer can be selected from natural polysaccharide, protein or synthetic hydro-colloid, and exists scope to be generally 0.01-99 weight %, is more typically 30 to 80 weight %.
Other may comprise antioxidant, tinting material, seasonings and sweetener, sanitas, saliva stimulant, refrigerant, cosolvent (comprising oil), lubricant, weighting agent, defoamer, tensio-active agent and odor mask by composition.
The aqueous film that film of the present invention normally will be coated on strippable backing or the paper makes through evaporation drying.This operation can be reached in loft drier or drying tunnel (being generally built-up type coating moisture eliminator), or by frost drying or vacuumize and reach.
The solid preparation that is used for oral administration can be prepared into quick-releasing type and/or slow release type.Slow release type preparation comprises and postpones to discharge, continues release, pulse release, controlled release, target discharges and plan discharges (programmed release).
Be applicable to that the object of the invention sustained release preparation is described in United States Patent (USP) the 6th, 106, in No. 864.The details of the drug release technology (such as high energy dispersion agent and infiltration and coated granule) that other is fit to are referring to people's such as Verma ＂ Pharmaceutical TechnologyOn-line ＂, 25 (2), 1-14 (2001).Utilize chewable tablet to realize that the technical description of sustained release is in WO00/35298.
Compound of the present invention also can directly deliver medicine in blood flow, muscle or the internal organs.The mode that is applicable to parenteral administration comprises in vein, artery, abdominal cavity, the sheath, in the ventricle, in the urethra, in the breastbone, encephalic, muscle and subcutaneous.The device that is applicable to parenteral administration comprises pin (comprising micro-needle) syringe, needleless injector and infusion techniques.Non-gastrointestinal preparation is generally the aqueous solution that can contain vehicle (such as salt, carbohydrate) and buffer reagent (preferred pH3-9), yet use for some, be more suitable for the dried forms that they are mixed with aseptic non-aqueous solution or use with the solvent (such as aseptic pyrogen-free water) that is fit to.(for example by freeze-drying) preparation non-gastrointestinal preparation can use the standard pharmaceutical technology of well known to a person skilled in the art to realize at an easy rate under aseptic condition.
The solvability that is used to make formula (I) compound of parenteral administration solution can strengthen by utilizing appropriate formulations technology (such as adding solubility enhancer).The preparation that is used for parenteral administration can be made into quick-releasing type and/or slow release type.Sustained release preparation comprises and postpones slowly-releasing, lasting slowly-releasing, pulse slow-releasing, controlled release, target release and plan slowly-releasing.Therefore, compound of the present invention can be made into solid, semisolid or thixotropic fluid, as the implantation bank drug delivery system that the slowly-releasing active compound can be provided.The said preparation example comprises (PGLA) suspension of microballoon of coating support and poly-(dl-lactic-co-glycolic acid).
Compound of the present invention also can be local, skin (interior) or transdermal administration be in skin or mucous membrane.Be used for this purpose exemplary formulations and comprise gel, hydrogel, lotion, solution, emulsion, ointment, dusting, dressings, foam, film, transdermal patches, bag medicine wafer paper, implant, sponge, fiber, bandage and microemulsion.Also can use liposome.Typical supporting agent comprises alcohol, water, mineral oil, whiteruss, white vaseline, glycerine, polyoxyethylene glycol and propylene glycol.Can add penetration enhancer, for example referring to the J PharmSci of Finnin and Morgan, 88 (10), 955-958.Other topical mode comprises by electroporation, iontophoresis, ultrasonic method, phonophoresis method and micro-needle or needleless (for example, the Powderject of penetrating
TM, Bioject
TMDeng) injection transmission medicine.The preparation that is used for topical can be prepared as quick-releasing type and/or slow release type.Sustained release preparation comprises and postpones slowly-releasing, lasting slowly-releasing, pulse slow-releasing, controlled release, target release and plan slowly-releasing (programmed release).
Compound of the present invention can also intranasal in or pass through inhalation; Usually with dry powder form (for example to use separately or, for example to use) administration with phosphatide (such as phosphatidylcholine) blended form as the blending ingredients particle with the drying composite form of lactose from Diskus.Perhaps use or do not use suitable propelling agent (such as 1,1,1,2-Tetrafluoroethane or 1,1,1,2,3,3, the 3-heptafluoro-propane), as sprays administration, or as nasal drop from pressurizing vessel, pump, spray thrower, spraying gun (preferably utilizing electric ydrodynamics to produce the spraying gun of mist) or atomizer.For intranasal administration, this pulvis can comprise bioadhesive polymer, for example, and chitosan or cyclodextrin.
Pressurizing vessel, pump, spray thrower, spraying gun or atomizer contain the solution or the suspension of compound of the present invention, this solution or suspension for example comprise ethanol, aqueous ethanolic solution be applicable to dispersion, solubilising or prolong the substituting agent of release active compound, as the propelling agent of solvent and optional tensio-active agent, such as sorbitan trioleate, oleic acid or lact-acid oligomer.
Before being used for dry powder or suspension formulations, with the pharmaceutical product micronize to the size (usually below 5 microns) that is suitable for transmitting by inhalation.This can realize by any breaking method that is fit to, such as treatment with supercritical fluid method, high pressure homogenization method or the spray-drying process of spiral spray polishing, fluidised-bed spray polishing, formation nanoparticle.
Capsule (for example, being made by gelatin or HPMC), bubble-cap and the cartridge case that is used for sucker or insufflator can be made into the powdered mixture that contains compound of the present invention, is fit to powder matrix (such as lactose or starch) and properties modifier (such as 1-leucine, N.F,USP MANNITOL or Magnesium Stearate).Lactose can be lactose hydrous or is the monohydrate form, the preferred latter.Other vehicle that is fit to comprises dextran, glucose, maltose, sorbyl alcohol, Xylitol, fructose, sucrose and trehalose.
The The compounds of this invention, the ejection volume that are adapted at making the electricity consumption ydrodynamics produce the every spray 1 μ g to 20mg of pharmaceutical solutions that uses in the spraying gun of mist are 1 μ l to 100 μ l.Typical formulation can comprise compound, propylene glycol, aqua sterilisa, ethanol and the sodium-chlor of formula (I).The replace solvents that alternative propylene glycol uses comprises glycerine and polyoxyethylene glycol.
Seasonings (such as menthol and left-handed menthol) or the sweeting agent (such as asccharin or soluble saccharin) that is fit to can be added into the preparation of the present invention that is used for inhalation/intranasal administration.
The formulation example that is used for inhalation/intranasal administration can be prepared as quick-releasing type and/or slow release type as using PGLA.Sustained release preparation comprises and postpones to discharge, continues release, pulse release, sustained release, target discharges and plan discharges.
When being Diskus and aerosol, dose unit is judged by the valve that transmits dosing.Dose unit according to the invention is usually designed to dosing or " emitted dose " that contains 1 μ g to 100mg formula (I) compound.Every day, the scope of total dosage was generally 1 μ g to 200mg, and it can the single dose administration, or is more typically in one day with multiple dose administration.
Compound of the present invention for example can suppository, hysterophore, kill the form per rectum or the vagina administration of little dose, pesseulum or enema.Theobroma oil is traditional suppository base, but then can use various surrogates if be fit to.The preparation that is used for rectum/vagina administration can be prepared as quick-releasing type and/or slow release type.Sustained release preparation comprises and postpones to discharge, continues release, pulse release, sustained release, target discharges and plan discharges.
Compound of the present invention can also directly give eye or ear through the drop form that the grade of pH regulator is oozed micronize suspension in the stroke-physiological saline solution or solution usually.Be fit to (for example to comprise ointment, biodegradable through eye and through other preparation of ear administration; can absorb gel sponge, collagen protein) and biological non-degradable is (for example; polysiloxane) implant, bag medicine wafer paper, lens and particulate or vesica system are such as class lipid vesicle or liposome.Can be with adding following polymkeric substance: (for example such as cross linked polyacrylate, polyvinyl alcohol, hyaluronic acid, cellulose polymer compound such as sanitass such as benzalkonium chlorides, HPMC, Natvosol or methylcellulose gum) or mixed polysaccharide polymkeric substance (for example, gelling gum).Said preparation also can transmit by iontophoresis.Be used for through eye/can be prepared as quick-releasing type and/or slow release type through the preparation of ear administration.Sustained release preparation comprises and postpones to discharge, continues release, pulse release, sustained release, target discharges or plan discharges.
Compound of the present invention can with soluble large molecule entity (such as cyclodextrin and suitable derivative thereof or contain the polymkeric substance of polyoxyethylene glycol) combination, be used for above-mentioned any one administering mode to improve its solvability, dissolution rate, taste masking, bioavailability and/or stability.Have been found that for example the drug-cyclodextrin mixture generally can be used for most of formulations and route of administration.Inclusion complex and non-inclusion complex all can use.As with medicine directly compound (complexing) but selection mode, cyclodextrin can be used as supplementary additive, that is, as supporting agent, thinner or solubilizing agent.Being most commonly used to this purpose is alpha-cylodextrin, beta-cyclodextrin and γ-Huan Hujing, and the example can be referring among No. 98/55148, international patent application WO 91/11172, No. 94/02518, WO and the WO.
Because for example in order to treat concrete disease or symptom, therefore may need to give the combination of active compound, the present invention cover two or more pharmaceutical composition (wherein at least a contain compound of the present invention) is combined into the kit form that is fit to co-administered easily.Therefore, the member that medicine box of the present invention comprises two or more independent pharmaceutical composition (wherein at least a formula of the present invention (I) compound that contains) and holds said composition respectively is such as container, sub-bottling or cellular-type paper tinsel bag.The example of this medicine box is the Blister Package that is usually used in package troche, capsule etc.Medicine box of the present invention especially is fit to for example administration of different dosage form such as per os and parenteral administration, is adapted at different dosing and gives independent composition interval, or be used for the composition separately of titration each other.For helping conformability, this medicine box comprises the medication instruction book usually and so-called memory support can be provided.
For the administration of human patient, the scope of total day clothes dosage of The compounds of this invention is generally 1mg to 10g, and as 10mg to 1g, as 25mg to 500mg, certainly, this depends on administering mode and curative effect.For example, oral administration may need the total day clothes dosage of 50mg to 100mg.Total day clothes dosage can single dose or multidose administration, and can judge by the doctor and exceed specified general range herein.These dosage all are based on the general population experimenter with about 60kg to 70kg body weight.The doctor easily can judge and is applicable to that body weight exceeds the experimenter of this scope (for example child and the elderly's) dosage.
For the improvement dissolution characteristic, be prepared as follows 4-amino-1-benzyl-6-Trifluoromethyl-1, the 3-dihydro-imidazol-is [4,5-c] pyridin-2-ones (hereinafter embodiment 15) and HPMC (HPMC E3 Prem LV, Methocel also
, available from Dow ChemicalCompany, Midland, solid amorphous spraying drying dispersion (SDD) MI).At first, formation contains the spray solution of 2.97g water, 16.83g methyl alcohol and 250 μ L 1M KOH (containing the 9.8mg potassium cationic), to its 4-amino-1-benzyl-6-Trifluoromethyl-1 that adds 51.27mg, the 3-dihydro-imidazol-is the crystallization neutral form of [4,5-c] pyridin-2-ones also.Then, 140.4mg HPMC is added in this solution and with this solution stirring 5 minutes and supersound process 2 minutes.This solution is controlled the small-sized spray drying device that fast syringe pump suction is made up of the Stainless Steel Case chamber of diameter 11cm with 1.1ml/min flow velocity, usefulness Cole Parmer 74900 series connection.Use heated nitrogen gas stream, with this solution with 1 standard ft
3/ minute flow velocity with two-fluid spray nozzle (Spraying Systems Co., Wheaton, Illinois, model: SU1A) atomizing.Hot gas enters the shell chamber with 85 ℃ temperature in and discharges with 22 ℃ temperature out.The gained solid amorphous dispersions is collected on the Whatman #1 Microcrystalline Cellulose filtration medium (11 μ m apertures, 11cm external diameter), dry under vacuum, and be stored in the moisture eliminator.This dispersion contains 25.4wt%4-amino-1-benzyl-6-Trifluoromethyl-1, and the 3-dihydro-imidazol-is [4,5-c] pyridin-2-ones, 4.9wt% potassium cationic and 69.7wt% HPMC also.Yield is about 60%.
For avoiding suspecting, described herein ＂ treatment ＂ comprises and relates to therapeutic, the property alleviated and prophylactic treatment.
Following process description is used for the general method of preparation formula (I) compound and intermediate thereof.
Some programs described in the preparation flow of formula (I) compound or its intermediate that it will be understood by those skilled in the art that may not be suitable for that some are possible for substituting group.
Those skilled in the art it will also be appreciated that and might need sometimes or preferred to carry out the conversion described in the flow process with described different order, maybe need to revise one or more and transform, to form required formula (I) compound.
Those skilled in the art it should be understood that in addition as illustrated in the flow process hereinafter, may need or preferably one or more sensitive group in any stage protection molecule of synthesis type (I) compound so that prevent unwanted side reaction.In detail, the amido that may need protection.Used protecting group can be used in a usual manner in formula (I) compound.For example referring to Theodora W Green and Peter G M Wuts " Protective Groups in OrganicSynthesis " the 3rd edition (John Wiley and Sons, 1999) those contents described in (especially the 7th chapter, 494-653 page or leaf (＂ Protection for the Amino Group ＂)), as a reference, it had also described the method that removes such group during this article was incorporated herein.
Amino protecting group boc, benzyloxycarbonyl, benzyl and ethanoyl are particularly useful for preparation formula (I) compound and intermediate thereof.
Except as otherwise noted, R in the flow process
1-R
7And Y all as defined herein.PG
1And PG
2Be nitrogen-protecting group.
Formula (I) compound can prepare described in flow process 1, and hereinafter preparation example 1-27 then further specifies flow process 1.
It should be understood that the amino protecting group N (PG1) in the formula (XVII) to (XIX) (PG2) can be N (H) PG in some cases
1
Flow process 1
Flow process 1 has been described the variety of way of preparation formula (I) compound.
A) for example, in the presence of the Zn source, make commercial nitrile (II) or pass through prepared nitrile (II) of any standard method described in the chemical literature and halogenated acetic acids ester (III) (for example ethyl bromoacetate) reaction.Tet.Letts, 1997,38,443-446 has described if the using basic condition is separated this product, and then this conversion reaction can produce the enamine of universal architecture (IV).
B) if above-mentioned steps is used acidic conditions in a), then produce ketone ester (V), can use ammonia source (for example ammonium acetate) then, in separating step, make it be converted into enamine (IV) again.This shows that the various ketone esters of universal architecture (V) can locate to intercept and capture said synthesis route at intermediate (IV).C) can make then enamine (IV) alkaline condition (such as sodium ethylate, sodium hydride or potassium tert.-butoxide) down with dialkyl malonate (VII) reaction with generation (VIII).J.Org.Chem., 1981,46 (15), 3040-3048 has described the example of this conversion.
D) or, enamine (IV) is reacted with generation amidation form (IX) with malonyl chloride (VI) down at the alkali (such as salt of wormwood or triethylamine) that is fit to.
E) can make (IX) then is pyridine (VIII) with the cyclization with the alkali reaction that is fit in separating step.The alkali that is fit to comprises sodium ethylate, sodium hydride or potassium tert.-butoxide.
F) make (VIII) saponification under acidity that corresponding acid (for example, HCl, HBr, sulfuric acid), sodium hydroxide or lithium hydroxide are provided or alkaline condition then under heat effect, spontaneous decarboxylationization is to produce pyridine (X).The case description of this conversion is in WO01101949.
G) (X) can use any document condition well known by persons skilled in the art (for example using the mixture of nitric acid and vitriolic mixture or acetate and nitric acid) nitrated to produce nitropyridine (XI).For example, Bioorg.Med.Chem.Lett., 1996,6 (2), this conversion has been described among the 173-178.
H) (XI) can use various conversion hydroxyls as condition (such as thionyl chloride or the phosphoryl chloride) chlorination of chlorine to produce (XII).It will be understood by those skilled in the art that the chlorination or be converted into alternate leavings group (such as another halogen atom) or Acibenzolar (such as methane sulfonate or trifluoromethane sulfonic acid ester) respectively of 2 hydroxyls.The example of these all methods is included in hereinafter in the part.
I) make (XII) and general formula R
3YNH
2Amine reaction (it is preferentially in the reaction of 4-cl radical) to produce (XIII).Look R
3The character of Y group and deciding can exist the part transposition of 2 cl radicals or a small amount of transposition at 2-cl radical place, but without detriment to the ability of remarkable acquisition (XIII).
(XIII) and ammonia or ammonia equivalent (such as ammonium acetate) are reacted to produce (XIV).
K) can make under (XIV) known in the literature any condition (for example using iron or tin among the HCl) reduction nitro-aromatics is reduced to amine then, in the presence of transition-metal catalyst (such as palladium, platinum or nickel) or chemical reducing agent (such as lithium aluminum hydride), carry out hydrogenation again with generation (XV).
L) (XV) and C=0 source (such as 1,1-carbonyl dimidazoles or phosgene) are reacted to produce imidazolone (XVI) and mixture (I), wherein (I) can obtain by careful chromatography purification.
M) or, (XIII) can with the reaction of the protected form (such as dibenzyl amine or diallylamine) of ammonia, wherein 2 hydrogen atoms are replaced by 2 groups that remove under mild conditions subsequently.About substituting of these examples, for example referring to Theodora W Green and Peter G M Wuts " Protective Groups in Organic Synthesis " the 3rd edition (John Wileyand Sons, 1999), those groups described in the 7th chapter, the 494-653 page or leaf (＂ Protection for theAmino Group ＂) especially.
N)-o) referring to step k)-l).
P) be fit to remove protecting group PG then
1And PG
2Various conditions under with (XIX) deprotection to produce (I).For example referring to Theodora W Green and Peter G M Wuts " Protective Groups in Organic Synthesis " the 3rd edition (John Wiley andSons, 1999), those groups described in the 7th chapter, the 494-653 page or leaf (＂ Protection for the AminoGroup ＂) especially, with and remove condition.
Q) or; (XIII) can preferably use highly basic such as sodium hydride, potassium tert.-butoxide or diisopropylaminoethyl amine lithium and the acylating agent that is fit to (such as Vinyl chloroformate or other any chloroformic acid alkane ester or chloroformic acid aromatic ester; the combination of chloroform or acid anhydrides is as amido alkyl formate R
13CO
2X (R wherein
13Be C
1-6Alkyl and X are halogen) protected, to form (XX).
R) can be to (XX) as above applying step j) and k), can be (I) by locational choice ground cyclisation with the product of sequence of steps gained thus by protonic acid (such as acetate or formic acid) simple process then.
Also can use the compound of alternate configuration (wherein halogen atom be present in the C2 position and form the intermediate (XXVII in the flow process 2) that is fit to be used for further operation) the preparation general formula (I) of intermediates (XVII) according to following flow process 2.
Flow process 2
Thereby the processing of the available some steps of commercial dihalo pyridine (for example, dibromo pyridine XXI) is to produce many analogues of general formula (I).
A)-e) commercial dibromo pyridine (XXI) can be according to modified document program (being described among the WO2005026164) operation to produce intermediate (XXVI).Between (XXI) and the many steps (XXVI) depend on hot hazardous agents or produce the dangerous product of potential underground heat, therefore should careful operation.
F) (XXVI) be to use and variously knownly can produce the conditioned response of diazotization thing and get from amino, for example, the nitrous acid condition that replaced by the C1 atom of diazotization thing by HCl and on-the-spot generation of Sodium Nitrite and wherein.(XXVI) is converted into key intermediate (XXVII) and can realizes by adding excessive amine (for example benzylamine) to thick muriate then.This step is substituted by amino with C2 halogen atom and C4 halogen atom.Any primary amine or secondary amine group all are applicable to this conversion.
C2 halogen atom in (XXVII) is reacted under the condition that various replacement C2 halogen groups are various functional groups, thereby can prepare multiple alternative product (I).For example, use multiple organometallic reagent (boric acid, zincate, azoviolet, cuprate, stannane etc.) that heterocycle and (XXVII) coupling can be produced (XXVIII), use vinyl organometallic reagent (such as the vinyl tributyl tin) and palladium catalyst (such as Pd (PPh
3)
4) heterocycle and (XXVII) coupling can be produced vinyl material (XXX), and oxonation, wherein (XXVII) is in the presence of such as alkali such as triethylamine and palladium catalyst, under pressure, by the CO gas processing, with the acyl group product of generation universal architecture (XXIX).Can make structure (XXVIII) and compound (XXIX) be converted into the compound of formula (I) according to step n, o and the p of flow process 1 then.
J)-l) (XXX) can handle to produce aldehyde (XXXII) by oxygenizement then, then (XXXII) or (XXXI) can handle or use reductive agent processing such as sodium triacetoxy borohydride with generation product (I) (according to the step n in the flow process 1, o and p) respectively in the presence of such as alkali such as triethylamines with amine.
The alternate configuration of intermediate (XIII) can be according to flow process 3 preparations, following then operation production (I) compound.
Flow process 3
A)-e) step a)-e) similar to flow process 1 described those step essence, except that preparation monohalide (XXXIV) with the position chemical integrity of guaranteeing C6 and C4 in (XXXVI).
F) (XXXVIII) can be under various conditions well known by persons skilled in the art (such as the bromine water in the non-polar solvent (such as DCM or MeCN)) bromination to produce C
3-bromide (XXXIX).
G) can use then CO gas, such as alkali such as triethylamines, such as alcohol such as methyl alcohol and such as Pd (PPh
3)
4Exist down, under pressure, make (XXXIX) carbonylation Deng palladium catalyst to produce ester (XXXX).
H)-i) can make (XXXX) and amine NR then
6R
7Reaction to be producing acid amides (XXXXI), its can be as above by deprotection to produce product (I).
Alternative synthetic being showed in the following flow process 4 of intermediate (XI).
Flow process 4
A) can make any nitrile (XXXXII) of having a methylene radical at the nitrile functionality adjacent and malonyl chloride (XXXXIII) reaction to form pyridine (XXXXIV).This conversion is described in Synthesis, and 1984, among the 765-766.
B) can use any document condition well known by persons skilled in the art then, for example use the mixture of nitric acid and vitriolic mixture or acetate and nitric acid that pyridine (XXXXIV) is nitrated to form nitropyridine (XXXXV).
C) the chlorine atom coupling under various conditions then in (XXXXV), wherein can be with reactive organometallic reagent (for example at (in the presence of palladium catalyst) in the presence of the transition-metal catalyst, stannane, zincate or boric acid) handle (XXXXV), to produce substituted pyridine (XI).R therein
1During=H, in the presence of such as the suitable catalyzer of palladium charcoal or palladium hydroxide, can effectively carry out simple hydrogenation.
Another of intermediate (X) substitutes synthetic being showed in the following flow process 5.
Flow process 5
In the method, make malonyl ester, preferred diphenyl ester (XXXXVI) and schiff bases (XXXXVII) reaction and heating to produce the pyridine of general formula (X).
Another alternative of preparation general formula (X) compound is showed in the flow process 6.
Flow process 6
A) ketone acid (its saponification reaction commercially available or ketone ester by formula V directly makes) that makes general formula (XXXXVIII) at high temperature, in the solvent that is fit to C=0 source (such as 1, the 1-carbonyl dimidazoles) reaction to produce cyclisation pyrone (XXXXIX).
B) (XXXXIX) used such as the strong inorganic acid of sulfuric acid or hydrochloric acid and handle to remove the C3-acyl substituent and to produce pyrone (L).
C) under heating, can make (L) with such as ammonia sources such as dense ammonium hydroxide aqueous solution reactions the pyrone ring being converted into pyridine (X), thereby intercept and capture the identical intermediate described in the flow process 1.Perhaps, some kinds of pyrone of general formula (L) can be available from commercial source, and it can directly apply to step c.Those seriess of compounds that general formula (L) compound is converted into general formula (X) are described in the several sources of WO9504730 for example.
One alternative of preparation general formula (XIX) compound is showed in the flow process 7.
Flow process 7
A) can make the commercial dichloropyridine and the formula R of general formula (LI)
3YNH
2Amine reaction replace the 4-cl radical with selectivity, thereby produce pyridine (LII).
B) can make the protected form PG1NH of (LII) and ammonia then
2Or PG1PG
2NH (such as benzylamine, allylamine, dibenzylamine or diallylamine) reaction is to replace the 2-cl radical, and wherein 2 hydrogen atom systems are replaced by 2 groups that can remove under mild conditions subsequently.About substituting of this example, see also " ProtectiveGroups in Organic Synthesis " the 3rd edition (John Wiley and Sons, 1999) of for example Theodora W Greene and Peter G M Wuts, those groups described in the 7th chapter, the 494-653 page or leaf (＂ Protection for the Amino Group ＂) especially.If use excessive amine R from step a
3YNH
2, then this group can replace 2-cl radical and 4-cl radical.
C) ester (LIII) can be under known various conditions with the ester deprotection (for example, sodium hydroxide or lithium hydroxide) hydrolysis to produce acid (LIV).About substituting of this reagent, see also for example Theodora W Greene and Peter G M Wuts " Protective Groups inOrganic Synthesis " the 3rd edition (John Wiley and Sons, 1999), those conditions described in the 5th chapter, the 373-441 page or leaf (＂ Protection for the Carboxylgroup ＂) especially.
D) can make (LIV) and the known reagent react that makes acid be converted into acid azide (for example diphenylphosphine acyl azide) then.Under heat effect, the rearrangement reaction that intermediate acid azide experience wherein produces isocyanic ester and holds back through 4-amido substituting group in inside with generation imidazolone (XIX), thereby is intercepted and captured the identical intermediate described in the flow process 1.
One alternative of preparation general formula (I) compound is showed in the flow process 8.
Flow process 8
A) according to Org.BioMol.Chem., 2003,1, prepared (LVI) of 1354-1365 can be by (for example making amino in (LVI) and active agent, Isopentyl nitrite) and halogenating agent (such as methylene iodide or methylene bromide) reaction come halogenation, to produce halogenation material (LVII).
B) (LVII) can experience the coupled reaction of various transition metal mediation then, wherein iodine group optionally with for example terminal alkyne reaction.About example to this conversion of imidazoles configuration, referring to J.Med.Chem., 34 (2), 1991,778-786.
C) can make (LVIII) and ammonia react so that alkynyl-formonitrile HCN cyclisation is a pyridine ring then.About example to this conversion of imidazoles configuration, for example referring to Tetrahedron, 49 (3), 1993,557-570.
D) can make bromine atoms (for example, hydrochloric acid or sulfuric acid) hydrolysis under strong acidic condition in (LIX) then; Or with the reaction of the nucleophilic source (such as sodium hydroxide or sodium methylate) of OH, Shi Du acidic hydrolysis then is with generation (I).
Intermediate (LVIII) also can be used to prepare the compound of general formula (I) according to following flow process 9.
Flow process 9
E) (LVIII) reacted to form acetal (LX) under the heating of appropriateness with alcohol (for example, methyl alcohol, ethanol, propyl alcohol or other any alcohol).
F) acetal (LX) can make (for example, aqueous hydrochloric acid) experience hydrolysis under any condition that acetal or ketal be hydrolyzed to ketone known then.About substituting of this condition, see also for example Theodora W Green and Peter G M Wuts " Protective Groups in OrganicSynthesis " the 3rd edition (John Wiley and Sons, 1999), those conditions described in the 4th chapter, the 297-347 page or leaf (＂ Protection for the Carbonylgroup ＂) especially.
G) can make then ketone (LXI) in the presence of alkali (such as sodium hydride, potassium tert.-butoxide or salt of wormwood) that is fit to and alkylating agent (such as alkylogen, alkylsulfonate or alkyl trifluoro-methanyl sulfonate) alkylation with generation (LXII).
H) can make (LXII) and ammonia react so that ketone-formonitrile HCN cyclisation is a pyridine ring then.
I) can make bromine atoms (for example, hydrochloric acid or sulfuric acid) hydrolysis under strong acidic condition in (LXIII) then; Or with the reaction of the nucleophilic source (such as sodium hydroxide or sodium methylate) of OH, Shi Du acidic hydrolysis then is with generation (I).During alcoholysis step e, high temperature can make bromine atoms be replaced by alcohol, is introduced into (I) with the alternative of introducing oxo then.
Flow process 8 and 9 uses bromines (it is for preferred) to describe, but should be appreciated that also and can use other halogen atom.
Alternative synthetic being showed in the following flow process 10 of intermediate (XVII).
Flow process 10
A) (LXIV) can handle under any nitration condition well known by persons skilled in the art.Known the type transforms by carrying out with intermediate N nitro analogue.For example, referring to the same chemical content described in the WO2005026164.
B) (LXV) handled by HBr so that the chlorine atom is converted into bromine (LXVI).
C) then (LXVI) handled with any condition that amino is converted into N-nitroso-group or diazonium groups well known by persons skilled in the art, handle to produce muriate (LXVII) with HCl then.
D) (LXVII) available amine PG
1NH (for example benzylamine) handles to replace 4-chlorine and 2-bromine to produce (LXVIII).
E) use transition metal mediation method then, for example, Pd catalytic carbonylation, via the organo-metallic cross-coupling reaction of Sn, Zn or B reagent, or utilize Li or Mg reagent, use Fe or Ni as catalyzer, can make residue 6-bromine be used to introduce various substituting groups.In the example shown, the concrete analogue (LXIX) shown in oxonation produces.Can make this thing be converted into formula (I) compound according to the step n in the flow process 1, o and p then.
One alternative of preparation general formula (XIX) compound is showed in the flow process 11.
Flow process 11
A) successively can introduce under the various conditions of halogen atom (for example NCS, NBS, NIS, bromine water etc.) with (LXX) halogenation to produce two halogen pyridines (LXXI).
B) use universal architecture R3YNH then
2Amine handle (LXXI) to produce two compounds (LXXII) and (LXXIII) mixture.
C)-e) required compound (LXXII) but cyclisation then replaces residual halogen, last then deprotection can produce (I).
The other method of preparation general formula (X), (XI) and compound (I) is showed in the flow process 12.
Flow process 12
Thereby a), can use general dewatering agent (such as POCl
3, SOCl
2, PPA or trifluoromethanesulfanhydride anhydride), in the presence of the highly basic, can form under the condition of nitrile at the scene, make commercial formula (LXXV) acid amides and malonyl-diester (for example, 1,3-acetonedicarboxylic acid dialkyl) through the dehydration of initial acid amides and react.This condition directly causes the formation of dihydroxy-pyridine (X).
B) (X) can be nitrated to produce (XI) according to method described in the flow process 1.
C) (X) can be according to method saponification and decarboxylation described in the flow process 1.
D) and e) can use any method described in the flow process 1 to make (X) then or (XI) be converted into formula (I) compound.
The preparation method of prodrug derivatives (I) is showed in the following flow process 13.
Flow process 13
The reactive precursor compound be characterized as radicals R
4Or R
5Be connected in reagent reaction in the presence of the alkali that is fit to of suitable leavings group, can produce the prodrug derivatives of (I).The reagent that is fit to includes but not limited to alkylogen as follows, acyl chlorides, chloro-formic ester and urea chloride.
The alkali that is fit to comprises triethylamine, diisopropylethylamine, salt of wormwood, cesium carbonate, sodium hydride and n-Butyl Lithium.Multiple solvent (including but not limited to THF, acetonitrile, dimethyl formamide, methylene dichloride and ether) also can be used for realizing this conversion.The specific selection of solvent and alkali can influence the regioselectivity of alkylation reaction/acylation reaction, that is, whether reactive group connects O atom (R
5) or N atom (R
4).For example, reaction can produce the O acidylate significantly in the presence of parent molecule and the Vinyl chloroformate triethylamine in DCM.
Above-mentioned respond and aforesaid method in disclosed new initial substance be prepared as conventional, and to those skilled in the art, reference precedent and embodiment and preparation can be known and be used for the reagent and the reaction conditions that are fit to of its execution or preparation and the program of separating required product.
Compound of the present invention is useful owing to it has pharmacologically active in Mammals (comprising the people).In detail, it is applicable to the relevant disease of adjusting (especially agonism) for the treatment of with TLR7.
In another program, the present invention is provided for treating formula (I) compound or its pharmacy acceptable salt or the solvate of disease relevant with the adjusting of TLR7 acceptor or illness in addition.
Thereby the invention provides and be used for the treatment of wherein known or provable adjusting TLR7 and be subjected to physical efficiency to produce the disease of beneficial effect or (I) compound or its pharmacy acceptable salt or the solvate of illness.
In another scheme, compound of the present invention is applicable to the treatment virus infection, such as by the caused infection of following virus: adenovirus, simplexvirus (for example, HSV-I, HSV-II, CMV or VZV), poxvirus (for example, vaccinia subgroup virus such as smallpox or cowpox, or molluscum contagiosum), picornavirus (for example, rhinovirus or enterovirus), orthomyxovirus (for example influenza virus), Paramyxo virus (for example, secondary common cold virus, mumps virus, Measles virus or respiratory syncytial virus (RSV)), coronavirus (for example, SARS), papovavirus (for example, papillomavirus, such as producing Genital warts, those viruses of common wart or sufficient sole wart), hepadnavirus (for example, hepatitis B virus), flavivirus (for example, hepatitis C virus or dengue fever virus), retrovirus (for example, slow virus such as HIV) or inovirus (for example, Ebola virus or Marburg virus (marbug virus)).
In another program, compound of the present invention is applicable to the treatment infection with hepatitis C virus.
In another scheme, compound of the present invention is applicable to treatment tumour or cancer, it includes but not limited to cancer, sarcoma and leukemia, for example, squamous cell carcinoma, renal cell carcinoma, Kaposi sarcoma, melanoma, renal cell carcinoma, myelomatosis, lymphocytic leukemia, multiple myeloma, non_hodgkin lymphoma.
In another scheme, compound of the present invention is applicable to treatment infectation of bacteria, fungi infestation and protozoal infections, includes but not limited to by the caused infection of following Pseudomonas bacterium: Escherichia (Escherichia), enterobacter (Enterobacter), salmonella (Salmonella), Staphylococcus (Staphylococcus), klebsiella (Klebsiella), proteus (Proteus), Rhodopseudomonas (Pseudomonas), streptococcus (Streptococcus), chlamydiaceae (Chlamydia); Or fungi infestation, as moniliosis (candidiasis), aspergillosis (aspergillosis), histoplasmosis (histoplasmosis), crypotococcal (cryptococcal meningitis).
In another scheme, compound of the present invention is applicable to that the disease of treatment T-helper (Th2) mediation is (for example referring to people such as Dabbagh, Curr Opin Infect Dis 2003,16:199-204, during this article is incorporated herein as a reference), these diseases include but not limited to atopic disorder, such as atopic dermatitis or eczema, acidophilia polycyth(a)emia, asthma, transformation reactions, allergic rhinitis.
In another scheme, compound of the present invention is applicable to treatment damage or aged skin, such as scar and wrinkle.
In another scheme, compound of the present invention is applicable to the treatment autoimmune disease, such as Crohn disease and inflammatory bowel.
Formula (I) compound and pharmacy acceptable salt thereof or solvate can be individually dosed or be carried out administration as the part of conjoint therapy.Therefore, scope of the present invention comprises the example of the composition that comprises compound of the present invention and one or more other therapeutical agents and the example of co-administered thereof.
In a scheme, array configuration of the present invention comprises with formula (I) compound or its pharmacy acceptable salt or solvate and one or more other medicaments with anti-HCV activity treats, the medicament of this anti-HCV activity is the medicament that can suppress following target, such as, but not limited to: HCV NS3 albumen, HCV NS5A albumen, HCV NS4B albumen, HCV polysaccharase, HCV metalloprotease, HCV serine protease, HCV helicase, p7 albumen.The example of this type of medicament includes but not limited to: Interferon, rabbit, Peg-Intron (for example, Pegylation α-2a Interferon, rabbit and Pegylation α-2b Interferon, rabbit), long-acting interferon (for example, albumin interferon alpha), lamivudine (lamivudine), ribavirin (ribavarin), emtricitabine (emtricitabine), Wella rice fixed (viramidine), Xi Gewei (celgosivir), cut down his shore (valopicitabine), Lip river, HCV-086, HCV-796, RMZ702, BILN2061, IDN6566, NM283, SCH 6 and VX-950.
In another program, array configuration of the present invention comprise with the compound of formula (I) or its pharmacy acceptable salt or solvate and one or more other TLR agonists for example the agonist of TLR3, TLR7, TLR8 or TLR9 acceptor treat.
In another program, array configuration of the present invention comprises with the compound of formula (I) or its pharmacy acceptable salt or solvate and one or more and is selected from other antiviral agent treatment HCV-HIV coinfection of following inhibitor: hiv protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), nucleoside/nucleotide reverse transcriptase inhibitors (NRTI), the CCR5 antagonist, the interactional medicament that suppresses gp120 and CD4, suppress HIV and enter the medicament (as fusion inhibitor) of target cell, integrase inhibitor, the prenylation inhibitor, RNase H inhibitor and ripe inhibitor.
The example of NNRTI includes but not limited to: efavirenz (efavirenz), HBY-097, nevirapine (nevirapine), TMC-120 (reaching a Wei Lin (dapivirine)), TMC-125, according to bent Wei Lin (etravirine), Delavirdine (delavirdine), DPC-083, DPC-961, capravirine (capravirine), sharp a Wei Lin (rilpivirine), 5-{[3,5 diethyl-1-(2-hydroxyethyl)-1H-pyrazoles-4-yl] the oxygen base Isophthalodinitrile or its pharmacy acceptable salt, solvate or derivative; GW-678248, GW-695634, MIV-150, poon element (calanolide) and tricyclic pyrimidine ketone derivatives, such as among the WO 03/062238 announcement.
The example of CCR5 antagonist includes but not limited to: TAK-779; SC-351125; An Liweiluo (ancriviroc) (in the past being called SCH-C); Wei Liweiluo (vicriviroc) (in the past being called SCH-D); horse traction Wei sieve (maraviroc); PRO-140; I (also claims GW-873140 by Wei sieve (aplaviroc); Ono-4128; AK-602); AMD-887 CMPD-167; in the 1--8-[(3S)-3-(kharophen)-3-(3-fluorophenyl) propyl group]-8-azabicyclo [3.2.1] oct-3-yl }-2-methyl-4; 5; 6; 7-tetrahydrochysene-1H-imidazo [4; 5-c] pyridine-5-methyl-formiate or its pharmacy acceptable salt; solvate or derivative; in the 3--8-[(3S)-3-(kharophen)-3-(3-fluorophenyl) propyl group]-8-azabicyclo [3.2.1] oct-3-yl }-2-methyl-4; 5; 6; 7-tetrahydrochysene-3H-imidazo [4; 5-c] pyridine-5-methyl-formiate or its pharmacy acceptable salt; solvate or derivative; in the 1--8-[(3S)-3-(kharophen)-3-(3-fluorophenyl) propyl group]-8-azabicyclo [3.2.1] oct-3-yl }-2-methyl-4; 5; 6; 7-tetrahydrochysene-1H-imidazo [4; 5-c] pyridine-5-ethyl formate or its pharmacy acceptable salt; solvate or derivative; and in N-{ (1S)-3-[3--(5-isobutyryl-2-methyl-4; 5; 6; 7-tetrahydrochysene-1H-imidazo [4,5-c] pyridine-1-yl)-8-azabicyclo [3.2.1] suffering-8-yl]-1-(3-fluorophenyl) propyl group } ethanamide or its pharmacy acceptable salt; solvate or derivative.
The example that enters with fusion inhibitor includes but not limited to: BMS-806; BMS-488043; 5-{ (1S)-2-[(2R)-4-benzoyl-2-methyl-piperazine-1-yl]-1-methyl-2-oxo-oxyethyl group }-4-methoxyl group-pyridine-2-formic acid methyl nitrosourea and 4-{ (1S)-2-[(2R)-4-benzoyl-2-methyl-piperazine-1-yl]-1-methyl-2-oxo-oxyethyl group }-3-methoxyl group-N-methyl-benzamide; En Fuwei peptide (enfuvirtide) (T-20); the peptide SP-01A of Safeway (sifuvirtide SP-01A); T1249; PRO 542; AMD-3100; solubility CD4; disclosed compound reaches disclosed compound in JP 2003119137 in JP 2003171381.
The example of hiv integrase inhibitor includes but not limited to: among L000870810, GW-810781, the WO 03/062204 disclosed 1, disclosed 5-hydroxy pyrimidine-4-carboxamides derivatives, MK-0518 (disclosed 5-(1 among the WO 03016315 among disclosed compound and the WO 03/035076 among disclosed compound, the WO 03/049690 among 5-naphthyridines-3-carboxamides derivatives, the WO 03/047564,1-dioxo-1,2-sulfur nitrogen heterocycle hexyl (thiazinan)-2-yl)-N-(4-luorobenzyl)-8-hydroxyl-1,6-naphthyridines-7-methane amide), GS-9137 (JTK-303).
The example of prenylation inhibitor includes but not limited to: the HMG CoA-reductase inhibitors, and such as Statins (for example Zarator (atorvastatin)).
The example of ripe inhibitor comprises 3-O-(3 ' 3 '-dimethyl succinyl) betulinic acid (or being called PA-457) and α HGA.
In another scheme, array configuration of the present invention comprises with the compound of formula (I) or its pharmacy acceptable salt, solvate or polymorphic form and one or more other medicaments treats, described other medicament is for example but be not limited to: anti-mycotic agent, for example fluconazole (fluconazole), good fortune department fluconazole (fosfluconazole), itraconazole (itraconazole) or voriconazole (voriconazole); Antiseptic-germicide, for example, Azythromycin (azithromycin) or clarithromycin (clarithromycin); The Interferon, rabbit, daunorubicin (daunorubicin), Zorubicin (doxorubicin) and the taxol (paclitaxel) that are used for the treatment of AIDS dependency Kaposi sarcoma; And the cidofovir (cidofovir), Fomivirsen (fomivirsen), phosphine formic acid (foscarnet), ganciclovir (ganciclovir) and the Wan Saiwei (valcyte) that are used for the treatment of cytomegalovirus (CMV) retinitis.
In another scheme, array configuration of the present invention comprise with formula (I) but compound or its pharmacy acceptable salt or solvate and immune other therapeutical agent of one or more enhancing body treat, described other therapeutical agent comprises the endoxan of low dosage, thymostimulin, VITAMIN and nutritious supplementary are (for example, antioxidant, comprise vitamin A, C, E, β-Hu Luobusu, zinc, selenium, gsh, coenzyme q-10 and Echinacea), and vaccine immunostimulating complex (ISCOM) for example, this mixture comprises the vaccine preparation that the antigen that will express polymer 5 and adjuvant make up.
Comprise the combination of formula (I) compound or its pharmacy acceptable salt or solvate and following medicament according to other combination of application of the present invention, described medicament is: the CCR1 antagonist, such as BX-471; The beta-2 adrenoceptor agonist is such as Salmeterol (salmeterol); The reflunomide agonist is such as fluticasone propionate (fluticasone propionate); The LTD4 antagonist is such as Singulair (montelukast); Muscarine antagonist is such as tiotropium bromide (tiotropium bromide); The PDE4 inhibitor is such as cilomilast (cilomilast) or roflumilast (roflumilast); Cox 2 inhibitor is such as celecoxib (celecoxib), valdecoxib (valdecoxib) or rofecoxib (rofecoxib); Alpha-2-delta ligand is such as gabapentin (gabapentin) or Pregabalin (pregabalin); The TNF-receptor-alpha modulators is such as TNF-alpha inhibitor (for example, adalimumab (adalimumab)); Or immunosuppressor, such as S-Neoral (cyclosporin) or macrolide (macrolide), such as tacrolimus (tacrolimus).
Be included in the combination that also has formula (I) compound or its pharmacy acceptable salt or solvate and one or more other therapeutical agents in the scope of the invention, this other therapeutical agent can reduce the metabolic rate of The compounds of this invention, causes the increase that contacts with the patient thus.Increase by this way to expose and be called as synergy (boosting).The advantage of this effect is to have effect that strengthens The compounds of this invention or the required dosage of effect that minimizing reaches with synergy dosage is not identical.The metabolism of compound of the present invention comprises oxidising process of being undertaken by P450 (CYP450) enzyme, especially CYP 3A4 and the combination of being undertaken by UDP glucuronyl transferase and sulfurylase.Therefore, be those medicaments of inhibitor that can serve as at least a isotype (isoform) of Cytochrome P450 (CYP450) enzyme being used to increase medicament that the patient contacts with The compounds of this invention.Can be included but not limited to by the isotype of the CYP450 of favourable inhibition: CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4.The suitable medicament that can be used for suppressing CYP 3A4 includes but not limited to: ritonavir (ritonavir), saquinavir (saquinavir) or KETOKONAZOL (ketoconazole).
In aforesaid combination, with regard to formulation, formula (I) compound or its pharmacy acceptable salt or solvate and other therapeutical agent can the individually dosed or administrations that combines with one another; With regard to its administration time, can while or administration successively.Therefore, the administration of a component medicament can be before another component medicament administration, simultaneously or administration afterwards.
It should be understood that the mentioned treatment of this paper comprises therapeutic, the property alleviated and preventative treatment.
Should be appreciated that and the present invention includes following each side.
(i) pharmacy acceptable salt or the solvate of the compound of formula (I) or its tautomer or this compound or its tautomer;
(ii) comprise as above-mentioned each and invent the pharmacy acceptable salt of described formula (I) compound or its tautomer or this compound or its tautomer or the pharmaceutical composition of solvate and one or more pharmaceutically acceptable vehicle;
(iii) as formula (I) compound of medicine or the pharmacy acceptable salt or the solvate of its tautomer or this compound or its tautomer;
(iv) be used for the treatment of formula (I) compound of disease relevant or illness or the pharmacy acceptable salt or the solvate of its tautomer or this compound or its tautomer with the adjusting of TLR7 acceptor;
(v) the pharmacy acceptable salt of formula (I) compound or its tautomer or this compound or its tautomer or solvate are used for the treatment of purposes in the medicine of disease relevant with the adjusting of TLR7 acceptor or illness in preparation.
(the pharmaceutical composition that vi) comprises one or more other therapeutical agents;
(vii) comprise the pharmacy acceptable salt of formula (I) compound or its tautomer or this compound or its tautomer or the pharmaceutical prod (as kit form) of solvate and other therapeutic activity agent, it is as in the treatment disease relevant with the adjusting of TLR7 acceptor, simultaneously, separately or successively the compound artifact of Shi Yonging.
(viii) formula (I) thus the pharmacy acceptable salt of compound or its tautomer or this compound or its tautomer or solvate are used in combination in the treatment disease relevant with the adjusting of TLR7 acceptor while, separately or the purposes in the medicine of use successively in preparation and other therapeutic activity agent.
(ix) the treatment disease relevant with the adjusting of TLR7 acceptor or method of illness in the Mammals, it comprises and gives this Mammals with treating formula (I) compound of significant quantity or the pharmacy acceptable salt or the solvate of its tautomer or this compound or its tautomer.
(x) pharmacy acceptable salt of preparation formula (I) compound or its tautomer or this compound or its tautomer or the method for solvate.
(xi) new intermediates more disclosed herein.
Embodiment
The present invention describes by following non-limiting example, wherein uses following shortenings and definition:
Filtering medium (lignocellulose) is available from J.
Rettenmaier?&?Sohne，Germany
APCI
+Barometric point chemi-ionization (forward scan)
The Bn benzyl
The br broad peak
D is bimodal
The dd double doublet
The DMSO methyl-sulphoxide
The ELSD light scattering detector
ES
+Electron spray(ES) forward scan mass spectrum
The ESI electrospray ionization mass spectrometry
(forward scan or negative sense scanning)
The eq equivalent
The HRMS high resolution mass spec
1H NMR proton magnetic resonance (PMR)
LC-MS LC-MS instrument
LRMS low resolution mass spectrum
The m multiplet
The m/z mass spectra peak
Reacti-Vial
TMReaction flask is available from the U.S.
Fly generation that Scientific World company
The q quartet
S is unimodal
The t triplet
The δ chemical shift
* represent tie point
Embodiment 1
4-amino-1-benzyl-6-cyclopropyl-1,3-dihydro-imidazol-is [4,5-c] pyridin-2-ones also
With 4-allyl amino-1-benzyl-6-cyclopropyl-1, the 3-dihydro-imidazol-also [4,5-c] pyridin-2-ones (70mg 0.2mmol) is dissolved in the ethanol (2ml), and (70mg w/w), dropwise adds BF again to add 10% Pd-C
3OEt
2(27 1,0.2mmol).With mixture at N
2Heated overnight under the atmosphere, under refluxing.Mixture be cooled to room temperature and filter with Arbocel (lignocellulose), with new system EtOH flushing and with the filtrate vacuum concentration to produce crude product (150mg).Produce the title compound (17mg) of pale solid with 98:2 → 95:5 DCM:MeOH wash-out, with the silicon-dioxide column chromatography.
1H NMR (CD
3OD) δ 7.35-7.27 (m, 5H), 6.26 (s, 1H), 5.00 (s, 2H), 1.89-1.82 (m, 1H), 0.85-0.80 (m, 2H), 0.77-0.73 (m, 2H); C
16H
16N
4The HRMS of O: calculated value 281.1397, measured value 281.1395.
Embodiment 2
4-amino-1-benzyl-6-methyl isophthalic acid, 3-dihydro-imidazol-is [4,5-c] pyridin-2-ones also
With 1-benzyl-4-dibenzyl amino-6-methyl isophthalic acid, the 3-dihydro-imidazol-also [4,5-c] pyridin-2-ones (34mg, 0.08mmol) be suspended in the ethanol (5ml) and at room temperature, at 60psi, at 10% Pd (OH)
2(7mg) go up hydrogenation 6 hours.Reaction mixture is filtered with the short plug of Arbocel, is opaque glue with filtrate vacuum-evaporation then.In methyl alcohol, and preadsorption is on silica gel with this peptization, then with 5% methanol-eluted fractions among the EtOAc, by the column chromatography purifying.The elution fraction that is fit to is merged the title compound 7mg that also evaporates in a vacuum with the generation white solid.
1H?NMR(CD
3OD)δ?2.31(s，3H)，5.01(s，2H)，6.40(s，1H)，7.31(m，5H)；LRMS(ES
+)m/z?255(MH
+)。
Embodiment 3
1-benzyl-4-amino-6,7-dimethyl-1,3-dihydro-imidazol-be [4,5-c] pyridin-2-ones also
With 1-benzyl-4-two allyl amino-6,7-dimethyl-1,3-dihydro-imidazol-also [4,5-c] pyridin-2-ones (358mg 1mmol) is dissolved in water (10ml) and the acetonitrile (25ml), adds a RhCl (PPh
3)
3(286mg 0.3mmol), heats 16h with mixture then under refluxing.Mixture is cooled to room temperature, vacuum concentration then, use the gradient of 95:5 → 85:15 DCM:MeOH, by silica gel column chromatography with residue purified, to produce filbert solid title compound (77mg, 29%).
1H?NMR(DMSO)δ?1.98(s，3H)，2.14(s，3H)，5.13(s，2H)，5.34(s，2H)，7.03-7.31(m，5H)，10.38(s，1H)；LRMS(ES
+)m/z?269[MH]
+
Embodiment 4
4-amino-1-benzyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-6-methyl-formiate
With 1-benzyl-4-benzylamino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-6-methyl-formiate (0.02g) is dissolved in the sulfuric acid (2ml), stirred fast 15 minutes.Reaction mixture is cooled to 0 ℃, adds water, produce throw out, it is filtered also dry in a vacuum to produce the title compound (10mg) of white solid.
1H?NMR(d6-DMSO，400MHz)δ?3.75(s，3H)，4.95(s，2H)，7.20-7.50(m，6H)，10.20(s，1H)。LRMS(ES
+)m/z?299[MH]
+
Embodiment 5
4-amino-1-benzyl-6-pyrazine-2-base-1,3-dihydro-imidazol-is [4,5-c] pyridin-2-ones also
With N-2, N-4-dibenzyl-6-pyrazine-2-base-pyridine-2,3,4-triamine (100mg/0.261mmol) are dissolved among the DMF (5ml), add CDI (95.3mg/0.523mmol), at 60 ℃ of heating 5 hours, vacuum concentration then.Reaction mixture is dissolved in the vitriol oil (3ml) then, and at room temperature stirred 30 minutes.Add ice to reactant then, by pouring into the K in water (5ml)
2CO
3(8g) come quenching.Then with the EtOAc extraction, with dried over sodium sulfate and vacuum concentration.Resistates is by the column chromatography purifying.In detail, use EtOAc, 95:5EtOAc:MeOH to separate these two kinds of position isomer then to produce greenish orange look solid title compound (15mg).
1H?NMR(CD30D，400MHz)δ?5.10(s，2H)，7.20-7.40(m，5H)，7.55(s，1H)，8.45(d，1H)，8.55(d，1H)，9.4(s，1H)
Embodiment 6
4-amino-1-benzyl-6-morpholine-4-ylmethyl-1,3-dihydro-imidazol-is [4,5, c] pyridin-2-ones also
With N-2, N-4-dibenzyl-6-morpholine-4-base-methyl-pyridine-2,3, the 4-triamine (240mg 0.59mmol) is dissolved in the 20ml methylene dichloride, add 1,1 then '-(91mg 1.77mmol), and at room temperature stirred reactant 48 hours carbonyl dimidazoles.Add 20ml water and, also remove solvent in a vacuum with dried over mgso with the organic layer separation.Use 4% methyl alcohol in the methylene dichloride, by the thick resistates of silica gel column chromatography purifying, to produce 2 kinds of mixture of isomers of 140mg.Be dissolved in this mixtures of 2 kinds of isomer of 60mg in the 2ml vitriol oil and at room temperature stirred 30 minutes.Careful interpolation water (5ml) adds salt of wormwood (5.2g is until pH～7) then.With the mixture ethyl acetate extraction, organic layer is separated, also remove solvent in a vacuum with dried over mgso.Use 1% ammonia in the methylene dichloride and 10% methyl alcohol, by the thick resistates of silica gel column chromatography purifying, to produce another isomer of 10mg title compound and 6mg.
1H?NMR(CD
3OD)：δ?7.38-7.2(m，5H)，6.58(s，1H)，5.05(d，2H)，3.65(m，4H)，3.4(s，2H)，2.4(m，4H)；LRMS(ES
+)m/z?340[MH]
+
Embodiment 7
4-amino-1-benzyl-2-oxo-2,3-dihydro-1H-imidazo [4,5, c] pyridine-7-formic acid cyclopropyl methyl-acid amides
With 1-benzyl-4-dibenzyl amino-2-oxo-2, (10mg 0.02mmol) is dissolved in the 1ml vitriol oil 3-dihydro-1H-imidazo [4,5, c] pyridine-7-formic acid cyclopropyl methyl-acid amides, and mixture was at room temperature stirred 30 minutes.In case finish, then with mixture diluted in 5ml water, add salt of wormwood one by one until pH～12.Use ethyl acetate (2 * 50ml) extraction mixtures then.Organic layer is merged, use MgSO
4The dry solvent that also removes in a vacuum.Use 20% methyl alcohol in the ethyl acetate, by silica gel column chromatography purifying resistates, to produce the 1mg title compound; LRMS (ES
+) m/z 338[MH]
+
Embodiment 8
4-amino-1-benzyl-7-bromo-6-methyl isophthalic acid, the 3-dihydro-imidazol-is [4,5, c] pyridin-2-ones also
With 4-amino-1-benzyl-6-methyl isophthalic acid, the 3-dihydro-imidazol-also [4,5-c] pyridin-2-ones (20mg 0.08mmol) is suspended in the 5ml acetate, add then sodium acetate (5mg, 0.08mmol), dropwise add then bromine (4L, 0.08mmol).Mixture was at room temperature stirred 30 minutes.Mixture diluted in water (50ml) and with ethyl acetate (50ml) extraction, is separated organic layer, also remove solvent in a vacuum with dried over mgso.Use 10% methyl alcohol in the ethyl acetate, by silica gel column chromatography purifying resistates, to produce the title compound of 15mg brown solid.
1H?NMR(d6?DMSO)δ：7.40-7.10(m，5H)，6.85(s，2H)，5.30(s，2H)，2.35(s，3H)；LRMS(ES
+)m/z?333，335[MH]
+
Embodiment 9
4-amino-1-benzyl-6-methyl-5-Oxy-1,3-dihydro-imidazol-is [4,5, c] pyridin-2-ones also
With 4-amino-1-benzyl-6-methyl isophthalic acid, the 3-dihydro-imidazol-also [4,5-c] pyridin-2-ones (20mg 0.08mmol) is dissolved in the 10ml methylene dichloride, and (15mg 0.09mmol), and at room temperature stirred mixture 2 hours to add the 3-chloroperoxybenzoic acid then.Mixture is washed with water, also remove solvent in a vacuum, to produce the 5mg title compound with dried over mgso.
1H?NMR(CD30D)δ：7.40-7.20(m，5H)，6.59(s，1H)，5.05(s，2H)，2.45(s，3H)；LRMS(ES
+)m/z?271[MH]
+
Embodiment 10
4-amino-1-benzyl-6-(2-methoxyl group-ethyl)-1,3-dihydro-imidazol-is [4,5-c] pyridin-2-ones also
With 1-benzyl-4-benzylamino-6-(2-methoxyl group-ethyl)-1, the 3-dihydro-imidazol-also [4,5-c] pyridin-2-ones (32mg 0.082mmol) stirred in the vitriol oil (2ml) 30 minutes.Add water (5ml) and mixture dropwise is added into saturated NaHCO
3The solution that is stirred in to obtain the alkaline pH value.With the aqueous solution with 2 * EtOAc extraction and the organism that is merged is dry and concentrate to produce yellow solid.(gradient increases to DCM:MeOH:NH with DCM:MeOH 97:3
395:5:0.5) wash-out, the mixture by silicon-dioxide column chromatography separating isomerism body, to produce the title compound (3.1mg, 13%) of light yellow solid.
1H?NMR(MeOD)δ?2.82-2.85(t，2H)，3.66-3.69(t，2H)，5.08(s，2H)，6.36(s，1H)，7.19-7.34(m，5H)；LRMS(ES)m/z?299[MH]
+
Embodiment 11
4-amino-1-benzyl-6-[2-(2-methoxyl group-ethylamino)-ethyl]-1, the 3-dihydro-imidazol-is [4,5-c] pyridin-2-ones also
(64mg 0.12mmol) stirred 30 minutes in the vitriol oil (2ml) with [2-(1-benzyl-4-benzylamino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-6-yl)-ethyl]-(2-methoxyl group-ethyl)-t-butyl carbamate.Add water (5ml) and mixture dropwise is added into saturated NaHCO
3The solution that is stirred in to obtain the alkaline pH value.With the aqueous solution with 2 * EtOAc extraction and the organism that is merged is dry and concentrate to produce yellow solid.(gradient increases to DCM:MeOH:NH with DCM:MeOH 98:2
390:10:1) wash-out, the mixture by silicon-dioxide column chromatography separating isomerism body are to produce the title compound (4.2mg, 11%) of yellow solid.
1H?NMR(MeOD)δ?2.84-2.86(t，2H)，3.02-3.05(t，2H)，3.27(s，3H)，3.45-3.48(t，2H)，5.09(s，2H)，6.34(s，1H)，7.20-7.34(m，5H)；LRMS(ES)m/z?342[MH]
+
Embodiment 12
4-amino-1-benzyl-6-oxazole-2-base-1,3-dihydro-imidazol-is [4,5-c] pyridin-2-ones also
(821mg 5.06mmol) is added into N with CDI
*2
*, N
*4
*-dibenzyl-6-oxazole-2-base-pyridine-2,3, (940mg is 2.53mmol) in the solution in THF (15ml) for the 4-triamine.With solution under nitrogen atmosphere, 60 ℃ the heating 18 hours.With reaction mixture cooling, vacuum concentration then.Then crude mixture is dissolved in dense H
2SO
4Also at room temperature left standstill 30 minutes (15ml).Dark brown solution dropwise is added on the trash ice.By adding K
2CO
3Saturated aqueous solution is adjusted to the pH value～and 9, filtering mixt then.Solid with EtOAc (200ml) washing, is changed over to organism and aqueous filtrate in the separating funnel then.Extract again with EtOAc (200ml) with each layer separation and with the aqueous solution.With organism merging, dry (MgSO
4) and be evaporated to orange gluing solid.Thick material is ground with EtOAc and toluene.Wash to produce pale solid with the gained solid filtering and with EtOAc.With 0.05% formic acid among 0.05% formic acid (aqueous solution) and the MeCN with 15ml/min flow velocity wash-out, by at Phenomenex Gemini 5 μ m posts (this material of HPLC purifying on 150 * 21.2mmid).Make gradient degree 0.6 minute such as when 5% organism, go through increasing to 80% organism by 5% linearly in 12 minutes then.
The filtrate of self-grind evaporation in the future, (12g carries out column chromatography on Redisep) at Isco Companion silica column then.Use EtOAc:MeOH wash-out gained material then, gradient is increased to 98:2 linearly by 95:5 through 8 column volumes.Required elution fraction merged and be evaporated to orange gluing solid.As above by this material of HPLC purifying.All required elution fractions from the HPLC post are merged and evaporation to produce the title compound (26mg, 3%) of white solid.
1H?NMR(CD30D)δ?5.07(s，2H)7.17-7.36(m，7H)7.92(s，1H)LCMS?R
t＝2.15m/z?308[MH]
+
The alternative of preparation embodiment 12 is described below.
4-amino-1-benzyl-6-oxazole-2-base-1,3-dihydro-imidazol-is [4,5-c] pyridin-2-ones also
-78 ℃, at N
2Under the atmosphere with hexane (1.6M, 183 μ l, 0.29mmol) butyl lithium solution in dropwise Tian Jia Zhi oxazole (16 μ l, 0.24mmol) solution in THF (1ml).Solution was stirred 10 minutes at-78 ℃, dropwise add zinc chloride (100mg, 0.73mmol) solution in THF (1ml) then.Solution was stirred 15 minutes at-78 ℃, heat to room temperature then.With syringe solution is added into then and contains 4-amino-1-benzyl-6-bromo-1,3-dihydro-imidazol-also [4,5-c] pyridin-2-ones (13mg, 0.04mmol) and two (triphenylphosphine) palladium chloride (12mg, 0.02mmol) pre-sealed by the microwave bottle of purging with nitrogen gas (Biotage, 0.5-2.0ml).Should the bottle under microwave irradiation (Biotage, Initiator 8 (microwave synthesizer)), 110 ℃ the heating 15 minutes.With reaction mixture at ethyl acetate (20ml) and saturated NH
4Cl (aq) divides between (10ml) molten.With the mixture diatomite filtration, with ethyl acetate (20ml) washing.With each layer separation and with organism water (10ml) and salt solution (10ml) washing, use MgSO
4Dry also vacuum concentration is to produce crude product.This sample is dissolved in acetonitrile: water: in the mixture of DMSO (2:1:1), by the title compound (2mg) of preparation property HPLC (FractionLynx) purifying with the generation white solid.
1H NMR (d6-DMSO) δ 10.60 (brs, 1H), 8.10 (s, 1H), 7.36-7.27 (m, 6H), 7.19 (s, 1H), 6.01 (br s, 2H), 5.04 (s, 2H); LRMS (APCI and ES) m/z 308[MH]
+
Embodiment 13
4-amino-1-benzyl-6-(1-methyl isophthalic acid H-imidazoles-2-yl)-1, the 3-dihydro-imidazol-is [4,5-c] pyridin-2-ones also
(184mg 1.13mmol) is added into N in reaction flask with CDI
*2
*, N
*4
*-dibenzyl-6-(1-methyl isophthalic acid H-imidazoles-2-yl)-pyridine-2,3, (218mg is 0.567mmol) in the solution in DMF (3ml) for the 4-triamine.Bottle is washed with nitrogen, then sealing and in aluminium block, heat 60 ℃ (aluminium block temperature).Dark brown solution was stirred 16 hours under this temperature.Solution is concentrated under high vacuum, be dissolved in then in the vitriol oil (5ml).Brown solution was at room temperature stirred 30 minutes, pour into then trash ice (～20ml) on.The saturated aqueous solution that dropwise adds salt of wormwood is until pH～8.Decant goes out the aqueous solution in the solid that precipitation is separated out during the self-neutralization, uses EtOAc (2 * 50ml) extractions then.With merged organism drying (MgSO
4), be evaporated to yellow solid (106mg).
(150 * 21.2mmid) go up by HPLC chromatography sample (58mg) at Phenomenex Gemini 5 μ m posts.With 0.05% DEA among 0.05% DEA (aq) and the MeCN, with 18ml/min flow velocity wash-out.Make gradient degree 0.6 minute such as when 5% organism, go through increasing to 100% organism linearly by 5% in 15 minutes then.
Required elution fraction merged and evaporation to produce the title compound (10mg, 6%) of white solid.
1H?NMR(CD30D)δ?3.94(s，3H)5.08(s，2H)6.91-6.95(m，1H)7.00(s，1H)7.07-7.10(m，1H)7.16-7.38(m，5H)；LRMS(ES
+)m/z?321[MH]
+
Embodiment 14
4-amino-1-benzyl-6-(the 3-methyl-[and 1,2,4] oxadiazole-5-yls)-1, the 3-dihydro-imidazol-is [4,5-c] pyridin-2-ones also
With 1-benzyl-4-benzylamino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-6-formic acid (1-oximino-ethyl)-acid amides be suspended in the toluene and be sealed in the microwave bottle (Biotage, 0.5-2.0ml).With the bottle sealing and under microwave irradiation (Biotage Initiator 8), 150 ℃ of heating 15 minutes.With sample in microwave, 150 ℃ of reheat 30 minutes, again 150 ℃ of heating 30 minutes.With the mixture evaporation, between EtOAc (10ml) and water (5ml), divide molten then.Use EtOAc (more than 2 * 10ml) extracting twice, the aqueous solution then with the organism drying (MgSO that is merged
4) and evaporation.Resistates be suspended in the acetonitrile (2ml) and with this mixture be sealed in the microwave bottle, then under microwave irradiation, 170 ℃ of heating 30 minutes, then 190 ℃ of reheat 30 minutes.With the reaction mixture vacuum concentration, be dissolved in dense H then
2SO
4(2ml).With solution stirring 30 minutes, pour on trash ice then.Dropwise add saturated K
2CO
3The aqueous solution is～8 until the pH value.The aqueous solution is gone in the separating funnel from the solid decant, use EtOAc (3 * 15ml) extractions then.The organism drying that is merged (is used MgSO
4) and evaporation.(150 * 21.2mmid) go up, pass through the HPLC purifying at 10 microns C18 of Luna (2) post with isomer mixture.With 0.1% formic acid among 0.1% formic acid (aq) and the MeCN, with 25ml/min flow velocity wash-out.Make gradient degree 0.6 minute such as when 5% organism, go through increasing to 90% organism linearly by 5% in 8.50 minutes then.With the title compound (0.5mg, 1%) of required elution fraction evaporation with the generation white solid.
LCMS?R
t＝2.46m/z?323[MH]
+。
Embodiment 15
4-amino-1-benzyl-6-Trifluoromethyl-1,3-dihydro-imidazol-is [4,5-c] pyridin-2-ones also
With 1-benzyl-4-benzylamino-6-Trifluoromethyl-1, the 3-dihydro-imidazol-also [4,5-c] pyridin-2-ones (2.63g 6.60mmol) is dissolved in the vitriol oil (50ml) and with reaction mixture and at room temperature stirred 30 minutes.Reaction mixture is cooled to 0 ℃, adds ice.With K
2CO
3(150g) in water-soluble (700ml) and dropwise add reaction mixture.(6 * 500ml) extract with EtOAc with the aqueous solution.The organism that is merged is washed with salt solution (200ml), use MgSO
4Dry also vacuum concentration is to produce the title compound (1.20g) of white solid.
1H NMR (CDCl
3) δ 10.77 (brs, 1H), 7.36-7.25 (m, 5H), 7.01 (s, 1H), 6.20 (br s, 2H), 5.04 (s, 2H); LRMS (APCI and ES) m/z 309[MH]
+, 307[MH]
-Measured value C.54.55 H.3.60 N.18.17%.C
14H
11F
3N
4N.17.86 O needs %C.54.36H.3.61.
Alternative synthetic being described below of embodiment 15;
With ethyl-(35gm 99mmol) at room temperature is dissolved in the Glacial acetic acid (300ml) [2,3-diamino-6-(trifluoromethyl)-pyridin-4-yl]-benzylamino manthanoate.Filtration removes any insoluble substance and under agitation glassy yellow filtrate is heated to 80 ℃ then.Begin to form white depositions in 10 minutes.Lasting heating totally 40 minutes.Reaction mixture is cooled to envrionment temperature and with throw out by filter collecting, with the acetate washing and in a vacuum, 50 ℃ of dryings 3 hours to produce the title compound (26.4gm, 86% yield) of white solid.
Embodiment 16
4-amino-1-(6-methyl-pyridin-3-yl methyl)-6-oxazole-2-base-1, the 3-dihydro-imidazol-is [4,5-c] pyridin-2-ones also
CDI (272mg) is added into N2, and N2-dibenzyl-N4-(6-methyl-pyridin-3-yl methyl)-6-oxazole-2-base-pyridine-2,3 is in the solution of 4-triamine (400mg) in THF (10ml).With solution at N
2Under the atmosphere, 60 ℃ of stirrings 5 hours.Add 3 normal CDI (408mg) again and with reactant heating 16 hours under refluxing.Reaction mixture is cooled off vacuum concentration then.Then crude mixture is dissolved in dense H
2SO
4Also at room temperature left standstill 30 minutes (5ml).Dark brown solution dropwise is added on the trash ice.By adding K
2CO
3Saturated solution is adjusted to the pH value～and 8, filtering mixt then.The solid that is obtained is washed with EtOAc (50ml), then organism and aqueous filtrate are changed in the separating funnel.Extract again with EtOAc (50ml) with each layer separation and with the aqueous solution.Organism is merged, and drying (is used MgSO
4) and evaporate to produce gluing solid.With this thing Et
2O grinds, and Et is collected and used to solid by filtration
2The O washing, the title compound (30mg) of generation pale solid.
1H?NMR(CDCl
3，400MHz)δ?2.45(s，3H)，5.09(s，2H)，7.21-7.28(m，2H)，7.30(s，1H)，7.70(dd，1H)，7.95(s，1H)，8.42(d，1H)。LCMS?R
t＝2.29m/z?323[MH]
+
Embodiment 17
4-amino-1-benzyl-6-(2-methoxyl group-oxyethyl group)-1,3-dihydro-imidazol-is [4,5-c] pyridin-2-ones also
[2-amino-6-(2-methoxyl group-oxyethyl group)-3-nitro-pyridin-4-yl]-benzyl-urethanum (118mg) is dissolved in the ethanol (5ml), adds 10% Pd/ carbon (15mg).With reactant under nitrogen atmosphere (50psi), at room temperature stirred 1 hour.Then reaction mixture is filtered and evaporation with Celite pad.Be dissolved in crude product in the Glacial acetic acid (2ml) and change over to the microwave bottle (Biotage, 0.5-2.0ml) in.With the bottle sealing and under microwave irradiation, 100 ℃ of heating 5 minutes.Gained brown mixture is evaporated, with solids laden on silicon-dioxide and at IscoCompanion silica column (4g, Redisep) carry out column chromatography on, use EtOAc: heptane wash-out (making gradient increase to 100% EtOAc linearly by 60:40) through 8 column volumes (CV), then when 100% EtOAc to 8 degree such as CV.Required elution fraction merged and evaporation to produce the title compound (50mg) of white solid.
1H?NMR(CDCl
3，400MHz)δ?3.35(s，3H)，3.62(t，2H)，4.20(t，2H)，4.95(s，2H)，5.80(s，1H)，7.20-7.38(m，5H)。LCMS?R
t＝2.13m/z?315[MH]
+
Embodiment 18
4-amino-1-(6-methyl-pyridin-3-yl methyl)-6-Trifluoromethyl-1, the 3-dihydro-imidazol-is [4,5-c] pyridin-2-ones also
With (2-amino-3-nitro-6-trifluoromethyl-pyridin-4-yl)-(6-methyl-pyridin-3-yl methyl)-urethanum (27mg 0.07mmol) places Glacial acetic acid (5ml) to stir, and with solution at ambient temperature, at 40psi H
2Under the atmosphere, (5.4mg 20%wt) exists down and stirred 4 hours at 10% Pd/C.Suspension is filtered with the Arbocel pad, with 2 * 3ml AcOH washing and with the filtrate vacuum concentration.(5ml) is added in the resistates with acetonitrile, and this material is ground, and the gained solid by filtration removed and the dry in a vacuum title compound with the generation white solid.
1H?NMR(d6-DMSO)：δ?8.45(s，1H)，7.57-7.55(d，1H)，7.20-7.18(d，1H)，7.10(s，1H)，6.20(bs，2H)，5.01(s，2H)，2.40(s，3H)；LRMS(APCI)m/z?324[MH]
+
The alternative of preparation embodiment 18 is described below.
4-amino-1-(6-methyl-pyridin-3-yl methyl)-6-Trifluoromethyl-1,3-dihydro-imidazol-also (4,5-c) pyridin-2-ones
With 4-benzylamino-1-(6-methyl-pyridin-3-yl methyl)-6-Trifluoromethyl-1, also (4,5-c) (30mg 0.07mmol) is dissolved in the 1ml vitriol oil and with reaction mixture and at room temperature stirred 1 hour pyridin-2-ones the 3-dihydro-imidazol-.Mixture is poured in the entry (100ml), add salt of wormwood one by one and be alkalescence until the pH value.Use ethyl acetate (100ml) extraction then.Organic layer is separated, remove in a vacuum to produce the title compound of 16mg white solid with dried over mgso and with solvent.
1H?NMR(d6-DMSO)：δ?8.45(s，1H)，7.57-7.55(d，1H)，7.20-7.18(d，1H)，7.10(s，1H)，6.20(bs，2H)，5.01(s，2H)，2.40(s，3H)；LRMS(APCI)m/z?324[MH]
+
Embodiment 19
4-amino-6-(4-methyl-oxazoles-2-yl)-1-(6-methyl-pyridin-3-yl methyl)-1, the 3-dihydro-imidazol-is [4,5-c] pyridin-2-ones also
Raney nickel (5mg) and [2-amino-6-(4-methyl-oxazoles-2-yl)-3-nitro-pyridin-4-yl]-mixture of (6-methyl-pyridin-3-yl methyl)-urethanum (69mg) in acetate (3ml) were stirred 1 hour down in nitrogen atmosphere (80psi).Arobcel is added on sulfonic acid cationic exchange filter cylinder, and (Bakerbond 1g) on the top, and is loaded in reaction mixture on this top and filters.Catalyzer and Arbocel are removed with scraper, then filter cylinder is washed to remove impurity with methyl alcohol (5ml).By (2M, 2 * 5ml) wash-outs make product disengage from filter cylinder with the ammonia in the methyl alcohol.With thick solution evaporation, add IPA (3ml) then, make solid precipitation, collect and wash by filtering with IPA.The gained pale solid is dry to produce title compound (16mg) under high vacuum.
1H?NMR(400MHz，DMSO-d
6)δ?ppm?2.13(s，3H)2.42(s，3H)5.05(s，2H)5.98(s，2?H)7.21(d，J＝7.90Hz，1?H)7.25(s，1?H)7.56(dd，J＝7.90，2.44Hz，1?H)7.80(s，1?H)8.47(d，J＝2.44Hz，1?H)10.68(br.s.，1H)；LRMS(ESI)m/z?337[MH]
+，335[MH]
-
Embodiment 20
4-amino-6-(4-ethyl-oxazoles-2-yl)-1-(6-methyl-pyridin-3-yl methyl)-1, the 3-dihydro-imidazol-is [4,5-c] pyridin-2-ones also
[2-amino-6-(4-ethyl-oxazoles-2-yl)-3-nitro-pyridin-4-yl]-(6-methyl-pyridin-3-yl methyl)-urethanum (74mg) is dissolved in the acetate (2ml) and with zinc powder (113mg, Aldrich, 99%) is added in the reactant.With mixture at room temperature, under nitrogen atmosphere, stirred 16 hours.(Bakerbond SCX, the bonding phase of sulfonic acid 1g) go up direct filtration at the cationic exchange filter cylinder with reaction mixture.(2 * 4ml) washings are to remove impurity, and (2M 4ml) disengages product to use ammonia in the methyl alcohol then with methyl alcohol with the SCX filter cylinder.Required elution fraction is merged and be evaporated to pale solid, grind, filter, use washed with isopropyl alcohol then, produce the title compound (32mg) of white solid with Virahol.
1H?NMR(400MHz，DMSO-d
6)δ?ppm?1.16(t，J＝7.42Hz，3?H)2.40(s，3?H)2.44-2.56(m，2?H)5.04(s，2?H)5.98(s，2?H)7.19(d，J＝8.02Hz，1?H)7.23(s，1?H)7.54(dd，J＝8.02，2.34Hz，1?H)7.79(s，1?H)8.45(d，J＝2.34Hz，1?H)10.65(s，1?H)；LCMS?R
t＝1.73m/z?351[MH]
+
Embodiment 21
4-amino-1-benzyl-6-(1H-imidazoles-2-yl)-1, the 3-dihydro-imidazol-is [4,5-c] pyridin-2-ones also
Use { 2-amino-3-nitro-6-[1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-yl]-pyridin-4-yl }-benzyl-urethanum (174mg) and Raney nickel (5mg) in the acetate (3ml), prepare title compound according to the method for embodiment 20.Can tentatively produce the imidazolium compounds of being protected by SEM thus.Dropwise add diox (4M, 1ml) hydrogenchloride in and solution at room temperature stirred 24 hours then.Then reaction mixture is changed over to the microwave bottle (Biotage, 2-5ml) in, and under microwave irradiation (Biotage Initiator 8), 110 ℃ the heating 10 minutes.With reaction mixture evaporation, and then be dissolved in the methyl alcohol, and with solution be loaded in the cationic exchange filter cylinder (Bakerbond, the bonding phase of sulfonic acid, 1g) on.(2 * 5ml) washings are to remove impurity then by (2M, 5ml) wash-out disengages product with the ammonia in the methyl alcohol with methyl alcohol with filter cylinder.Required elution fraction merged and be evaporated to brown solid.This thing is ground with Virahol, and solid by filtration is collected, use more washed with isopropyl alcohol then, produce light brown solid title compound (28mg).
1H?NMR(400MHz，DMSO-d
6)δ?ppm?5.02(s，2?H)5.58(s，2?H)6.91(s，1H)7.06(s，1?H)7.11(s，1?H)7.25-7.36(m，5?H)10.53(s，1?H)11.99(s，1?H)；LCMS?R
t＝1.52m/z?307[MH]
+。
Embodiment 22
4-amino-1-benzyl-6-(2-fluoro-phenyl)-1, the 3-dihydro-imidazol-is [4,5-c] pyridin-2-ones also
[2-amino-6-(2-fluoro-phenyl)-3-nitro-pyridin-4-yl]-benzyl-urethanum (31mg) is dissolved in the acetate (1ml).Add zinc powder (Aldrich, 99%, 20mg) and at room temperature, under nitrogen atmosphere, stirred 2 hours with mixture.Add extra zinc powder (30mg) and with mixture restir 1 hour.Reaction mixture is diluted with methyl alcohol (2ml), and (Bakerbond SCX, the bonding phase of sulfonic acid 1g) go up direct filtration at the cationic exchange filter cylinder then.(2 * 5ml) washings are used ammonia in the methyl alcohol then (2M 5ml) are disengaged product to remove impurity with methyl alcohol with the SCX filter cylinder.Required elution fraction is evaporated to light brown solid.This thing is ground with ethyl acetate, filters then, and with polyacetic acid ethyl ester washing more with generation lavender solid title compound (8mg).
1H?NMR(400MHz，DMS0-d
6)δ?ppm?4.99(s，2?H)5.82(s，2?H)6.87(d，J＝1.95Hz，1?H)7.15-7.29(m，3?H)7.29-7.39(m，5?H)7.81(td，J＝8.01，1.95Hz，1?H)10.51(s，1?H)；LCMS?R
t＝2.21m/z?335[MH]
+
Following examples 23-119 can be with the similar mode of embodiment 1-22, by the similar intermediate preparation described in the preparation part of using the class quasi-chemical method.
Embodiment 23-28 is according to the method preparation of embodiment 1, embodiment 54-60,65-72 and 107-110 are all according to embodiment 15 and 18 described method preparations, embodiment 31 and 61 is according to embodiment 3 described method preparations, embodiment 42-49,83-95 and 101-102 are all according to embodiment 17 described method preparations, embodiment 73-78,96-99,103-106 and 111-112 are all according to embodiment 19 described method preparations, embodiment 79-81 is according to embodiment 22 described method preparations, embodiment 34-35 and 40 is according to embodiment 6 described method preparations, embodiment 29-30,36-39,41 and 50-53 according to the described methods preparation of embodiment 4, embodiment 32-33 is according to embodiment 5 described method preparations, according to embodiment 14 described method preparations.
Embodiment 62-64 can be according to embodiment 15 and the preparation of 18 described methods, embodiment 82 can according to embodiment 14 described methods according to, embodiment 100 can be according to embodiment 17 described methods preparations.
In following examples table, tie point represented in asterisk.
Preparation 1
3-amino-3-cyclopropyl-ethyl propenoate
With cyclopropylniitrile (2.7g 40.5mmol) is dissolved among the anhydrous THF (100ml), add then zinc (13.2g, 202.3mmol) and zinc oxide (1.6g, 20.2mmol), dropwise add then ethyl bromoacetate (6.7g, 40.5mmol).With mixture at N
2Supersound process is 2 hours under the atmosphere, in the 35kHz ultrasonic bath.Observe green color after 30 minutes.With mixture with diatomite filtration to remove zinc and zinc oxide.Filtrate is added into 50% K of 20ml
2CO
3(aq) in the solution.Formed thick throw out is filtered removing solid, and with the aqueous solution with 100ml EtOAc extraction.Extract with the water washing of 20ml salt, is used MgSO
4Drying, and vacuum concentration is to produce crude product (3.8g).Use the 90:10 pentane: EtOAc wash-out, by the thick material of silica gel chromatography, to produce yellow oily title compound (1.32g).
1H NMR (CDCl3) δ 4.47 (s, 1H), 4.11 (quartet, 2H), 1.45-1.39 (m, 1H), 1.26 (t, 3H), 0.88-0.83 (m, 2H), 0.76-0.72 (m, 2H); LRMS (APCI+) m/z156[MH]
+
Preparation 2
6-cyclopropyl-2,4-dihydroxyl-Nikithan
With sodium Metal 99.5 (8.1g, 119mmol) be cut into small pieces and at room temperature, under nitrogen atmosphere, be added into one by one in the ethanol (120ml) that is stirred.Then with mixture 60 ℃, at N
2Stir under the atmosphere and spend the night, to guarantee the dissolving fully of metal.With diethyl malonate (18.1ml, 119mmol) 60 ℃ be added in the alcohol sodium solution and with mixture at N
2Under the atmosphere, 60 ℃ of stirrings 1 hour.60 ℃ dropwise add 3-amino-3-cyclopropyl-ethyl propenoate (10.3g, the 40mmol) solution in ethanol (10ml), and with mixture under reflux temperature, at N
2Heat 5 days under the atmosphere to produce orange suspension.Mixture is cooled to room temperature and collects the gained solid by filtering.With the filtrate vacuum concentration to produce more solids.In the solid that is merged water-soluble (150ml), and with solution EtOAc (150ml) washing.Use dense HCl with acidified aqueous solution to pH 2, make white solid precipitation.Solid by filtration is collected, then with cold water and Et
2O washing, then in a vacuum, 40 ℃ of dried overnight to produce tenderly white look solid title product (5.32g).With filtrate vacuum concentration half, make more voluminous thing precipitation to its volume.The solid by filtration of this 2nd time results is collected water and Et
2O washing, and in a vacuum, 40 ℃ of dryings to produce the beige solid title compound of other 0.35g.
1H NMR (d6-DMSO) δ 12.71 (br s, 1H), 11.43 (br s, 1H), 5.51 (s, 1H), 4.26 (quartet, 2H), 1.86-1.79 (m, 1H), 1.26 (t, 3H), 1.06-1.01 (m, 2H), 0.90-0.86 (m, 2H); LRMS (APCI) m/z 224[MH]
+
Preparation 3
6-cyclopropyl-2,4-dihydroxyl-pyridine
With 6-cyclopropyl-2, (5.3g 20.5mmol) is dissolved among the dense HCl (25ml) 4-dihydroxyl-Nikithan, and the mixture backflow is spent the night.Mixture is cooled to room temperature then with dense ammonia neutralization.With the gained throw out by filter collecting, with cold water and acetonitrile washing and in a vacuum, 40 ℃ of dryings 2 days to produce the Powdered title compound of beige (3.39g).
1H?NMR(d6-DMSO)δ?10.96(br?s，1H)，10.25(br?s，1H)，5.38，(d，1H)，5.32(d，1H)，1.79-1.72(m，1H)，0.93-0.89(m，2H)，0.75-0.71(m，2H)；LRMS(ES)m/z?152[MH]
+。
Preparation 4
6-cyclopropyl-2,4-dihydroxyl-3-nitro-pyridine
With 6-cyclopropyl-2,4-dihydroxyl-pyridine (1g, 6.6mmol) at room temperature be suspended in AcOH:EtOAc (4:1,10ml) in.Heat mixture to 30 ℃ and dropwise add the sub-fraction of nitrosonitric acid (0.05ml 1.2mmol), remains between 30 ℃ and 35 ℃ temperature.Add the back mixture and become clear solution.Dropwise interpolation residue nitrosonitric acid (0.25ml, 6.3mmol).Clear solution is cooled to room temperature, so throw out begins to form.Mixture at room temperature stirred spend the night.Solid by filtration is collected, with cold water and Et
2O washing and in a vacuum, at room temperature drying every other week (weekend) to produce yellow powder shape title compound (1.21g).
1H?NMR(d6-DMSO)δ?12.17(br?s，1H)，11.88(br?s，1H)，5.57(s，1H)，1.88-1.81(m，1H)，1.08-1.03(m，2H)，0.87-0.83(m，2H)；LRMS(APCI)m/z?197[MH]
+。
Preparation 5
6-cyclopropyl-2,4-two chloro-3-nitro-pyridines
With 6-cyclopropyl-2, (1.2g 6.1mmol) is suspended in POCl to 4-dihydroxyl-3-nitro-pyridine
3(5mL).With mixture under caustic scrubber, 85 ℃ of heated overnight.With excessive POCl
3Remove in a vacuum, reaction residue is dissolved in EtOAc (50ml) and under using the ice controlled temperature, dropwise is added in the warm water (50ml) that is stirred.Extract with 90:10 EtOAc:MeOH (100ml) with each layer separation and with the aqueous solution.Organism with salt solution (50ml) washing, is used MgSO
4Dry and concentrated to produce crude product (2g).Use the 90:10 pentane: the EtOAc wash-out, can produce the title compound (893mg) of light yellow crystalline solid with silica gel column chromatography.
1H?NMR(d6-DMSO)δ?7.94(s，1H)，2.31-2.24(m，1H)，1.18-1.14(m，2H)，1.06-1.02(m，2H)；LRMS(APCI)m/z?233[MH]
+。
Preparation 6
Benzyl-(2-chloro-6-cyclopropyl-3-nitro-pyridin-4-yl)-amine
With 6-cyclopropyl-2,4-two chloro-3-nitro-pyridines (160mg 0.8mmol) is dissolved among the THF (2ml), add triethylamine (1041,0.8mmol) and benzylamine (811,0.8mmol).With mixture at room temperature, under nitrogen atmosphere, stirred 48 hours, form yellow mercury oxide then.Volatile matter removed in a vacuum and at room temperature, in the jam-pack flask, stored 10 days resistates.Use 99:1 DCM:MeOH, 98:2 DCM:MeOH wash-out then, pass through the silica gel chromatography resistates to produce yellow crystal solid title compound (185mg).
1H?NMR(CDCl3)δ?7.42-7.31(m，5H)，7.05(br?s，1H)，6.47(s，1H)，4.49(d，2H)，1.88-1.81(m，1H)，1.09-1.04(m，2H)，1.01-0.96(m，2H)；LRMS(APCI)m/z?304[MH]
+。
Preparation 7
Benzyl-(3-amino-2-chloro-6-cyclopropyl-pyridin-4-yl)-amine
With benzyl-(2-chloro-6-cyclopropyl-3-nitro-pyridin-4-yl)-(245mg 0.8mmol) is dissolved in AcOH:H to amine
2Among the O (9.0:0.9ml).Add iron powder (270mg, 4.8mmol) and with mixture at room temperature, under nitrogen atmosphere vigorous stirring every other week, precipitation is separated out the pale precipitation thing during this.Reaction mixture with EtOAc (20ml) and water (20ml) dilution, is washed with diatomite filtration and with filter cake mixture with EtOAc (20ml).To respectively be separated and with the saturated NaHCO of organic layer
3MgSO is used in the aqueous solution (10ml) and salt solution (10ml) washing
4Dry also vacuum concentration.With resistates in a vacuum, 40 ℃ of dried overnight to produce the title compound (215mg) of canescence crystalline solid.
1H?NMR(CDCl
3)δ?7.40-7.31(m，5H)，6.29(s，1H)，4.59(br?s1H)，4.37(d，2H)，3.30(br?s?2H)，1.89-1.82(m，1H)，0.87-0.86(m，4H)；LRMS(APCI)m/z?274[MH]
+。
Preparation 8
1-benzyl-4-chloro-6-cyclopropyl-1,3-dihydro-imidazol-also [4,5-c] pyridin-2-ones with benzyl-(3-amino-2-chloro-6-cyclopropyl-pyridin-4-yl)-(210mg 0.8mmol) is dissolved in the acetonitrile (10ml) amine.Add 1, the 1-carbonyl dimidazoles (370mg, 2.3mmol) and with mixture under nitrogen atmosphere, 80 ℃ of heating 2 hours.Add 1 of 250mg (1.5mmol) again, the 1-carbonyl dimidazoles and with mixture 80 ℃ of heated overnight.Mixture is cooled to room temperature and removes solvent in a vacuum.Resistates is dissolved in uses 1N HCl (10ml), water (10ml) and salt solution (10ml) washing among the DCM (20ml) then, use MgSO
4Dry also vacuum concentration.With resistates in a vacuum, 40 ℃ of dried overnight to produce white fluffy solid title compound (217mg).
1H?NMR(CDCl
3)δ?8.20(brs，1H)，7.38-7.31(m，5H)，6.59(s，1H)，5.03(s，2H)，1.96-1.91(m，1H)，0.94-0.92(m，4H)；LRMS(APCI)m/z300[MH]
+。
Preparation 9
4-allyl amino-1-benzyl-6-cyclopropyl-1,3-dihydro-imidazol-is [4,5-c] pyridin-2-ones also
With 1-benzyl-4-chloro-6-cyclopropyl-1, the 3-dihydro-imidazol-also [4,5-c] pyridin-2-ones (100mg 0.3mmol) is dissolved in reaction flask Reactivial
TMIn allylamine (2mL) in.(83mg 0.3mmol) and with bottle seals to add copper sulfate (II).With mixture 85 ℃ of heated overnight.Add more parts copper sulfate (II) (83mg, 0.3mmol) and allylamine (1ml) and once more bottle being sealed.With mixture every other week 85 ℃ of heating.Mixture is cooled to room temperature.Excessive allylamine removed in a vacuum and be dissolved in resistates among the EtOAc (50ml) and use saturated NaHCO
3The aqueous solution (20ml) is handled.Use how saturated NaHCO again with each layer separation and with organism
3MgSO is used in the aqueous solution (10ml), salt solution (10ml) washing
4Dry also vacuum concentration is to produce crude product (120mg).Produce the title compound (73mg) of pale solid with 98:2 DCM:MeOH wash-out, with silica gel column chromatography.
1H?NMR(CDCl
3)δ?10.40(br?s，1H)，7.34-7.25(m，5H)，6.17-6.15(m，1H)，5.96-5.87(m，1H)，5.17(d，1H)，5.02-5.00(m，1H)，4.89(s，2H)，4.05-4.00(m，2H)，1.85-1.80(m，1H)，0.97-0.93(m，2H)，0.84-0.76(m，2H)；LRMS(APCI)m/z?321[MH]
+。
Preparation 10
Benzyl-(2-chloro-6-methyl-3-nitro-pyridin-4-yl)-amine
With 2,4-two chloro-6-methyl-3-nitro-pyridines (2g, 9.7mmol) and triethylamine (1.35mL 9.7mmol) is dissolved among the 40ml THF and extremely～5 ℃ of coolings (ice/water).(1.04g, 9.7mmol) solution in 10ml THF is heated mixture to ambient temperature overnight then gradually dropwise to add benzylamine.Mixture is evaporated in a vacuum, between EtOAc (50ml) and water (20ml), divide molten.With the saturated NaHCO of organic layer
3MgSO is used in the aqueous solution (10ml) washing
4Drying also is evaporated to orange colloid in a vacuum.This colloid preadsorption on silica gel, is used DCM then: pentane 3:1 wash-out, by the column chromatography purifying.The elution fraction that is fit to is merged the title compound (716mg) that also evaporates in a vacuum with the generation yellow solid.
1H NMR (CDCl
3) δ 2.32 (s, 3H), 4.38 (d, 2H), 6.39 (s, 1H), 6.90 (wide unimodal, 1H), 7.21 (m, 2H), 7.29 (m, 3H).LC-MS(ELSD，ES
+)m/z?278(MH
+)。
Preparation 11
N-2 ', N-2 ', N-4 '-tribenzyl-6-methyl-3-nitro-2,4-diamines
With benzyl-(2-chloro-6-methyl-3-nitro-pyridin-4-yl)-amine (99mg, 0.4mmol) with triethylamine (55 1,0.4mmol) be dissolved in THF (2ml) and dropwise add dibenzylamine (77mg, 0.4mmol).The gained reaction mixture at room temperature stirred spend the night, then evaporation in a vacuum.With resistates at EtOAc (5ml) and saturated NaHCO
3Divide molten between the aqueous solution (3ml).The organic layer drying (is used MgSO
4) and be evaporated to yellow colloid in a vacuum, the colloid preadsorption is used 1:1 DCM then on silica gel: pentane wash-out, by the column chromatography purifying.The elution fraction merging that is fit to also is evaporated to the aureus colloid in a vacuum, leaves standstill curing to produce title compound (75mg).
1H NMR (CDCl
3) δ 2.32 (s, 3H), 4.45 (d, 2H), 4.54 (s, 4H), 5.96 (s, 1H), 7.13-7.40 (m, 15H), 8.12 (wide unimodal, 1H).LRMS(ES
+)m/z?439(MH
+)。
Preparation 12
N-2 ', N-2 ', N-4 '-tribenzyl-6-methyl-2,3,4-triamine
With N-2 ', N-2 ', N-4 '-tribenzyl-6-methyl-3-nitro-2, the 4-diamines (59mg, 0.14mmol) be dissolved in the ethanol (5ml) and at room temperature, under 30psi through Raney nickel (6mg) hydrogenation 1 hour.Add the 12mg Raney nickel again and with mixture hydrogenation 1.5 hours again under 30psi and room temperature.Reaction mixture is filtered with the short plug of Arbocel, is opaque colloidal title compound (39mg) then with filtrate vacuum-evaporation.
1H NMR (DMSO) δ 2.08 (s, 3H), 4.07 (s, 4H), 4.21 (s, 2H), 4.30 (d, 2H), 5.83 (t, 1H is commutative), 6.05 (s, 1H), 7.14-7.34 (m, 15H); LRMS (APCI
+) m/z409 (MH
+).
Preparation 13
1-benzyl-4-dibenzyl amino-6-methyl isophthalic acid, 3-dihydro-imidazol-be [4,5-c] pyridin-2-ones also
With N-2 ', N-2 ', N-4 '-tribenzyl-6-methyl-2,3, (35mg, 0.09mmol) and 1, (139mg 0.86mmol) is dissolved in the acetonitrile (3ml) and with mixture heating 3 hours under refluxing the 1-carbonyl dimidazoles 4-triamine.Reaction mixture is evaporated in a vacuum, use DCM as elutriant, by column chromatography purifying resistates.The elution fraction that is fit to is merged the title compound (30mg) that also evaporates in a vacuum with the generation white solid.
1H NMR (CDCl3) δ 2.32 (wide unimodal, 3H), 4.68 (s, 4H), 4.85 (s, 2H), 6.18 (s, 1H), 7.18-7.26 (m, 15H); LRMS (ES
+) m/z 435 (MH
+).
Preparation 14
N4-benzyl-2-chloro-6-trifluoromethyl-pyridine-3, the 4-diamines
(345mg 1.0mmol) is dissolved in the mixture of AcOH (18ml) and water (2ml) with benzyl-(2-chloro-3-nitro-6-trifluoromethyl-pyridin-4-yl)-amine.(349mg is 6.2mmol) and with mixture vigorous stirring 24 hours at room temperature to add iron powder.Dilute with EtOAc (10ml) and water (10ml) with the reaction mixture vacuum concentration and with resistates.With the mixture diatomite filtration, with EtOAc (20ml) washing.With each layer separation and with the saturated NaHCO of organic layer
3The aqueous solution (2 * 10ml) and salt solution (10ml) washing, use MgSO
4Dry also vacuum concentration is to produce the title compound (304g) of light yellow solid.
1H NMR (CDCl
3) δ 7.43-7.34 (m, 5H), 6.87 (s, 1H), 4.46 (brs, 1H), 4.42 (d, 2H), 3.72 (br s, 2H); LRMS (APCI and ES) m/z 302[MH]
+
Preparation 15
1-benzyl-4-chloro-6-trifluoromethyl-pyridin-2-ones
With N4-benzyl-2-chloro-6-trifluoromethyl-pyridine-3, (300mg 1.0mmol) is dissolved among the MeCN (20ml) the 4-diamines.(806mg 4.9mmol) and with mixture heated 48 hours at 80 ℃ to add CDI.Mixture is cooled to room temperature and removes solvent in a vacuum.With resistates be dissolved in use then among the EtOAc (50ml) 1N HCl (aq) (20ml), the washing of water (20ml) and salt solution (20ml), use MgSO
4Dry also vacuum concentration is to produce the title compound (325g) of light yellow solid.
1H NMR (CDCl
3) δ 7.41-7.33 (m, 5H), 7.14 (s, 1H), 5.11 (s, 2H); LRMS (APCI and ES) m/z 328[MH]
+
Preparation 16
1-benzyl-4-benzylamino-6-Trifluoromethyl-1,3-dihydro-imidazol-be [4,5-c] pyridin-2-ones also
(100mg 0.3mmol) is dissolved in BnNH in the reaction flask with 1-benzyl-4-chloro-6-trifluoromethyl-pyridin-2-ones
2(2ml).Add CuSO
4(152mg 0.6mmol) and with bottle seals.Reaction mixture was heated 120 hours at 80 ℃.Then reaction mixture is cooled to room temperature and is dissolved among the EtOAc (20ml).With the saturated NaHCO of mixture
3The aqueous solution (2 * 5ml) and salt solution (5ml) washing, use MgSO
4Dry also vacuum concentration is to produce crude product (700mg).Can produce the title compound (50mg) of yellow solid with the 99:1DCM:MeOH wash-out, with the silicon-dioxide column chromatography.
1H NMR (CDCl
3) δ 10.66 (br s, 1H), 7.34-7.10 (m, 10H), 6.58 (s, 1H), 5.86-5.84 (m, 1H), 4.70 (d, 2H), 4.66 (s, 2H); LRMS (APCI and ES) m/z 399[MH]
+
The alternative preparation of above title compound is described below;
With N2, N4-dibenzyl-6-trifluoromethyl-pyridine-2,3, the 4-triamine (9.02g 24.2mmol) is dissolved among the TBME (180ml), and interpolation CDI (19.6g, 121mmol).Reaction mixture was at room temperature stirred 72 hours.Water (100ml) is added into reaction mixture and with each layer separation.The aqueous solution is extracted with EtOAc (200ml).The organism that is merged is washed with salt solution (50ml), use MgSO
4Dry also vacuum concentration is to produce crude product (25g).With 30:70 → 60:40 heptane: the EtOAc wash-out, produce white fluffy solid title compound (2.64g) with the silicon-dioxide column chromatography.
1H NMR (CDCl
3) δ 10.52 (br s, 1H), 7.44-7.12 (m, 10H), 6.60 (s, 1H), 5.76-5.72 (m, 1H), 4.71-4.70 (m, 4H); LRMS (APCI and ES) m/z 399[MH]
+
Preparation 17
N2, N4-dibenzyl-3-nitro-6-trifluoromethyl-pyridine-2,4-diamines
With 3-nitro-6-trifluoromethyl-pyridine-2, (5.0g 22.3mmol) is dissolved among the DCM (50ml) the 4-glycol, adds Et
3N (6.22ml, 44.6mmol).Mixture is cooled to 0 ℃ and dropwise add Tf
2O (7.32ml, 44.6mmol).Heat mixture to room temperature and stirred 1 hour.Be dissolved among the THF (50ml) with the reaction mixture vacuum concentration and with resistates.Add BnNH
2(7.3ml 66.9mmol) and with mixture stirred 24 hours at 50 ℃.Reaction mixture is cooled to room temperature and vacuum concentration.Resistates water (50ml) is handled, and extracted with EtOAc (150ml).Extract with salt solution (50ml) washing, is used MgSO
4Dry also vacuum concentration is to produce crude product (27g).
With second batch of 3-nitro-6-trifluoromethyl-pyridine-2, (11.06g 49.4mmol) is dissolved among the DCM (100ml) the 4-glycol, adds Et
3N (13.8ml, 98.7mmol).Mixture is cooled to 0 ℃ and dropwise add Tf
2O (16.2ml, 98.7mmol).Heat mixture to room temperature and stirred 1 hour.Be dissolved among the THF (100ml) with the reaction mixture vacuum concentration and with resistates.Add BnNH
2(16.2ml 148mmol) and with mixture stirred 24 hours at 50 ℃.Reaction mixture is cooled to room temperature and vacuum concentration.Resistates water (100ml) is handled, and extracted with EtOAc (200ml).Extract with salt solution (50ml) washing, is used MgSO
4Dry also vacuum concentration is to produce crude product (53g).Two kinds of crude products are merged.With 95:5 → 90:10 pentane: the EtOAc wash-out, produce the title compound (15.93g) of yellow solid with the silicon-dioxide column chromatography.
1H NMR (CDCl
3) δ 9.68-9.64 (m, 1H), 9.36-9.32 (m, 1H), 7.43-7.29 (m, 10H), 6.38 (s, 1H), 4.81 (d, 2H), 4.55 (d, 2H); LRMS (APCI and ES) m/z 403[MH]
+
Preparation 18
N2, N4-dibenzyl-6-trifluoromethyl-pyridine-2,3,4-triamine
With N2, N4-dibenzyl-3-nitro-6-trifluoromethyl-pyridine-2, (15.9g 35.6mmol) is dissolved in the mixture of THF (100ml) and MeOH (200ml) the 4-diamines.Add Raney nickel (3.18g, 20wt%) and with mixture at room temperature, at 80psi H
2Under stirred 1 hour.With mixture with diatomite filtration with remove catalyzer and with the filtrate vacuum concentration to produce oily matter.In MeOH, produce throw out, collect by filtering with the less water grinding, also dry in a vacuum with cold MeOH washing to produce the title compound (9.02g) of white solid.
1H NMR (CDCl
3) δ 7.43-7.28 (m, 10H), 6.57 (s, 1H), 4.66 (d, 2H), 4.62-4.59 (m, 1H), 4.57-4.54 (m, 1H), 4.39 (d, 2H), 2.49 (br s, 2H); LRMS (APCI and ES) m/z 373[MH]
+
Preparation 19
2,4-dihydroxyl-6-trifluoromethyl-Nikithan
Add pyridine (53ml/660mmol) with the 3-amino-4,4 among the dissolving DCM (6000ml), 4-trifluoro butenoic acid ethyl (100g/546mmol).Then mixture is placed under the nitrogen atmosphere and and be cooled to 5 ℃ by being suspended in ice bath.Dropwise added the ethyl malonyl chloride so that temperature is no more than 20 ℃ through about 1 hour.The gained brown solutions was stirred 3 hours at 5 ℃, heat then to ambient temperature overnight to produce sap green solution.Then with the mixture 1M HCl aqueous solution (200ml), saturated NaHCO
3The aqueous solution (250ml) washing.Water lotion is continued (2 * 250ml) extractions again with other DCM.Organic layer is merged, use Na
2SO
4Drying is filtered and the thick 3-of simmer down to sap green buttery (2-ethoxycarbonyl-kharophen)-4,4 4-three fluoro-but-2-ene acetoacetic esters (175g).Be dissolved in the thick material of a part (120g) among the EtOH (300ml) and be positioned under the nitrogen atmosphere.Divide some parts to add potassium tert.-butoxide (54g/480mmol) then, thereby produce purple solution so that temperature is no more than 60 ℃.Then mixture was heated 3 hours at 70 ℃.Add EtOH (100ml) then to reduce viscosity and 80 ℃ of reheat 1 hour.Then mixture being cooled off then, vacuum concentration is a red solid.In mixture water-soluble (500ml), add citric acid (180g), produce precipitation.Add EtOAc (600ml) then and mixture is poured in the separating funnel and with water layer and discharge.The organic layer that will contain a large amount of undissolved solids filters to produce the title compound (46.5g) of white solid.Concentrate organism filtrate and grind, produce the title compound (15.3g) of more white solid with MeOH.
1H?NMR(d6-DMSO，400MHz)δ?1.20-1.25(t，3H)，4.20-4.25(q，2H)，6.8(s，1H)
Preparation 20
6-trifluoromethyl-pyridine-2, the 4-glycol
Under reflux temperature with 2,4-dihydroxyl-6-trifluoromethyl-Nikithan (62g/247mmol) divide some parts through be added in 30 minutes 6M HCl (aq) (620ml) in.Then under vigorous stirring with the gained mixture 100 ℃ of heated overnight to obtain complete solution.Be white solid with this solution cooling and vacuum concentration then.This thing furnishing slurries in water (250ml) also are adjusted to pH7 to obtain thick white suspension with dense ammonia.The gained solid by filtration is collected, with fresh water flushing and dry to produce the title compound (44.0g) of white solid.
1H?NMR(d6-DMSO，400MHz)δ?6.05(s，1H)，6.6(s，1H)
Preparation 21
Ethyl-[2,3-diamino-6-(trifluoromethyl)-pyridin-4-yl]-benzylamino manthanoate
With thick ethyl-(65gm 170mmol) is dissolved in the ethanol (1000ml) [2-amino-3-nitro-6-(trifluoromethyl)-pyridin-4-yl]-benzylamino manthanoate, adds 10% Pd-C (6gm).Under 40 ℃ and 40psi, carried out hydrogenation 1 hour, nitro is reduced fully.Catalyzer removed by filtration and with filtrate under reduced pressure evaporate to dryness to produce light brown semisolid.Grind with t-butyl methyl ether (150ml), filter then and wash, produce the title compound (36gm, 60% yield) of white solid with above-mentioned same solvent (30ml).
1H NMR (DMSOd
6) δ 7.30-7.21 (m, 5H), 6.32 (broad peak s, 1H), 6.15 (broad peak s, 2H), 5.39 (broad peak s, 2H), 5.00 (broad peak d, 1H), 4.25 (broad peak d), 4.09 (broad peak d, 2H), 1.12 (broad peak s, 3H); LRMS (ES
+) m/z 355 (MH
+)
Preparation 22
Ethyl-[2-amino-3-nitro-6-(trifluoromethyl)-pyridin-4-yl]-benzylamino manthanoate
(63gm 160mmol) is dissolved in the tetrahydrofuran (THF) (300ml) and to wherein adding 0.880 ammonia solution (100ml) to produce two-phase with ethyl-[2-chloro-3-nitro-6-(trifluoromethyl)-pyridin-4-yl]-benzylamino manthanoate.This thing is changed in the pressurized vessel, and also under agitation being heated to 80 ℃ lasts 2 hours in sealing.With tetrahydrofuran (THF) evaporation and between saturated brine and ether, divide resistates molten.With the organic extract dried over sodium sulfate, filtration and evaporation are to produce thick yellow slurry (65gm) crude product; LRMS (ES
+) m/z 385 (MH
+), (ES
-) m/z 383 (M
-H).
Preparation 23
Ethyl-[2-chloro-3-nitro-6-(trifluoromethyl)-pyridin-4-yl]-benzylamino manthanoate
With benzyl-(57gm 170mmol) is dissolved in the tetrahydrofuran (THF) (750ml) and at N (2-chloro-3-nitro-6-trifluoromethyl-pyridin-4-yl)-amine
2The following stirring.The gained mixture is cooled to-5 ℃ then in ice/salt bath.In about 30 minutes, dropwise add potassium tert.-butoxide (21.2gm, the 189mmol) solution in tetrahydrofuran (THF) (200ml), make temperature maintenance between-5 ℃ and 0 ℃ to produce the scarlet reaction mixture.Then with the gained mixture after this temperature stirs 15 minutes, (21.4gm, the 198mmol) solution in tetrahydrofuran (THF) (100ml) remains on below 5 ℃ temperature dropwise to add Vinyl chloroformate again.
Remove cooling bath, allow reaction mixture to reach envrionment temperature through 1 hour to produce light brown turbid solution.Evaporating solvent divides resistates molten between saturated brine (50ml) and t-butyl methyl ether (300ml) then.With organic phase water successively (50ml), saturated brine (50ml) washing, use dried over sodium sulfate, filtration and evaporation are to produce brown oil.This oil is dissolved in the Skellysolve A (250ml) and stores and spend the night in envrionment temperature.
Skellysolve A solution controlled oneself, and decant goes out in the precipitation dun tar of separating out.Evaporating solvent produces light brown viscosity oily title compound (63gm, 91% yield).
1H?NMR(CDCl
3)δ?7.28-7.10(m，5H)，4.80(s，2H)4.15(q，2H)1.18(t，3H)；LRMS(ES
+)m/z?404/406(MH
+)。
Preparation 24
Benzyl-(2-chloro-3-nitro-6-trifluoromethyl-pyridin-4-yl)-amine
(61.7gm 197mmol) is added in the phenyl phosphonyl chloride (180ml), and at N with 4-benzylamino-3-nitro-6-trifluoromethyl-pyridine-2-alcohol
2Being heated to 100 ℃ under the atmosphere, in oil bath spends the night.The heating for dissolving initial substance is to produce yellow solution.The mixture quenching is gone up to produce light yellow solid in frozen water (600gm ice+100ml water).Leaching solid also, water suitably washs.Solid is dissolved in the ethyl acetate (600ml) and is alkalescence until the pH of foaming and washing lotion water no longer with sodium bicarbonate aqueous solution (10%w/v) washing.With the organic layer dried over sodium sulfate, filtration and evaporation are to produce turbid yellow solid.Then solid is dissolved in the ether.Then to wherein adding normal hexane till the solution muddiness.A thick cotton-shaped solid forms in several minutes, leaches then, with normal hexane washing and dry to produce title compound (60.59gm, 92% yield).
1H NMR (CDCl
3) δ 7.44-7.30 (m, 5H), 7.04 (s, 1H), 6.95 (the s broad peak, and 1H) 4.53 (d, 2H); LRMS (ES
+) m/z 332 (MH
+).
Preparation 25
2-chloro-3-nitro-6-trifluoromethyl-pyridin-4-yl amine
(3.1g 9.3mmol) stirred in the 5ml vitriol oil 0.5 hour, again with in the careful beaker that is poured into trash ice of solution with benzyl-(2-chloro-3-nitro-6-trifluoromethyl-pyridin-4-yl)-amine.Add solid K one by one
2CO
3Until reaching the alkaline pH value, and with 2 * 50ml EtOAc extraction water solution.With the organism MgSO that is merged
4Dry also vacuum concentration is to produce the title compound of 2.2g light yellow solid.
1H?NMR(CDCl
3)δ?7.06(s，1H)，5.87(bs，2H)；LRMS(ESCI)m/z?240[M-H]+
Preparation 26
(2-chloro-3-nitro-6-trifluoromethyl-pyridin-4-yl) urethanum
Will (2-chloro-3-nitro-6-trifluoromethyl-pyridin-4-yl amine (2.2g 9.1mmol) stirs in 2-MeTHF (20ml), and the interpolation triethylamine (1.52ml, 10.9mmol).Solution is cooled in ice bath～5 ℃, (1.04ml 10.9mmol), heats solution and stirred 16 hours to envrionment temperature and under nitrogen atmosphere dropwise to add Vinyl chloroformate again.Add 20ml EtOAc and 10mlH
2O also will respectively be separated, with other 2 * 10ml saturated brine solution washing.With organic extract MgSO
4Drying, vacuum concentration and preadsorption are on silica column.Use heptane: EtOAc9:1 wash-out, the title compound of generation 2.1g white solid.
1H?NMR(CDCl
3)δ?8.79(s，1H)，8.02(bs，1H)，4.35-4.30(t，2H)，1.38-1.35(qt，3H)；LRMS(ESCI)m/z?312[M-H]+
Preparation 27
(2-benzylamino-3-nitro-6-trifluoromethyl-pyridin-4-yl) urethanum
With 2-chloro-3-nitro-6-trifluoromethyl-pyridin-4-yl) urethanum (300mg, 0.96mmol) be dissolved in the 10ml tetrahydrofuran (THF), add then benzylamine (0.103ml, 0.96mmol), triethylamine (0.194ml, 1.91mmol), and reaction mixture spent the night 60 ℃ of stirrings.Remove solvent and solid is divided in ethyl acetate/water (50ml/30ml) molten, with organic layer MgSO
4Drying, concentrate and with 0% in the ethyl acetate to the gradient elution of 10% methyl alcohol, by the title compound of silica column chromatogram purification with generation 323mg yellow solid.
1H?NMR(CDCl
3)：δ?10.75(s，1H)，8.89(s，1H)，8.22(s，1H)，7.35(m，5H)，4.82(d，2H)，4.31(q，2H)，1.36(t，3H)；LRMS(APCI)m/z?385[MH]
+
Preparation 28
(3-amino-2-benzylamino-6-trifluoromethyl-pyridin-4-yl) urethanum is with (2-benzylamino-3-nitro-6-trifluoromethyl-pyridin-4-yl)-urethanum (95mg, 0.25mmol) be dissolved in the 10mL ethanol, add Raney nickel (20mg, 20%MW), then at room temperature, under 50PSI hydrogen, in pressure-pot, stirred 2 hours with reaction mixture.Mixture filtered with Arbocel (lignocellulose) and with the filtrate vacuum concentration to produce 88mg light green colloidal title compound; LRMS (APCI) m/z 355[MH]
+
Preparation 29
4-benzylamino-6-Trifluoromethyl-1,3-dihydro-imidazol-also (4,5-c) pyridin-2-ones
(88mg 0.25mmol) is dissolved in the 5ml acetate and with reaction mixture and spends the night 80 ℃ of stirrings with (3-amino-2-benzylamino-6-trifluoromethyl-pyridin-4-yl)-urethanum.Remove solvent and in water/ethyl acetate, divide this jelly molten.Organic layer is separated, use MgSO
4Drying removes solvent in a vacuum, and with 1% in the ethyl acetate to the gradient elution of 5% methyl alcohol, by the silica column chromatogram purification to produce the colourless colloidal title compound of 37mg.
1H?NMR(CDCl3)：δ?10.56(s，1H)，7.51-7.47(m，5H)，6.61-6.58(m，2H)，5.87(s，1H)，4.61(d，2H)；LRMS(APCI)m/z?309[MH]
+
Preparation 30
4-benzylamino-1-(6-methyl-pyridin-3-yl methyl)-6-Trifluoromethyl-1,3-dihydro-imidazol-also (4,5-c) pyridin-2-ones
With 4-benzylamino-6-Trifluoromethyl-1,3-dihydro-imidazol-also (4,5-c) pyridin-2-ones (100mg, 0.32mmol) be dissolved in and add salt of wormwood (89mg in the 5mL dimethyl formamide then, 0.65mmol), 5-chloromethyl-2-methyl-pyridine (46mg, 0.32mmol), and reaction mixture spent the night 80 ℃ of stirrings.The mass spectroscopy displaying is contemplated to some diphenylmethylation products.Solvent is removed in a vacuum and in ethyl acetate/water, divide resistates molten.Organic layer is separated, use MgSO
4Drying removes solvent in a vacuum, and with the resistates gradient elution of 1% to 10% methyl alcohol in the ethyl acetate, by the title compound of silica column chromatogram purification with generation 30mg white solid.
1H?NMR(d6?DMSO)：δ?8.46(s，1H)，7.57-7.55(dd，1H)，7.38-7.16(m，7H)，6.63(t，1H)，5.02(s，2H)，4.59(d，2H)，2.40(s，3H)；LRMS(APCI)m/z?414[MH]
+
Preparation 31
(2-chloro-3-nitro-6-trifluoromethyl-pyridin-4-yl)-(6-methyl-pyridin-3-yl methyl)-urethanum
(88mg, (100mg is 0.32mmol) in the solution that is stirred in acetone (10ml) 0.64mmol) to be added into (2-chloro-3-nitro-6-trifluoromethyl-pyridin-4-yl)-urethanum with salt of wormwood.Add then 5-(chloromethyl)-2-picoline (54.2mg, 0.38mmol), (57.4mg 0.38mmol) and with suspension stirred 16 hours under nitrogen atmosphere sodium iodide.Add 20ml EtOAc and with organic phase with 2 * H
2MgSO is used in the O washing
4Dry also vacuum concentration is to produce reddish oil.Use heptane: EtOAc 3:2 wash-out, by the title compound of silica column chromatogram purification this thick material with generation 54mg orange solids.
1H?NMR(CDCl
3)δ?8.35(d，1H)，7.54-7.51(dd，1H)，7.31(s，1H)，7.16-7.15(d，1H)，4.84(s，2H)，4.23-4.18(qt，2H)，2.55(s，3H)，1.26-1.22(t，3H)；LRMS(ESCI)m/z?419[MH]
+
Preparation 32
(2-amino-3-nitro-6-trifluoromethyl-pyridin-4-yl)-(6-methyl-pyridin-3-yl methyl)-urethanum
(54mg 0.13mmol) is dissolved among the THF (1ml) and changes in the 10ml reaction flask with (2-chloro-3-nitro-6-trifluoromethyl-pyridin-4-yl)-(6-methyl-pyridin-3-yl methyl)-urethanum.Add 880 ammoniacal liquor (1ml), with container sealing and with mixture envrionment temperature vigorous stirring 16 hours.To produce thick oil, is the title compound of yellow residue with 100% EtOAc wash-out, by silicon-dioxide column chromatography direct purification to produce 27mg with it with solution for vacuum concentration.
1H?NMR(CDCl
3)δ?8.39(s，1H)，7.61-7.59(d，1H)，7.15-7.13(d，1H)，6.76(s，1H)，6.25(bs，2H)，4.92(s，2H)，4.23-4.14(qt，2H)，2.54(s，3H)，1.22-1.19(t，3H)：LRMS(APCI)m/z?400[MH]
+
Preparation 33
4-benzylamino-3-nitro-6-trifluoromethyl-pyridine-2-alcohol
With 4-chloro-3-nitro-6-trifluoromethyl-pyridine-2-alcohol (65.1gm 268mmol) is dissolved in the tetrahydrofuran (THF) (350ml), and at room temperature, at N
2Stir under the atmosphere.Dropwise added benzylamine in the tetrahydrofuran (THF) (50ml) (86.3gm was 805mmol) to produce bright yellow solution through 30 minutes.Reactant is heated 18 hours (forming solid between the reaction period) in 50 ℃ oil bath.Then the gained mixture is cooled to envrionment temperature, leaches gained solid (aniline hydrochloride) then with ether (200ml) dilution.Under reduced pressure filtrate is evaporated to low volume to produce yellow thick slurries.Add ether (300ml) and leach yellow solid, dry to produce benzylamine salt (96.5gm) on filter bed.By dividing molten disengaging with solid between the 2N HCl aqueous solution and methylene dichloride, crystallization in ethyl acetate/Skellysolve A produces the title compound (61.7gm, 73.4% yield) of light yellow solid with required product.
1H NMR (DMSO d
6δ 9.04 (wide unimodal, 1H), 7.38-7.25 (m, 5H), 6.54 (s, 1H), 4.67 (d, 2H); LRMS (ES
+) m/z 314 (MH
+).
Preparation 34
4-chloro-3-nitro-6-trifluoromethyl-pyridine-2-alcohol
With 3-nitro-6-trifluoromethyl-pyridine-2, the 4-glycol (5.8gm, 26mmol) in phenyl phosphonyl chloride (30ml), 100 ℃ the heating 19 hours.Cool off the gained mixture then and pour into ice (60gm) on, use then ethyl acetate (3 * 50ml) extraction.The organic extract that is merged is alkalescence (pH～8) with sodium bicarbonate aqueous solution (10%w/v) washing until washing lotion.Then the deep yellow organic layer is washed with saturated brine, use dried over sodium sulfate, filtration and evaporation are to produce yellow colloid.Grind this colloid with methylene dichloride, produce yellow solid, it is leached and dry (4.65gm).With in the solid water-soluble (25ml) and with 2N hydrochloric acid (7.5ml) acidifying to produce white thick throw out, it is leached and washes with water.Throw out is dissolved in the ethyl acetate, uses dried over sodium sulfate, filtration and evaporation are to produce the title compound (3.75gm) of white solid.
1H?NMR(DMSOd6)δ?7.78(s，1H)。
13C?NMR(DMSOd6)δ?157.2(s)145.2(q)138.1(s)136.98(s)120.6(q)113.86(s)；LRMS(ES
-)m/z?241/243[MH]
-
Preparation 35
3-nitro-6-trifluoromethyl-pyridine-2, the 4-glycol
Under agitation, with 6-trifluoromethyl-pyridine-2, (56gm 310mmol) is added in the vitriol oil (140ml) with every part of 3-5mg the 4-glycol, to produce brown solutions.During the interpolation temperature be increased to～50 ℃.Dropwise add nitric acid (70% HNO3 d=1.4gm/ml), lasts about 90 minutes for 21.1ml, 328mmol so that temperature of reaction maintains flow velocity between 45 ℃ and 50 ℃.In case nitric acid has all added, then go through reactant was cooled to envrionment temperature in 3 hours.Then under agitation, with reaction mixture be poured into ice/water (～1.3kg) in, behind the several minutes, form the light-yellow precipitate thing, it is leached, be dissolved in the ethyl acetate and use dried over sodium sulfate, filter and evaporate.With the 2nd time results material by obtaining with the ethyl acetate extraction aqueous filtrate.Each is obtained the thing merging and by crystallization purifying in ethyl acetate/normal heptane, produces the fluffy ＂ solid of white ＂ title compound (49.5gm, 71% yield).
1H?NMR(DMSOd
6)δ?6.82(s，1H)。
13C NMR (DMSOd
6) 159.82 (s) 157.58 (s) 143.10 (wide unimodal), 127.26 (s) 120.85 (q) 102.83 (s).
Preparation 36
2,6-dibromo pyridine 1-oxide compound
With 2, the 6-dibromo pyridine (79g 334mmol) is dissolved in the 800ml anhydrous methylene chloride and is cooled to 5 ℃ under nitrogen atmosphere, in portion, add then Urea Peroxide (104g, 1.1mol).When mixture is cooled to 3 ℃ again, goes through and added trifluoroacetic anhydride with dropping funnel in 45 minutes (140ml, the 1mol) solution in 100ml DCM make temperature remain between 5-7 ℃ simultaneously.Heat mixture to room temperature and stirred 20 hours.Mixture is cooled to 10 ℃ and go through and dropwise added 10% Na in 60 minutes in ice bath
2SO
3The aqueous solution (～50g/500ml) until negative with the starch iodide paper test.The gained mixture is filtered to remove a large amount of fluffy solids and with each layer separation.(2 * 200ml) extractions are and with the extract MgSO that is merged with methylene dichloride with water layer
4Dry and under reduced pressure concentrated to produce light brown solid.Use 600ml boiling acetone to make the crude product recrystallization, produce the 48.47g title compound.
1H?NMR(CDCl
3)δ?7.65(d，2H)，6.95(m，1H)。
Preparation 37
2,6-two bromo-4-nitropyridine 1-oxide compounds
At room temperature, with 2, (10g 39.5mmol) is added in the 65ml vitriol oil 6-dibromo pyridine 1-oxide compound, need not cooling.The vitriol oil (15ml) is mixed with nitric acid (13.3ml) and be positioned in the pressure equilibrium dropping funnel.Reaction mixture is heated to 79 ℃, goes through then and added nitrating mixture in 25 minutes one by one.When interpolation is finished, mixture was stirred 3.5 hours at 83-85 ℃.Mixture is cooled to room temperature and slowly pours on a 250g trash ice.Form very shallow yellow solid, it leached and water (100ml) washing, in vacuum drying oven, 50 ℃ of dried overnight to produce the 10.9g title compound.
1H?NMR(CDCl
3)δ?8.45(s，2H)。
Preparation 38
2,6-dibromo pyridine-4-base amine
With 2, (14.5g 48.6mmol) is dissolved in the 130ml acetate 6-two bromo-4-nitropyridine 1-oxide compounds, and (11g 196.9mmol), and at room temperature stirred mixture 45 minutes to add iron powder one by one.Add 500ml water and use EtOAc (500ml) to extract product.Organic layer is used 300ml water, the saturated K of 300ml successively
2CO
3Solution, the water washing of 300ml salt.Organic layer is removed to produce the title compound of 11.1g white solid in a vacuum with dried over mgso and with solvent.
1H NMR (CDCl
3) δ 6.65 (s, 2H), 4.4-4.1 (the s broad peak, 2H); LRMS (ES
+) m/z251,253[MH]
+
Preparation 39
2,6-dibromo pyridine-4-base-N-nitra-amine
At room temperature with 2, the 6-dibromo pyridine-(11g 43.6mmol) is dissolved in the 100ml sulfuric acid then-5 ℃ of coolings 4-base amine.Dropwise add 6ml nitric acid, temperature is remained between-10 ℃ to-5 ℃, and mixture was stirred 30 minutes at-5 ℃.Then mixture is poured on the 400ml trash ice.Formed solid is leached, be dissolved among the EtOAc then.Residuary water is removed and, remove in a vacuum to produce the title product of 12.5g yellow solid with dried over mgso and with solvent with organic layer 300ml salt water washing.
1H NMR (CDCl
3) δ 6.85 (s 1H), and 5.7-5.4 (the s broad peak, 2H).
Preparation 40
2,6-two bromo-3-nitro-pyridin-4-yl amine
The vitriol oil (250ml) heated until sour temperature in oil bath reach 47 ℃.Go through and added 2 one by one in 35 minutes, and 6-dibromo pyridine-4-base-N-nitra-amine (34.0g, 114.5mmol).The temperature of mixture rises during whole interpolation gradually until it is 56 ℃ at last.Mixture was stirred 1 hour at 53-55 ℃.In case reaction is finished, then under agitation reaction mixture is cooled off in ice bath and pour on～2L trash ice.The product precipitation also is filtered off.Merge with other batch of material 00110916-140-001 available from identical scale reaction.The amino nitropyridine that will slightly wet is dissolved among the 700ml EtOAc and separates water layer.With the organic layer water (2 * 150ml), 1 * 150mlNaHCO
3(2 * 150ml) washings, drying (is used MgSO for the aqueous solution, salt solution
4), under reduced pressure concentrate to produce the 28g title compound.
1H NMR (CDCl
3) δ 7.3-7.2 (the s broad peak, 1H), 7.55 (s, 2H).
Preparation 41
N-2, N-4-dibenzyl-6-bromo-3-nitro-pyridine-2,4-diamines
With 2,6-two bromo-3-nitro-pyridin-4-yl amine (6.5g 21.9mmol) is suspended among the dense HCl (100ml) and is cooled to 0 ℃, add then Sodium Nitrite (7.5g, 109mmol).Mixture was stirred 30 minutes, heat to room temperature then.Add 100ml cold water and with mixture 100ml ethyl acetate extraction.With organic layer 100ml water washing, use dried over mgso, and remove solvent in a vacuum, to produce the orange buttery 2 of 5.8g, 6-two bromo-3-nitro-4-chloropyridines.Be dissolved in this oil among the 80ml THF and be cooled to 0 ℃.With benzylamine (94.9ml 44.9mmol) is dissolved among the 20ml THF and dropwise is added in the reactant, add then salt of wormwood (6.6g, 48.2mmol).Mixture is heated to room temperature, then 50 ℃ of heated overnight.In case reaction is finished, then in water (150ml) and ethyl acetate (100ml), divide mixture molten.Organic layer with 200ml water and the water washing of 200ml salt, is also removed solvent in a vacuum with dried over mgso.Add 100ml ethanol and with mixture supersound process five minutes and place stink cupboard to spend the night.Throw out leached and with the 30ml washing with alcohol to produce the title compound of 4.56g yellow solid.
1H NMR (CDCl
3) δ 9.6-9.4 (the m broad peak, 2H), 7.4-7.2 (m, 10H), 6.2 (s, 1H), 4.8 (d, 2H), 4.45 (d, 2H); LRMS (ES
+) m/z 413,415[MH]
+
Preparation 42
N-2, N-4-dibenzyl-3-nitro-6-vinyl-pyridine-2,4-diamines
With N-2, N-4-dibenzyl-3-nitro-6-vinyl-pyridine-2, the 4-diamines (2g 5mmol) is dissolved among the THF (60ml), add the vinyl tributyl tin (3.4g, 10.8mmol), acid chloride (350mg, 10 weight %) and triphenylphosphine (380mg).With the mixture argon-degassed, then in 80 degree heated overnight.Remove solvent in a vacuum, 10% ethyl acetate in the use pentane is as elutriant, by the title compound of the thick resistates of silica gel column chromatography purifying with generation 1.9g orange solids.
1H NMR (CDCl
3) δ 9.65 (the s peak width, 1H), 9.4 (the s peak width, 1H), 7.45-7.2 (m, 10H), 6.5-6.4 (m, 1H), 6.35 (m, 1H), 5.95 (s, 1H), 5.5 (m, 1H), 4.85 (d, 2H), 4.55 (d, 2H); LRMS (ES
+) m/z 361[MH]
+
Preparation 43
4,6-pair-benzylamino-5-nitro-pyridine-2-formaldehyde
With N-2, N-4-dibenzyl-3-nitro-6-vinyl-pyridine-2, the 4-diamines (800mg 2mmol) is dissolved in 10ml tetrahydrofuran (THF) and the 30ml water, add successively then perosmic anhydride (60mg, 0.2mmol), sodium metaperiodate (1.2g, 5.6mmol).Mixture at room temperature stirred spend the night.In water (30ml) and ethyl acetate (30ml), divide mixture molten, with organic layer 50ml salt water washing, use dried over mgso, 10% ethyl acetate in the use pentane is as elutriant, by the title compound of the thick resistates of silica gel column chromatography purifying with generation 450mg orange solids.
1H NMR (CDCl
3) δ 9.78 (s, 1H), 9.55 (wide unimodal, 1H), 9..3 (the s broad peak, 1H), 7.4-7.2 (m, 10H), 7.62 (s, 1H), 5.5 (m, 1H), 4.9 (d, 2H), 4.6 (d, 2H); LRMS (ES
+) m/z 363[MH]
+
Preparation 44
N-2, N-4-dibenzyl-6-morpholine-4-base-methyl-3-; Nitro-pyridine-2, the 4-diamines
At room temperature with 4,6-is two-benzylamino-5-nitro-pyridine-2-formaldehyde (150mg 0.41mmol) is dissolved in the 15ml methylene dichloride, add then 2-methoxyl group-ethamine (43mg, 0.49mmol), acetate (25mg, 0.41mmol).Mixture was stirred 5 minutes, and (130mg 0.62mmol) and with mixture at room temperature stirred 1 hour to add sodium triacetoxy borohydride then.20ml water is added in the mixture, then organic layer is separated, use the 20ml water washing, use MgSO then
4Dry.Remove solvent in a vacuum to produce the orange colloidal title compound of 180mg.
1H NMR (CDCl
3) δ 9.55 (wide unimodal, 1H), 9.4 (wide unimodal, 1H), 7.4-7.2 (m, 10H), 6.19 (s, 1H), 4.8 (d, 2H), 4.55 (d, 2H), 3.6 (m, 4H), 3.45 (m, 2H), 3.3 (s, 2H), 2.35 (m, 4H); LRMS (ES
+) m/z 434[MH]
+
Preparation 45
N-2, N-4-dibenzyl-6-morpholine-4-base-methyl-pyridine-2,3,4-triamine
With N-2, N-4-dibenzyl-6-morpholine-4-base-methyl-3-nitro-pyridine-2, (190mg 0.43mmol) is dissolved in the 30ml methyl alcohol 4-diamines, adds Raney nickel (40mg, 20 weight %), then with mixture at room temperature, stirred 1 hour under 80psi hydrogen.After finishing, mixture is filtered and removes in a vacuum solvent to produce the green oily title compound of 180mg with Arbocel (lignocellulose).
1H NMR (CD
3OD): δ 7.4-7.2 (m, 10H), 6.1 (s, 1H), 4.6 (d, 2H), 4.4 (d, 2H), 3.3 (m, 6H), 2.4-2.2 (wide unimodal, 2H), 2.15 (m, 4H); LRMS (ES
+) m/z 417[MH]
+
Preparation 46
N-2, N-4-dibenzyl-6-ethyl-pyridine-2,3,4-triamine
With N-2, N-4-dibenzyl-3-nitro-6-vinyl-pyridine-2, (300mg 0.75mmol) is dissolved in the 20ml tetrahydrofuran (THF) 4-diamines, adds Raney nickel (40mg, 13 weight %), then with mixture at room temperature, stirred 1.5 hours under 60psi hydrogen.After finishing, mixture is filtered and removes in a vacuum solvent to produce the 230mg title compound with Arbocel (lignocellulose).
1H NMR (CDCl
3): δ 7.40-7.20 (m, 5H), 6.0 (s, 1H), 4.90-4.80 (wide unimodal, 2H), 4.65 (d, 2H), 4.35 (d, 2H), 2.55 (q, 2H), 1.20 (t, 3H).
Preparation 47
1-(4,6-couple-benzylamino-5-nitro-pyridine-2-yl)-ethyl ketone
With N-2, N-4-dibenzyl-6-bromo-3-nitro-pyridine-2,4-diamines (800mg, 1.94mmol) be dissolved in the 40ml tetrahydrofuran (THF), add successively then (1-vinyl ethyl ether base)-three-positive fourth tin (909mg, 2.52mmol), acid chloride (90mg, W/W) and triphenylphosphine (100mg, w/w), and with mixture stirred 1 hour at 80 ℃.In case reaction is finished, add the 3N HCl solution of 30ml ethyl acetate and 40ml.With mixture 60 ℃ of vigorous stirring 30 minutes.Organic layer is separated, remove in a vacuum with the water washing of 50ml salt and with solvent.Use 10% ethyl acetate in the pentane, by the thick resistates of silica gel column chromatography purifying to produce the title compound of 680mg yellow solid.
1H NMR (CDCl
3): δ 9.55 (wide unimodal, 1H), 9.35 (wide unimodal, 1H), 7.40-7.0 (m, 10H), 6.75 (s, 1H), 5.25 (s, 1H), 4.85 (d, 2H), 4.55 (d, 2H), 2.50 (s, 3H); LRMS (ES
+) m/z 377[MH]
+
Preparation 48
N-2, N-4-dibenzyl-6-difluoromethyl-3-nitro-pyridine-2,4-diamines
With 4,6-pair-benzylamino-5-nitro-pyridine-2-formaldehyde (250mg, 0.69mmol) be dissolved in the 15ml methylene dichloride and be cooled to 0 ℃, add then two-(611mg 2.76mmol) and with reaction mixture at room temperature stirred 3 hours (2-methoxy ethyl) amino sulfur trifluoride.In case reaction is finished, then 30ml water is added in the mixture, then organic layer is separated, with 30ml saturated solution of potassium carbonate and salt water washing, use MgSO then
4Dry.Remove solvent in a vacuum, use 10% ethyl acetate in the pentane, by the thick resistates of silica gel column chromatography purifying to produce the title compound of 220mg yellow solid.
1H NMR (CDCl
3) δ 9.60 (wide unimodal, 1H), 9.3 (wide unimodal, 1H), 7.4-7.2 (m, 10H), 6.30 (s, 1H), 6.35-6.05 (t, 1H), 6.75 (d, 2H), 6.50 (d, 2H); LRMS (ES
+) m/z 385[MH]
+
Preparation 49
4,6-pair-benzylamino-5-nitro-pyridine-2-formonitrile HCN
With N-2, N-4-dibenzyl-6-bromo-3-nitro-pyridine-2,4-diamines (500mg, 1.21mmol) be suspended in the 10ml toluene, add successively then the cyaniding tributyl tin (765mg, 2.42mmol), acid chloride (60mg, W/W) and triphenylphosphine (70mg, w/w), and with mixture 130 ℃ of microwave treatment 25 minutes.In case reaction is finished, and then solvent is removed in a vacuum, use 10% ethyl acetate in the pentane, by the thick resistates of silica gel column chromatography purifying to produce the title compound of 408mg yellow solid.
1H NMR (CDCl
3): δ 9.65 (wide unimodal, 1H), 9.30 (wide unimodal, 1H), 7.40-7.20 (m, 10H), 6.40 (s, 1H), 4.75 (d, 2H), 4.50 (d, 2H); LRMS (ES
+) m/z 360[MH]
+
Preparation 50
(4,6-pair-benzylamino-5-nitro-pyridine-2-yl)-methyl alcohol
With N-2, N-4-dibenzyl-6-bromo-3-nitro-pyridine-2, (315mg 0.87mmol) is suspended in the 20ml tetrahydrofuran (THF) and is cooled to 0 ℃ the 4-diamines, and (40mg 1.1mmol) and with mixture stirred 15 minutes at 0 ℃ to add sodium borohydride then.In water (10ml) and ethyl acetate (10ml), divide mixture molten.Organic layer is separated,, remove in a vacuum to produce the title compound of 315mg yellow solid with dried over mgso and with solvent with the water washing of 15ml salt.
1H NMR (CDCl
3): δ 9.50 (wide unimodal, 1H), 7.40-7.20 (m, 10H), 5.85 (s, 1H), 4.59 (d, 2H), 4.45 (d, 2H), 4.35 (s, 2H); LRMS (ES
+) m/z[MH]
+
Preparation 51
N-2, N-4-dibenzyl-6-brooethyl-3-nitro-pyridine-2,4-diamines
With (4,6-pair-benzylamino-5-nitro-pyridine-2-yl)-methyl alcohol (300mg, 0.82mmol) be dissolved in the 20ml methylene dichloride and be cooled to 0 ℃, add triphenylphosphine (237mg then successively, 0.91mmol), N-bromosuccinimide (161mg, 0.82mmol), and mixture stirred 30 minutes at 0 ℃, heat to room temperature then and stirred 2 hours.Remove solvent in a vacuum, use 20% ethyl acetate in the pentane, by the thick resistates of silica gel column chromatography purifying to produce the title compound of 220mg yellow solid.
1H NMR (CDCl
3): δ 9.59 (wide unimodal, 1H), 9.40 (wide unimodal, 1H), 7.40-7.20 (m, 10H), 6.15 (s, 1H), 4.80 (d, 2H), 4.55 (d, 2H), 4.15 (s, 2H); LRMS (ES
+) m/z 427,429[MH]
+
Preparation 52
N-2, N-4-dibenzyl-6-methoxymethyl-3-nitro-pyridine-2,4-diamines
With N-2, N-4-dibenzyl-6-brooethyl-3-nitro-pyridine-2, (100mg 0.23mmol) is dissolved in the 10ml methyl alcohol 4-diamines, and (25mg 0.46mmol), spends the night 60 ℃ of stirrings then to add sodium methylate then.Solvent is removed in a vacuum and in 10ml methylene dichloride and 10ml water, divide crude product molten.Organic layer is separated, remove in a vacuum to produce the title compound of 80mg yellow solid with dried over mgso and with solvent.
1H NMR (CDCl
3): δ 9.59 (wide unimodal, 1H), 9.40 (wide unimodal, 1H), 7.40-7.20 (m, 10H), 6.20 (s, 1H), 4.80 (d, 2H), 4.55 (d, 2H), 4.25 (s, 2H), 3.35 (s, 3H); LRMS (ES
+) m/z 379[MH]
+
Preparation 53
N-2, N-4-dibenzyl-3-nitro-6-pyrazine-2-base-pyridine-2,4-diamines
With N-2, N-4-dibenzyl-6-bromo-3-nitro-pyridine-2,4-diamines (100mg/0.242mmol), 2-three-normal-butyl stannane base pyrazine (116mg/0.315mmol), acid chloride (15mg) and triphenylphosphine (20mg) be dissolved in the toluene (2ml) and in BiotageInitiator, at 130 ℃ through microwave irradiation 25 minutes.In 2 above occasions according to identical scale reaction repeated.Three kinds of reactants are merged, with EtOAc (10ml) dilution, water (5ml) washing and vacuum concentration.Use the 10:1 pentane: the EtOAc wash-out, produce the title compound (105mg) of yellow solid by the column chromatography purifying.
1H NMR (CDCl3,400MHz) δ 4.60-4.65 (d, 2H), 4.90-4.95 (d, 2H), 7.20-7.40 (multiplet, 10H), 8.55-8.60 (multiplet, 2H), 9.40-9.50 (multiplet, 2H), 9.60 (multiplet, 1H); LRMS (ESCI) m/z 413[MH]
+
Preparation 54
N-2, N-4-dibenzyl-6-pyrazine-2-base-pyridine-2,3,4-triamine
With N-2, N-4-dibenzyl-3-nitro-6-pyrazine-2-base-pyridine-2,4-diamines (105mg/0.255mmol) are dissolved among MeOH (20ml)/THF (20ml).Add Raney nickel (30mg) and at room temperature, under 80psi hydrogen, placed 5 hours with reactant.With diatomite filtration and vacuum concentration to produce light green oily title compound (95mg); LRMS (ESCI) m/z 383[MH]
+, 381[MH]
-
Preparation 55
6-allyl group-N2, N4-dibenzyl-3-nitro-pyridine-2,4-diamines
With N
*2
*, N
*4
*-dibenzyl-6-bromo-3-nitro-pyridine-2, the 4-diamines (1g 2.4mmol) stirs in anhydrous tetrahydro furan (20ml) and solution is outgased with nitrogen, add again acid chloride (109mg, 0.48mmol) and allyl tributyltin (1.1ml, 3.6mmol).With the reaction mixture degassing 10 minutes, suspension was heated 16 hours at 80 ℃.Suspension is cooled to envrionment temperature, and vacuum concentration also use pentane: EtOAc 9:1 wash-out, by silicon-dioxide column chromatography direct purification, with the title compound (696mg, 77%) of generation yellow solid.
1H?NMR(CDCl
3)δ?3.23-3.25(d，2H)，4.47-4.49(d，2H)，4.81-4.82(d，2H)，5.07-5.14(m，2H)，5.89-5.99(m，1H)，7.29-7.40(m，11H)；LRMS(ES)m/z?375[MH]
+
Preparation 56
(4,6-pair-benzylamino-5-nitro-pyridine-2-yl)-acetaldehyde
With 6-allyl group-N2, N4-dibenzyl-3-nitro-pyridine-2, (1.0g 2.7mmol) is suspended in the mixture of 15ml tetrahydrofuran (THF) and 30ml water the 4-diamines.Add potassium osmate (148mg, 0.4mmol) and sodium periodate (1.17g, 5.4mmol) after, with solution vigorous stirring 30 minutes at room temperature.Be added into ethyl acetate (20ml) in the reaction mixture and divide each molten mutually, with the organic extract dried over mgso, vacuum concentration and with 100% EtOAc wash-out, pass through the silica column chromatography purification, to produce 3-(4,6-pair-benzylamino-5-nitro-pyridine-2-yl)-propane-1,2-glycol (992mg, 91%).With the intermediate glycol in 20ml acetone, (1.17g 5.5mmol) exists down and stirs at sodium periodate.Behind the 2h, solution is divided molten between EtOAc and water, the organic extract drying (is used MgSO
4) and concentrate to produce orange oily title compound (962mg, 96%).
1H?NMR(CDCl
3)δ?3.49(d，2H)，4.49-4.50(d，2H)，4.65-4.66(d，2H)，7.52-7.90(m，11H)，10.03(s，1H)；
LCMS(APCI+)
RT@3.74min，m/z?409[MH]
+
Preparation 57
2-(4,6-couple-benzylamino-5-nitro-pyridine-2-yl)-ethanol
With (4,6-pair-benzylamino-5-nitro-pyridine-2-yl)-(250mg 0.66mmol) places the 15ml methylene dichloride to stir to acetaldehyde.(38mg stirs at ambient temperature 0.99mmol) and with solution and to spend the night to add sodium borohydride.Reaction mixture is divided molten between DCM and water, organism with dried over mgso and concentrate to produce thick solid, use pentane: EtOAc 4:1-1:1 wash-out, by the title compound (134mg, 53%) of silica column chromatogram purification with the generation yellow solid.
1H?NMR(CDCl
3)δ?2.68-2.70(t，2H)，3.83-3.86(t，2H)，4.49-4.51(d，2H)，4.72-4.74(d，2H)，5.86(s，1H)，7.29-7.38(m，10H)，9.50-9.54(bd，2H)；LRMS(ES)m/z?379[MH]
+
Preparation 58
N2, N4-dibenzyl-6-(2-methoxyl group-ethyl)-3-nitro-pyridine-2,4-diamines
(4,6-pair-benzylamino-5-nitro-pyridine-2-yl)-(134mg, (59 μ l are cooled to 5 ℃ in mixture 0.43mmol) and with solution to ethanol in ice bath with triethylamine 35mmol) to be suspended in methylene dichloride (15ml) with 2-.(33 μ 1 0.43mmol) and with reaction mixture stirred 1 hour at ambient temperature to add methylsulfonyl chloride.Add 10mlDCM again, with organism with 2 * K
2CO
3(10% aqueous solution) washing, dry and concentrated to produce thick oil.The intermediate mesylate is suspended in the acetone (20ml), and (96mg 1.7mmol), heats mixture 1 hour under refluxing to add sodium methylate.Remove residual solvent in a vacuum, add DCM and with solution with 2 * H
2The O washing.With the organism MgSO that is merged
4Drying, concentrate and with 8:1-4:1 Pent:EtOAc wash-out, by the silica column chromatography purification with generation yellow oily title compound (68mg, 47%).
1H?NMR(CDCl
3)δ?2.70-2.73(t，2H)，3.26(s，3H)，3.64-3.67(t，2H)，4.49-4.50(d，2H)，4.81-4.82(d，2H)，5.91(s，1H)，7.29-7.39(m，10H)，9.40-9.48(bd，2H)；LRMS(ES)m/z?393[MH]
+
Preparation 59
N
*2
*, N
*4
*-dibenzyl-6-(2-methoxyl group-ethyl)-pyridine-2,3, (20wt% 13mg) exists down, with N the 3-triamine at Raney nickel
*2
*, N
*4
*-dibenzyl-6-(2-methoxyl group-ethyl)-3-nitro-pyridine-2, (65mg 0.17mmol) places THF (10ml) to stir to the 4-diamines.With mixture at room temperature, at 60psi H
2Under stirred 2 hours, filter with the Arbocel pad then, wash with 2 * THF.To produce brown oily title compound (47mg, 78%), it can be directly used in next step and need not to be further purified with the filtrate vacuum concentration; LRMS (ES) m/z363[MH]
+
Preparation 60
1-benzyl-4-benzylamino-6-(2-methoxyl group-ethyl)-1,3-dihydro-imidazol-be [4,5-c] pyridin-2-ones also
With N
*2
*, N
*4
*-dibenzyl-6-(2-methoxyl group-ethyl)-pyridine-2,3, (47mg 0.13mmol) places acetonitrile (5ml) to stir to the 3-triamine.Add N, (105mg 0.65mmol) and with mixture heated 16 hours under refluxing the N-carbonyl dimidazoles.With solution for vacuum concentration and the light brown solid title compound (32mg, 64%) that exists as 3:2 mixture with generation with 100% DCM to 96:4 wash-out, by silicon-dioxide column chromatography direct purification with isomer 1-deazapurine; LRMS (ES) m/z 389[MH]
+
Preparation 61
N2, N4-dibenzyl-6-[2-(2-methoxyl group-ethylamino)-ethyl]-3-nitro-pyridine-2, the 4-diamines
With N
*2
*, N
*4
*-dibenzyl-3-nitro-6-vinyl-pyridine-2, (50mg 0.14mmol) is suspended in 2-methoxyl group-ethamine (1ml) and mixture was refluxed 1 hour the 4-diamines.Remove excess reagent in a vacuum, resistates is dissolved among the DCM (10ml), with 2 * H
2The O washing, dry and concentrated.With DCM:MeOH 92:8 wash-out, by the thick material of silica column chromatography purification to produce yellow oily title compound (58mg, 96%).
1H?NMR(CDCl
3)δ?2.75-2.80(m，4H)，2.96-3.00(t，2H)，3.29(s，3H)，3.48-3.51(t，2H)，4.48-4.49(d，2H)，4.76-4.78(d，2H)，5.87(s，1H)，7.27-7.40(m，10H)，9.41-9.51(dt，2H)；LRMS(ES)m/z?436[MH]
+
Preparation 62
[2-(4,6-couple-benzylamino-5-nitro-pyridine-2-yl)-ethyl]-(2-methoxyl group-ethyl)-t-butyl carbamate
With N
*2
*, N
*4
*-dibenzyl-6-[2-(2-methoxyl group-ethylamino)-ethyl]-3-nitro-pyridine-2,4-diamines (150mg, 0.34mmol) be suspended among the DCM (10ml) and with solution and be cooled to 0 ℃, (95 μ l 0.41mmol) dropwise add as the solution in 5ml DCM with the boc acid anhydrides again.Mixture is heated to room temperature, after 1 hour, use 10ml H
2The O quenching.Dry and vacuum concentration is to produce yellow oily title compound (170mg, 92%) with organic extract.
1H?NMR(CDCl
3)δ?1.41(s，9H)，2.68(t，2H)，3.30(s，3H)，3.42(bs，2H)，3.50(m，4H)，4.47-4.48(d，2H)，4.80-4.81(d，2H)，5.82(s，1H)，7.24-7.39(m，10H)；LRMS(ES)m/z?536[MH]
+
Preparation 63
N2, N4-dibenzyl-3-nitro-6-oxazole-2-base-pyridine-2,4-diamines
-78 ℃ (dry ice/acetone batch), with butyllithium (12.8ml, 20.5mmol) dropwise Tian Jia (1.13ml 17.1mmol) in the solution that is stirred in anhydrous THF (20ml), keeps adding speed slowly so that temperature of reaction is no more than-60 ℃ Zhi oxazole.With solution stirring 10 minutes, dropwise add zinc chloride (5.00g, 36.7mmol) solution in THF (30ml) in this temperature then.Solution was stirred 15 minutes at-78 ℃, remove cooling bath then, and reaction mixture is heated to room temperature.
With syringe be added into the aliquot sample (19ml) of reaction mixture pre-sealed and by the microwave bottle of purging with nitrogen gas (Biotage, 10-20ml) in, this bottle contains N
*2
*, N
*4
*-dibenzyl-6-bromo-3-nitro-pyridine-2, the 4-diamines (1.11g, 2.68mmol) and two (triphenylphosphine) palladium chlorides (373mg, 0.53mmol).Should the bottle under microwave irradiation (Biotage Initiator 8), 130 ℃ the heating 15 minutes.With the reaction mixture vacuum concentration, between 2-methyl THF (80ml) and saturated ammonium chloride solution (80ml), divide molten then.Mixture is filtered, change in the separating funnel then.Each layer separated, use more 2-methyl THF (50ml) extraction water solution then.The organism drying that is merged (is used MgSO
4) and evaporation.The gained brown solid is ground with EtOAc and, wash to produce the product (1.03g, 96%) of brown solid with EtOAc then by solid collected by filtration.
1H?NMR(CDCl3)δ?4.59(d，J＝5.47Hz，2H)4.91(d，J＝5.47Hz，2H)6.93(s，1H)7.21-7.47(m，11H)7.78(s，1H)9.31-9.44(m，1H)9.54-9.63(m，1H)；LRMS(ES
+)m/z?402[MH]
+
Preparation 64
N2, N4-dibenzyl-6-oxazole-2-base-pyridine-2,3,4-triamine
With N
*2
*, N
*4
*-dibenzyl-3-nitro-6-oxazole-2-base-pyridine-2, (1.02g 2.54mmol) is dissolved among the THF (60ml) the 4-diamines, adds MeOH (60ml) then.(210mg, 0.25mmol) hydrogenation is 1 hour through Raney nickel under nitrogen atmosphere (80psi) with solution.Reaction mixture is filtered with Celite pad, evaporate then to produce brown colloidal title compound (944mg, 100%).Consider that for stability it need not to be further purified just and can use.
LCMS?R
t＝2.41m/z?372[MH]
+
Preparation 65
N2, N4-dibenzyl-6-(1-methyl isophthalic acid H-imidazoles-2-yl)-3-nitro-pyridine-2,4-diamines
(0.728ml 9.18mmol) is dissolved among the anhydrous THF (25ml), then solution is cooled to-15 ℃ (ice/salt bath) with the N-Methylimidazole.(6.31ml, 10.1mmol) n-Butyl Lithium in dropwise is added into (color is by the colourless yellow that becomes) in the solution with hexane.Solution was stirred 1 hour at-15 ℃, dropwise add Zinc Chloride Anhydrous (5.00g, 36.7mmol) solution in anhydrous THF (35ml) then.Solution was stirred 1 hour at-15 ℃, slowly heat then, stirred then more than 1 hour to room temperature.
Be added into the aliquot sample (16ml) of this solution pre-sealed and by the microwave bottle of purging with nitrogen gas (Biotage, 2.0-5.0ml) in, this bottle contains N
*2
*, N
*4
*-dibenzyl-6-bromo-3-nitro-pyridine-2, the 4-diamines (400mg, 0.968mmol) and two (triphenylphosphine) palladium chlorides (136mg, 0.193mmol).With bottle 130 ℃, in down heating 15 minutes of microwave irradiation (Biotage Initiator8).With the reaction mixture vacuum concentration.Between EtOAc (15ml) and 2M ammonia solution (15ml), divide resistates molten.Use separating funnel most of water to be removed (a small amount of emulsion is arranged between each layer).Organic layer is used more 2M ammonia solution (15ml), salt solution (15ml) washing successively, and drying (is used MgSO then
4) and evaporation.(12g carries out column chromatography on Redisep) at Isco Companion silica column with crude product.Use EtOAc: the heptane wash-out, make gradient increase to 60:40 linearly through 8 column volumes by 20:80, make 4 column volumes at degree such as 60:40 then.Required elution fraction merged and evaporation to produce the title compound (240mg, 60%) of yellow solid.
1H?NMR(CD3OD)δ3.88(s，3H)4.67(d，J＝5.48Hz，2H)4.83(d，J＝5.48Hz，2H)6.92(d，J＝1.17Hz，1H)7.14(d，J＝1.17Hz，1H)7.17(s，1H)7.26-7.42(m，10H)9.43-9.66(m，2H)；LRMS(ES
+)m/z?415[MH]
+
Preparation 66
N2, N4-dibenzyl-6-(1-methyl isophthalic acid H-imidazoles-2-yl)-pyridine-2,3,4-triamine
With N
*2
*, N
*4
*-dibenzyl-6-(1-methyl isophthalic acid H-imidazoles-2-yl)-3-nitro-pyridine-2, (0.235g 0.567mmol) is dissolved among the THF (10ml) the 4-diamines, adds MeOH (10ml) then.(0.050g, 0.58mmol) hydrogenation is 1 hour through Raney nickel under nitrogen atmosphere (80psi) with solution.Reaction mixture is filtered with Celite pad, evaporate then to produce light green solid title compound (218mg, 100%).Consider that for stability it need not to be further purified just and can use.
LCMS?R
t＝2.22m/z?385[MH]
+
Preparation 67
(2,6-two bromo-3-nitro-pyridin-4-yls)-urethanum
At 0 ℃, the solution of Vinyl chloroformate (5.96g) in anhydrous 2-methyl THF (50ml) dropwise is added into 2, in 6-two bromo-3-nitros-pyridin-4-yl amine (15.00g) and the solution of triethylamine (10.1g) in anhydrous 2-methyl THF (100ml), keep adding speed and be no more than 5 ℃ so that temperature of reaction rises.Reaction mixture is heated to room temperature, under nitrogen atmosphere, stirred 1 hour then.Add a Vinyl chloroformate (0.54g) again and with mixture restir 1 hour.Add water (50ml) and each layer separated.Water layer (is used MgSO with EtOAc (50ml) extraction and with the organism drying that is merged
4) and be evaporated to brown solid.With this solid silicon-dioxide (～19g) go up preadsorption, use EtOAc then: the heptane wash-out, (330g carries out column chromatography on Redisep) at Isco Companion silica column.The gradient that makes 1 column volume (CV) increases to 30:70 through 6 CV by 10:90 then linearly at degree such as 10:90.Produce light yellow foaming solid title compound (12.6g) thus.
1H NMR (400MHz, and the δ ppm 1.36 of chloroform-d) (t, J=7.10Hz, 3H), 4.26 (q ,=7.10Hz, 2 H), 7.95 (br, s, 1 H), 8.59 (s, 1 H), LCMS R
t=3.22m/z368,370,372[MH]
+
Preparation 68
(2,6-two bromo-3-nitro-pyridin-4-yls)-(6-methyl-pyridin-3-yl methyl)-urethanum
Salt of wormwood (7.95g) is added in (2,6-two bromo-3-nitro-pyridin-4-yls) urethanum (10.62g) solution that is stirred in acetone (100ml).Add 5-(chloromethyl)-2-picoline (4.89g), sodium iodide (5.18g) then successively.Mixture was stirred 18 hours under nitrogen atmosphere.Reaction mixture is filtered, and vacuum concentration divides molten then between ethyl acetate (100ml) and water (100ml).The organism drying (is used MgSO
4) and be evaporated to dark violet coloring agent, use EtOAc: the heptane wash-out, (330g carries out column chromatography on Redisep), increases to 80:20 through 6 column volume gradients linearly by 40:60 at Isco Companion silica column.Form green gluey title compound (8.5g) thus, it is left standstill be cured as the light green solid.
1H NMR (400MHz, δ ppm 1.24 (t, the J=7.10Hz of chloroform-d), 3 H) 2.59 (s, 3 H), 4.19 (q, J=7.10Hz, 2 H) 4.79 (s, 2 H) 7.17 (s, 1 H), 7.19 (d, J=8.20Hz, 1 H) 7.57 (dd, J=8.20,2.34Hz, 1 H) and 8.38 (d, J=2.34Hz, 1 H), LCMSR
t=2.44m/z 473,475,477[MH]
+
Preparation 69
(2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-yl methyl)-urethanum
(2,6-two bromo-3-nitro-pyridin-4-yls)-(6-methyl-pyridin-3-yl methyl)-urethanum (6.00g) is dissolved in the 2-methyltetrahydrofuran (60ml).With solution equivalent branch go into 3 sealable containers (Biotage, 10-20ml) in.With ammonia soln (0.88gcm
-3, 20ml) be added in each bottle (60ml altogether).With bottle sealing, then with biphasic mixture at room temperature vigorous stirring spend the night.Three kinds of reaction mixtures are merged and change in the separating funnel.Add ethyl acetate (120ml) and water (120ml).To respectively be separated, then organism be washed with salt solution (100ml).The organism drying (is used MgSO
4), be evaporated to brown size then.This glue is dissolved in the ether again, evaporates then to form yellow foaming solid title compound (5.4g).
1H NMR (400MHz, δ ppm 1.16-1.27 (m, 3 H) 2.58 (s, 3 H) 4.10-4.21 (m, the 2 H) 4.87 (s of chloroform-d), 2 H) 6.34 (s, 2 H) 6.61 (s, 1 H) 7.18 (d, J=8.19Hz, 1 H), 7.66 (s, 1 H) 8.41 (d, J=2.34Hz, 1 H), LCMSR
t=1.94m/z 412[MH]
+
Preparation 70
[2-amino-6-(4-methyl-oxazoles-2-yl)-3-nitro-pyridin-4-yl]-(6-methyl-pyridin-3-yl methyl)-urethanum
-78 ℃ (dry ice/acetone batch), butyllithium (1.6M in hexane, 366 μ l) dropwise is added in the solution that is stirred of 4-Jia Ji oxazole (41mg) in THF (0.5ml) in reaction flask.With solution stirring 10 minutes, dropwise add the solution of zinc chloride (199mg) in THF (1ml) in this temperature then.Solution was stirred 15 minutes at-78 ℃, remove cooling bath then and reaction mixture is heated to room temperature.Be added into Ci Xin oxazole solution pre-sealed and by the microwave bottle (Biotage of purging with nitrogen gas with syringe, 0.5-2.0ml) in, this bottle contains (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-yl methyl)-urethanum (100mg) and two (triphenylphosphine) palladium chloride (34mg).Should the bottle under microwave irradiation (BiotageInitiator 8), 60 ℃ the heating 15 minutes.Between ethyl acetate (10ml) and saturated aqueous ammonium chloride (10ml), divide reaction mixture molten then.Each layer separated and with ethyl acetate (10ml) extraction water solution.The organism that is merged is washed with salt solution (10ml), and drying (is used MgSO then
4) and evaporation.With crude product with the eluent ethyl acetate of 4 column volumes (CV), (12g carries out column chromatography on Redisep), makes the methyl alcohol gradient in the ethyl acetate increase to 5% linearly by 0 through 10 CV then at Isco Companion silica column.Form yellow gluey title compound (69mg) thus.
1H NMR (400MHz, δ ppm 1.11-1.25 (m, the 3 H) 2.28 (s of chloroform-d), 3 H) 2.56 (s, 3 H) 4.13-4.23 (m, 2 H), 4.96 (s, 2 H) 6.37 (s, 2 H), 7.16 (d, J=7.80Hz, 1 H) 7.26 (s, 1 H) 7.53 (s, 1 H) 7.65-7.78 (m, 1 H), 8.43 (s, 1 H), LCMS R
t=1.86m/z 413[MH]
+
Preparation 71
5-ethyl-oxazoles
Ethyl-5-Yi Ji oxazole-4-manthanoate (3.5g) is dissolved in the ethanol (45ml), adds the solution of sodium hydroxide (2.07g) in water (18ml).Reactant was at room temperature stirred 16 hours.Reaction mixture reduced be～20ml, add the pH value of concentrated hydrochloric acid then with generation～1-2.With reaction mixture CH
2Cl
23 * 30ml extraction.Merged organic extract is washed with saturated brine, use Na
2SO
4Drying, filtration and evaporation are to produce light yellow solid.This thing is dissolved in the quinoline (3ml), adds 100mg cupric oxide (II).Then with reactant heating (160 ℃ of oil baths) and distill out transparent liquid under decompression a little at～60-70 ℃.Form transparent oily title compound (790mg) thus.
1H NMR (400MHz, the δ ppm 1.2 (t, 3 H) of chloroform-d), 2.6 (q, 2 H), 6.65 (s, 1H), 7.7 (s, 1 H).
Preparation 72
[2-amino-6-(5-ethyl-oxazoles-2-yl)-3-nitro-pyridin-4-yl]-(6-methyl-pyridin-3-yl methyl)-urethanum
Use 5-ethyl-oxazoles (47mg) and (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-yl methyl)-urethanum (100mg), the examples preparation title compound according in the preparation 70 produces yellow gluey product (79mg).
1H NMR (400MHz, δ ppm 1.13-1.25 (m, the 3 H) 1.33 (t of chloroform-d), J=7.61Hz, 3H) 2.56 (s, 3 H), 2.80 (q, J=7.41Hz, 2 H) 4.13-4.22 (m, 2 H) 4.96 (s, 2H) 6.31-6.45 (m, 2 H) 6.97 (s, 1 H) 7.16 (d, J=7.80Hz, 1 H) 7.26 (s, 1H) 7.63-7.79 (m, 1 H) 8.43 (s, 1 H), LCMS R
t=2.16m/z 427[MH]
+
Preparation 73
5-sec.-propyl-oxazoles-4-ethyl formate
0 ℃, under nitrogen atmosphere, isocyano acid B ester (4.52g) dropwise is added in the suspension that is stirred of KOtBu in THF (35ml).After interpolation is finished, the dark brown solution stirring was dropwise added the solution of isobutyryl chloride (2.1ml) in THF (15ml) in 30 minutes then, temperature is maintained at about below 10 ℃.Reactant is stirred 1 hour evaporate to dryness then.Resistates is handled with acetate (1.14ml) and water (25ml), used ether (3 * 30ml) extractions then.With the washing of the ether extract with saturated brine that merged, use dried over sodium sulfate, filter and evaporation producing brown oil, with its with the 1%MeOH wash-out in the methylene dichloride, pass through the column chromatography purifying.Produce colorless oil title compound (1.91g) thus.
1H NMR (400MHz, the δ ppm 1.25 (d, 6 H) of chloroform-d), 1.38 (t, 3 H), 3.8 (m, 1H), 4.35 (q, 2 H), 7.7 (s, 1 H), LRMS m/z (API) 184[MH]
+, 367[2MH]
+
Preparation 74
5-sec.-propyl-oxazoles
5-sec.-propyl-oxazoles-4-ethyl formate (1.89g) is dissolved in the solution of 1N sodium hydroxide (10ml) and ethanol (0.5ml), and mixture was at room temperature stirred 16 hours.Add 1NHCl solution (about 9ml) and mixture is stirred several minutes.The adularescent solid crystal is separated out and is collected by filtering.After the drying, this solid is dissolved in the quinoline (3ml), adds cupric oxide (120mg).Reactant is heated under vacuum, make that oil bath temperature is slow to be increased to～170 ℃.Distill out transparent liquid, produce the mixture of required product and quinoline.Then with this oil low pressure more (～180mBar) and temperature (70 ℃) redistillation down, produce transparent oily title compound (260mg).
1H NMR (400MHz, the δ ppm 1.24 (d, 6 H) of chloroform-d), 2.96 (m, 1 H), 6.7 (s, 1H), 7.7 (s, 1 H)
Preparation 75
[2-amino-6-(5-sec.-propyl-oxazoles-2-yl)-3-nitro-pyridin-4-yl]-(6-methyl-pyridin-3-yl methyl)-urethanum
Use 5-sec.-propyl-oxazoles (54mg) and (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-yl methyl)-urethanum (100mg), examples preparation title compound according in the preparation 70 produces yellow gluey product (48mg).
1H NMR (400MHz, δ ppm 1.13-1.26 (m, the 3 H) 1.34 (d of chloroform-d), J=6.63Hz, 6H) 2.56 (s, 3 H) 3.04-3.15 (m, 1 H) 4.10-4.23 (m, 2 H) 4.96 (s, 2 H) 6.39 (s, 2 H) 6.94 (s, 1 H), 7.16 (d, J=7.80Hz, 1 H) 7.21 (s, 1 H) 7.63-7.76 (m, 1 H), 8.43 (s, 1 H), LCMS R
t=2.30m/z 441[MH]
+
Preparation 76
[2-amino-6-(4,5-dimethyl-oxazoles-2-yl)-3-nitro-pyridin-4-yl]-(6-methyl-pyridin-3-yl methyl)-urethanum
Use 4,5-dimethyl-oxazoles (47mg) and (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-yl methyl)-urethanum (100mg), examples preparation title compound according in the preparation 70 produces yellow gluey product (75mg).
1H NMR (400MHz, δ ppm 1.03-1.26 (m, the 3 H) 2.19 (s of chloroform-d), 3 H) 2.37 (s, 3 H) 2.56 (s, 3 H) 4.09-4.26 (m, 2 H) 4.95 (s, 2 H), 6.40 (s, 2H) 7.16 (d, J=7.80Hz, 1 H) 7.21 (s, 1 H) 7.62-7.83 (m, 1 H), 8.42 (s, 1H), LCMS R
t=2.12m/z 427[MH]
+
Preparation 77
Oxazole-4-base-methyl alcohol
At-78 ℃, through 15 minutes with DIBAL-H (the 1.0M solution of 56ml in toluene) dropwise Tian Jia Zhi oxazole-4-ethyl formate (7.50g, 53.1mmol) solution in THF (140ml).With gained solution-78 ℃ stir added again through 15 minutes then in 30 minutes DIBAL-H (the 1.0M solution of 56ml in toluene, 56.0mmol).Then reactant is slowly heated to room temperature by-78 ℃ and last 16 hours.The gained bright yellow solution is cooled to 0 ℃ and add Na by aliquot in ice bath
2SO
4.10H
2O (15.9g-and the DIBAL-H that is added are equal in weight) (noting: slowly add to prevent heat release) is to impel aluminium salt precipitation.Mixture is heated to room temperature, stir after 90 minutes, the gained suspension is filtered with diatomite layer.With plug of celite with methylene dichloride (3 * 100ml) and methyl alcohol (2 * 100ml) flushings also merge filtrate.Under reduced pressure remove solvent, produce brown oily title compound (4.8g).
1H NMR (400MHz, the δ ppm 4.60 (s, 2 H) of chloroform-d), 7.6 (s, 1 H), 7.9 (s, 1 H)
Preparation 78
4-methoxymethyl-oxazoles
Oxazole-4-base-methyl alcohol (750mg) is dissolved among the anhydrous THF (38ml) and with solution is cooled to 0 ℃.Then through 4 minutes by aliquot add sodium hydride (365mg, 9.1mmol), add finish after, reactant heated to room temperature lasts 30 minutes.Reactant is cooled to 0 ℃ and add methyl tosylate (2.11g) by aliquot again.After add finishing, heat reactant to room temperature and stirred 16 hours.The crude product mixture preadsorption is passed through ISCOcombi-flash chromatography (SiO then on silica gel
2Among the DCM 2 be to the gradient elution of 5% MeOH, 1% NH
3) purifying to be to produce the title compound (473mg) of light yellow liquid.
1H NMR (400MHz, the δ ppm 3.41 (s, 3 H) of chloroform-d), 4.40 (s, 2 H), 7.61 (s, 1H), 7.85 (s, 1 H)
Preparation 79
[2-amino-6-(4-methoxymethyl-oxazoles-2-yl)-3-nitro-pyridin-4-yl]-(6-methyl-pyridin-3-yl methyl)-urethanum
Use 4-methoxymethyl-oxazoles (110mg), (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-yl methyl)-urethanum (200mg) and two (triphenylphosphine) palladium chloride (68mg), examples preparation title compound according in the preparation 70 produces yellow gluey product (107mg).
1H NMR (400MHz, δ ppm 1.11-1.29 (m, the 3 H) 2.54 (s of chloroform-d), 3 H) 3.47 (s, 3 H) 4.09-4.24 (m, 2 H), 4.49 (s, 2 H) 4.96 (s, 2 H), 6.34 (s, 2H) 7.13 (d, J=7.81Hz, 1 H) 7.32 (s, 1 H) 7.63-7.72 (m, 1 H) 7.76 (s, 1H) 8.42 (s, 1 H), LCMS R
t=1.62m/z 443[MH]
+
Preparation 80
(2-amino-3-nitro-6-thiazol-2-yl-pyridin-4-yl)-(6-methyl-pyridin-3-yl methyl)-urethanum
Use thiazole (42mg) and (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-yl methyl)-urethanum (100mg), the examples preparation title compound according in the preparation 70 produces yellow gluey product (79mg).
1H NMR (400MHz, δ ppm 1.06-1.30 (m, the 3 H) 2.56 (s of chloroform-d), 3 H) 4.07-4.25 (m, 2 H) 4.99 (s, 2 H) 6.26 (s, 2 H) 7.16 (d, J=7.80Hz, 1 H), 7.46 (s, 1 H) 7.54 (d, J=3.12Hz, 1 H) 7.64-7.84 (m, 1 H) 7.96 (d, J=3.12Hz, 1 H) 8.35-8.50 (m, 1 H), LCMS R
t=2.11m/z 415[MH]
+
Preparation 81
2-chloro-3-oxo-Valeric acid ethylester
At room temperature SULPHURYL CHLORIDE (6.50ml) dropwise is added in the propionyl ethyl acetate (11.70g) and and stirred 16 hours reactant.Reaction mixture is placed 1 hour to remove the height volatile matter under vacuum, then resistates is distilled under " height " vacuum to produce oil, with oil 75-79 ℃, 6Mbar (=4.5mmHg) distill under the vacuum, thereby produce transparent oily title compound (13.54g).
1H NMR (400MHz, the δ ppm 1.11 (t, 3 H) of chloroform-d), 1.31 (t, 3 H), 2.75 (q, 2H), 4.25 (q, 2 H), 4.80 (s, 1 H)
Preparation 82
4-ethyl-oxazoles-5-ethyl formate
2-chloro-3-oxo-Valeric acid ethylester (13.5g) is dissolved in 95% formic acid of 75ml.Add ammonium formiate (27.6g) and with reactant heating under the reflux temperature, under nitrogen atmosphere 6 hours.After being cooled to room temperature, (3 * 50ml) extract with ether with the reaction mixture evaporation and with resistates.With ether extract water and the salt water washing that is merged, drying (is used MgSO
4), filtration and evaporation are to produce thick oil (9g).With oil CH
2Cl
2/ MeOH 99:1 wash-out, by the silica gel chromatography purifying, produce light brown oily title compound (3.77g).
1H NMR (400MHz, the δ ppm 1.25 (t, 3 H) of chloroform-d), 1.41 (t, 3 H), 2.90 (q, 2H), 4.41 (q, 2 H), 7.85 (s, 1 H)
Preparation 83
4-ethyl-oxazoles-5-formic acid
Place the 1N NaOH (25ml) and the solution of ethanol (1ml) to stir 4-ethyl-oxazoles-5-ethyl formate (4.6g).Then reaction mixture was at room temperature stirred 16 hours.Add ether (25ml), then water layer is separated and with 1N HCl (26ml) acidifying.Form yellow solid by filtering to collect, water, Skellysolve A washing then, the title compound (2.6g) of generation white solid.
1H NMR (400MHz, the δ ppm 1.30 (t, 3 H) of chloroform-d), 2.95 (q, 2 H), 8.0 (s, 1H)
Preparation 84
4-ethyl-oxazoles
4-ethyl-oxazoles-5-formic acid (1.2g) is dissolved in the quinoline (3ml), adds CuO (50mg).Reactant is heated to 215-20 ℃ then, collects colourless cut, thereby produce muddy oily title compound (621mg).
1H NMR (400MHz, the δ ppm 1.21 (t, 3 H) of chloroform-d), 2.55 (q, 2 H), 7.4 (s, 1H), 7.8 (s, 1 H)
Preparation 85
[2-amino-6-(4-ethyl-oxazoles-2-yl)-3-nitro-pyridin-4-yl]-(6-methyl-pyridin-3-yl methyl)-urethanum
Use 4-ethyl-oxazoles (47mg) and (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-yl methyl)-urethanum (100mg), the examples preparation title compound according in the preparation 70 produces yellow gluey product (74mg).
1H NMR (400MHz, δ ppm 1.09-1.22 (m, the 3 H) 1.25 (t of chloroform-d), J=7.42Hz, 3H) 2.50 (s, 3 H) 2.56-2.68 (m, 2 H) 4.04-4.21 (m, 2 H) 4.92 (s, 2 H) 6.33 (s, 2 H) 7.10 (d, J=7.81Hz, 1 H), 7.23 (s, 1 H) 7.46-7.49 (m, 1 H) 7.59-7.69 (m, 1 H) 8.39 (s, 1 H), LCMS R
t=2.07m/z 427[MH]
+
Preparation 86
1-bromo-3-methyl-Ding-2-ketone
The solution of 3-methyl-2-butanone (5g) in methyl alcohol (55ml) is cooled to-30 ℃.Dropwise add bromine (2.97 μ l) then,, then reactant is heated to room temperature and stirred 3.5 hours in case add to finish.Reactant is poured in the entry (100ml) then, and (2 * 100ml) extractions (are used MgSO with the extract drying that is merged with ether
4), filter and concentrate.The oily resistates is left standstill the back form two-layer different oil reservoir, with its separation.Keep bottom, thereby produce light yellow oily title compound (5.14g).
1H NMR (400MHz, the δ ppm 1.15 (d, 6 H) of chloroform-d), 2.95 (m, 1 H), 3.95 (s, 1H)
Preparation 87
4-sec.-propyl-oxazoles
1-bromo-3-methyl-Ding-2-ketone (1.0g) is added in the methane amide (3.0ml) and reaction mixture is heated to 110 ℃ last 6 hours.After being cooled to room temperature, reaction mixture with 40% potassium hydroxide solution (10ml) dilution, is stirred several minutes and uses ether (3 * 10ml) extractions then.The ether extract is merged and evaporation modestly.Gained brown machine oil ground with Skellysolve A and with the solvent decant.Repeat this method (* 2), evaporation of residual pentane then is to produce light brown oily title compound (65mg).
1H NMR (400MHz, the δ ppm 1.30 (d, 6 H) of chloroform-d), 2.85 (m, 1 H), 4.41 (q, 2H), 7.35 (s, 1 H), 7.80 (s, 1 H)
Preparation 88
[2-amino-6-(4-sec.-propyl-oxazoles-2-yl)-3-nitro-pyridin-4-yl]-(6-methyl-pyridin-3-yl methyl)-urethanum
Use 4-sec.-propyl-oxazoles (54mg) and (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-yl methyl)-urethanum (100mg), examples preparation title compound according in the preparation 70 produces yellow gluey product (71mg).
1H NMR (400MHz, δ ppm 1.10-1.22 (m, the 3 H) 1.27 (d of chloroform-d), J=6.64Hz, 6H) 2.50 (s, 3 H) 2.82-2.97 (m, 1 H) 3.96-4.27 (m, 2 H) 4.92 (s, 2 H) 6.34 (s, 2 H) 7.10 (d, J=7.81Hz, 1 H), 7.23 (s, 1 H) 7.45 (s, 1 H) 7.59-7.70 (m, 1 H), 8.39 (s, 1 H), LCMS R
t=2.23m/z 441[MH]
+
Preparation 89
Benzyl-(2,6-two bromo-3-nitro-pyridin-4-yls)-urethanum
Salt of wormwood (5.57g) is added in (2,6-two bromo-3-nitro-pyridin-4-yls)-solution that is stirred of urethanum (7.44g) in acetone (100ml), adds bromotoluene (2.87ml), sodium iodide (3.63g) then successively.Mixture was stirred 36 hours under nitrogen atmosphere.Then reaction mixture is filtered to remove sedimentary white solid, vacuum concentration divides molten then between ethyl acetate (100ml) and water (100ml).The organism drying (is used MgSO
4) and be evaporated to yellow oil.This thick oil is adsorbed in uses EtOAc on the silica gel then: the heptane wash-out, (gradient increases to 50:50 linearly by 10:90 for 80g, Redisep) purification by chromatography by Isco Companion silica column.Produce yellow oily title compound (7.50g) thus.
1H NMR (400MHz, the δ ppm 1.20 (t, 3 H) of chloroform-d), 4.18 (q, 2 H), 4.8 (br, s, 2H), 7.0 (s, 1 H), 7.20 (m, 2 H), 7.35 (m, 3 H), LRMS m/z (API) 458,460,462[MH]
+
Preparation 90
(2-amino-6-bromo-3-nitro-pyridin-4-yl)-benzyl-urethanum
Benzyl-(2,6-two bromo-3-nitro-pyridin-4-yls)-urethanum (7.50g) is dissolved in 2-methyl-tetrahydrofuran (THF) (15ml) and with this solution and is positioned in the sealable container.Add concentrated ammonia solution (15ml) then with the bottle sealing, and with biphasic mixture vigorous stirring 36 hours at room temperature.Then reaction mixture is changed in the separating funnel, add ethyl acetate (120ml) and water (120ml).To respectively be separated, and then organism be washed with salt solution (100ml), drying (is used MgSO
4) and be evaporated to yellow oil.After leaving standstill, crystallization goes out yellow solid.This thing is collected and washed with pentane by filtering, produce the title compound (6.64g) of yellow solid.
1H NMR (400MHz, the δ ppm1.21 of chloroform-d) (t, 3H), 4.19 (q, 2H), 4.82 (br, s, 2H), 6.25 (br, s, 2H), 6.55 (s, 1H), 7.20-7.35 (m, 5H), LRMS m/z (API) 395,397[MH]
+
Preparation 91
[2-amino-6-(4-methoxymethyl-oxazoles-2-yl)-3-nitro-pyridin-4-yl]-benzyl-urethanum
Use 4-methoxymethyl-oxazoles (114mg), (2-amino-6-bromo-3-nitro-pyridin-4-yl)-benzyl-urethanum (200mg) and two (triphenylphosphine) palladium chloride (71mg), examples preparation title compound according in the preparation 70 produces yellow gluey product (160mg).
1H NMR (400MHz, δ ppm 1.20 (t, J=7.03Hz, 3 H) 3.46 (s, 3 H) 4.12-4.22 (m, 2 H) 4.47 (s, 2 H) 4.92-5.03 (m, 2 H) 6.32 (s, the 2 H) 7.28-7.35 (m, 6 H) 7.74 (s, 1 H) of chloroform-d), LCMS R
t=3.08m/z 428[MH]
+
Preparation 92
Dimethyl-oxazoles-4-ylmethyl-amine
Through 5 minutes with thionyl chloride (5.51ml) dropwise Tian Jia Zhi the cold soln (0 ℃) of oxazole-4-base-methyl alcohol (1.51g) in methylene dichloride (50ml).The gained turbid solution at room temperature stirred be heated to backflow in 5 minutes then.After the heating, solution becomes gets transparent and is deep yellow.After 10 minutes, solution is cooled to room temperature also under reduced pressure removes excessive thionyl chloride and solvent to produce the corresponding chlorinated compounds under reflux temperature, it need not to be further purified just and can use.In ice bath, dimethylamine (the 2.0M solution of 38ml in THF) is cooled to 0 ℃ and added the solution of this muriate (1.74g) in anhydrous THF (50ml) by aliquot through 10 minutes.Make gained suspension reaction 16 hours then.Remove solvent to produce dun/black solid, then with its preadsorption on silicon-dioxide and with 5 to 15%MeOH wash-outs in the methylene dichloride with 10% NH3, by the ISCO combi-purification by flash chromatography on the silica gel.Produce the sticking oily title compound (335mg) of dun thus.
1H NMR (400MHz, the δ ppm 2.35 (s, 6 H) of chloroform-d), 3.50 (s, 2 H), 7.62 (s, 1H), 7.85 (s, 1 H)
Preparation 93
[2-amino-6-(4-dimethylaminomethyl-oxazoles-2-yl)-3-nitro-pyridin-4-yl]-benzyl-urethanum
Use dimethyl-oxazoles-4-ylmethyl-amine (128mg), (2-amino-6-bromo-3-nitro-pyridin-4-yl)-benzyl-urethanum (200mg) and two (triphenylphosphine) palladium chloride (71mg), examples preparation title compound according in the preparation 70 produces yellow gluey product (99mg).
1H NMR (400MHz, δ ppm 1.20 (t, J=7.03Hz, 3 H) 2.32 (s, 6 H) 3.49 (s, 2 H) 4.13-4.23 (m, 2 H) 4.92-5.03 (m, 2 H) 6.33 (s, the 2 H) 7.28-7.36 (m, 6 H) 7.68 (s, 1 H) of chloroform-d), LCMS R
t=1.86m/z 441[MH]
+
Preparation 94
2-amino-3-nitro-6-[1-(2-TMS-ethoxyl methyl)-1H-imidazoles-2-yl]-pyridin-4-yl }-benzyl-urethanum
Use 1-(2-TMS-ethoxyl methyl)-1H-imidazoles (201mg), (2-amino-6-bromo-3-nitro-pyridin-4-yl)-benzyl-urethanum (200mg) and two (triphenylphosphine) palladium chloride (71mg), examples preparation title compound according in the preparation 70 produces yellow gluey product (174mg).
1H NMR (400MHz, δ ppm-0.04 (s, the 9 H) 0.87-0.94 (m of chloroform-d), 2 H) 1.19 (t, J=7.03Hz, 3 H) 3.49-3.59 (m, 2 H) 4.10-4.22 (m, 2 H) 4.98 (s, 2 H) 5.93 (s, 2 H) 6.18 (s, 2 H) 7.18 (s, 1 H) 7.23 (s, 1 H) 7.28-7.38 (m, 5 H) 7.53 (s, 1 H)
Preparation 95
(2-amino-6-methyl-monosilane base-3-nitro-pyridin-4-yl)-benzyl-urethanum
(3:1 is 4ml) in the suspension that is stirred in methyl alcohol: THF sodium methyl mercaptide (180mg) dropwise to be added into (2-amino-6-chloro-3-nitro-pyridin-4-yl)-benzyl-urethanum (300mg).Mixture is sealed in the reaction flask, at room temperature stirred then 2 hours.Reaction mixture is diluted with methyl alcohol, then directly preadsorption on silica gel.With thick material EtOAc: the heptane wash-out, (12g Redisep) carries out column chromatography, increases to 50:50 through 6 column volume gradients by the 30:70 linearity by Isco Companion silica column.Required elution fraction merged and evaporation to produce yellow gluey title compound (297mg).
1H NMR (400MHz, methyl alcohol-d
4) δ ppm 1.04-1.22 (m, 3 H) 2.43 (s, 3 H) 3.96-4.24 (m, 2 H) 4.35-4.55 (m, 1 H) 5.03-5.17 (m, 1 H) 6.13 (s, 2 H) 7.12-7.47 (m, 6 H), LCMS R
t=3.29m/z 363[MH]
+
Preparation 96
[2-amino-6-(2-fluoro-phenyl)-3-nitro-pyridin-4-yl]-benzyl-urethanum
2-fluoro-phenyl-boron dihydroxide (34mg), thiophene-2-carboxylic acid copper (I) (79mg) are reached two (triphenylphosphine) palladium chlorides (19mg) to be added in the microwave bottle.Then with bottle purging with nitrogen gas and sealing.Then (2-amino-6-methylthio group-3-nitro-pyridin-4-yl)-solution of benzyl-urethanum (42mg) in anhydrous THF (0.5ml) is added in this bottle, and with mixture under microwave irradiation (CEM), 100 ℃ the heating 10 minutes.Then reaction mixture is diluted with methyl alcohol, with Arbocel, in cationic exchange filter cylinder (Bakerbond, the bonding phase of sulfonic acid, 1g) last direct filtration.(2 * 5ml) washings are to remove impurity then by (2M, 5ml) wash-out disengages product with the ammonia in the methyl alcohol with methyl alcohol with filter cylinder.Required elution fraction merged and evaporation to produce yellow gluey title compound (31mg).
1H NMR (400MHz, δ ppm 1.03-1.31 (m, 3 H) 4.16 (s, 2 H) 4.91 (br.s., the 1 H) 6.20 (s of chloroform-d), 2 H) 6.95 (s, 1 H) 7.07 (dd, J=11.71,8.20Hz, 1H) 7.16-7.22 (m, 1H) 7.21-7.42 (m, 7H) 7.84-7.93 (m, 1H), LCMSR
t=3.50m/z 411[MH]
+
Preparation 97
[2-amino-6-(3-fluoro-phenyl)-3-nitro-pyridin-4-yl]-benzyl-urethanum
Use 3-fluoro-phenyl-boron dihydroxide, according to the examples preparation title compound in the preparation 96, produce yellow gluey product (18mg).
1H NMR (400MHz, δ ppm 1.08-1.35 (m, 3 H) 4.19 (s, 2 H) 5.29 (br.s., 2 H) 6.29 (s, 2 H) 6.66 (s, 1 H) 7.04-7.17 (m, 1 H) 7.28-7.40 (m, the 7 H) 7.43-7.55 (m, 1 H) of chloroform-d), LCMS R
t=3.53m/z 411[MH]
+
Preparation 98
[2-amino-6-(4-fluoro-phenyl)-3-nitro-pyridin-4-yl]-benzyl-urethanum
Use 4-fluoro-phenyl-boron dihydroxide, according to the examples preparation title compound in the preparation 96, produce yellow gluey product (28mg).
1H NMR (400MHz, δ ppm 1.19 (s, 3 H) 4.19 (s, 2 H) 5.33 (br.s., 2 H) 6.31 (s, 2 H) 6.63 (s, 1 H) 7.03-7.13 (m, 2 H) 7.29-7.38 (m, 5H) 7.68-7.77 (m, 2 H), the LCMS R of chloroform-d)
t=3.52m/z 411[MH]
+
Preparation 99
(2-amino-6-methoxyl group-3-nitro-pyridin-4-yl)-benzyl-urethanum
Modestly sodium hydride (9mg) is dissolved in the methyl alcohol (0.5ml) and at room temperature this solution is added into then in (2-amino-6-bromo-3-nitro-pyridin-4-yl)-solution of benzyl-urethanum (50mg) in THF (0.5ml).Reactant was stirred 2 hours under nitrogen atmosphere, then directly with the solution preadsorption on silica gel.With the mixture ethyl acetate: heptane wash-out, by Isco Companion chromatography purification, through several column volumes, gradient increases to 60:40 linearly by 20:80.Required elution fraction merged and evaporation to produce yellow gluey title compound (23mg).
1H NMR (400MHz, δ ppm 1.15 (s, 3 H) 3.84 (s, 3 H) 3.97-4.32 (m, the 2 H) 4.42 (d of chloroform-d), J=15.05Hz, 1 H) 5.21 (d, J=15.05Hz, 1 H), 5.77 (s, 1 H) 6.61 (br.s., 2 H) 7.23-7.38 (m, 5 H), LCMS R
t=3.19m/z347[MH]
+
Preparation 100
(2-amino-6-oxyethyl group-3-nitro-pyridin-4-yl)-benzyl-urethanum
Use ethanol, according to the examples preparation title compound in the preparation 99, produce the product (31mg) of pale solid.
1H NMR (400MHz, δ ppm 1.10-1.28 (m, the 3 H) 1.31 (t of chloroform-d), J=7.03Hz, 3H) 3.97-4.32 (m, 4 H) 4.43 (d, J=15.83Hz, 1 H) 5.20 (d, J=15.83Hz, 1H) 5.70-5.86 (m, 1 H) 6.61 (br.s., 2 H) 7.26-7.36 (m, 5 H), LCMS R
t=3.36m/z 361[MH]
+
Preparation 101
(2-amino-6-propoxy--3-nitro-pyridin-4-yl)-benzyl-urethanum
Use propyl alcohol, according to the examples preparation title compound in the preparation 99, produce the product (30mg) of pale solid.
1H NMR (400MHz, δ ppm 0.95 (t, the J=7.42Hz of chloroform-d), 3 H) 1.07-1.33 (m, 3H) 1.62-1.79 (m, 2 H) 3.95-4.29 (m, 4 H) 4.44 (d, J=15.63Hz, 1 H), 5.20 (d, J=15.63Hz, 1 H) 5.67-5.90 (m, 1 H) 6.61 (br.s., 2 H) 7.25-7.41 (m, 5 H), LCMS R
t=3.51m/z 375[MH]
+
Preparation 102
(2-amino-6-methylamino-3-nitro-pyridin-4-yl)-benzyl-urethanum
At room temperature methylamine (40% aqueous solution) (0.055ml) is added in (2-amino-6-bromo-3-nitro-pyridin-4-yl)-solution of benzyl-urethanum (50mg) in THF (0.5ml).Reactant was stirred 16 hours under nitrogen atmosphere, then directly with the solution preadsorption on silica gel.With the mixture ethyl acetate: heptane wash-out, by Isco Companion chromatography purification, through several column volumes, gradient increases to 60:40 linearly by 20:80.Required elution fraction merged and evaporation to produce yellow gluey title compound (30mg).
1H NMR (400MHz, δ ppm 1.04-1.40 (m, 3 H) 2.82 (s, 3 H) 3.97-4.33 (m, 3 H) 4.75-5.04 (m, 1 H) 5.22-5.49 (m, 2 H) 6.79 (br.s., the 2 H) 7.28-7.39 (m, 5 H) of chloroform-d), LCMS R
t=2.83m/z 346[MH]
+
Preparation 103
(2-amino-6-ethylamino-3-nitro-pyridin-4-yl)-benzyl-urethanum
Use ethamine (70% aqueous solution) (0.051ml), according to the examples preparation title compound in the preparation 102, produce yellow gluey product (35mg).
1H NMR (400MHz, δ ppm 1.05-1.37 (m, 6 H) 3.23 (s, 2 H) 3.93-4.35 (m, 3 H) 4.84 (s, 1 H) 5.17-5.52 (m, 2 H) 6.75 (br.s., the 2 H) 7.29-7.42 (m, 5 H) of chloroform-d), LCMS R
t=3.0m/z 360[MH]
+
Preparation 104
(2-amino-6-propyl group amino-3-nitro-pyridin-4-yl)-benzyl-urethanum
Use 1-propylamine (0.052ml), according to the examples preparation title compound in the preparation 102, produce yellow gluey product (35mg).
1H NMR (400MHz, δ ppm 0.91 (t, the J=7.42Hz of chloroform-d), 3 H) 1.06-1.38 (m, 3H) 1.44-1.55 (m, 2 H) 3.14 (s, 2 H) 3.93-4.30 (m, 3 H) 4.75-5.07 (m, 1H) 5.22-5.48 (m, 2 H) 6.77 (br.s., 2 H) 7.28-7.37 (m, 5 H), LCMS R
t=3.16m/z 374[MH]
+
Preparation 105
(2-amino-6-butyl amino-3-nitro-pyridin-4-yl)-benzyl-urethanum
Use n-Butyl Amine 99 (0.063ml), according to the examples preparation title compound in the preparation 102, produce yellow gluey product (39mg).
1H NMR (400MHz, δ ppm 0.92 (t, the J=7.42Hz of chloroform-d), 3 H) 1.12-1.37 (m, 5H) 1.41-1.51 (m, 2 H) 3.17 (s, 2 H) 3.98-4.31 (m, 3 H) 4.84 (s, 1 H) 5.26-5.47 (m, 2 H) 6.75 (br.s., 2 H) 7.28-7.36 (m, 5 H), LCMS R
t=3.31m/z 388[MH]
+
Preparation 106
[2-amino-6-(2-methoxyl group-ethylamino)-3-nitro-pyridin-4-yl]-benzyl-urethanum
Use 2-methoxyethyl amine (1.0ml) and (2-amino-6-bromo-3-nitro-pyridin-4-yl)-benzyl-urethanum (150mg), according to the examples preparation title compound in the preparation 102, produce yellow gluey product (121mg).
1H?NMR(400MHz，DMSO-d
6)δ?ppm?1.21(t，3?H)，3.35(s，3?H)，3.45(m，4H)，4.20(q，2?H)，5.25(br，s，2?H)，7.20-7.35(m，5?H)，LRMS?m/z(API)390[MH]
+，388[MH]
-。
Preparation 107
(2,6-two bromo-3-nitro-pyridin-4-yls)-(6-trifluoromethyl-3-ylmethyl)-urethanum
Use (2,6-two bromo-3-nitro-pyridin-4-yls)-urethanum (2.0g), 5-(chloromethyl)-2-5-flumethiazine (1.06g) and sodium iodide (0.98g) in salt of wormwood (1.50g), the acetone (40ml), according to the examples preparation title compound in the preparation 68.Produce yellow oil product (2.79g) thus.
1H?NMR(400MHz，DMSO-d
6)δ?ppm?1.20(t，3?H)，4.20(q，2?H)，4.85(s，2H)，7.28(s，1?H)，7.71(d，1?H)，7.88(dd，1?H)，8.61(d，1?H)
Preparation 108
(2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-trifluoromethyl-pyridin-3-yl methyl)-urethanum
Use (2,6-bromo-3-nitro-pyridin-4-yl)-(6-trifluoromethyl-pyridin-3-yl methyl)-urethanum (2.75g), ammoniacal liquor (11ml) and 2-methyl-THF (11ml), according to the examples preparation title compound in the preparation 69.Produce yellow oil product (1.92g) thus.
1H?NMR(400MHz，DMSO-d
6)δ?ppm?1.21(t，3?H)，4.11(q，2H)，4.95(br，s，2?H)，6.41(br，s，2?H)，6.60(s，1?H)，7.65(d，1H)，7.95(m，1?H)，8.65(m，1?H)
Preparation 109
(3-cyano group-benzyl)-(2,6-two bromo-3-nitro-pyridin-4-yls)-urethanum
Use (2,6-two bromo-3-nitro-pyridin-4-yls)-urethanum (2.0g), 3-chloromethyl-cyanobenzene (0.82g) and sodium iodide (0.98g) in salt of wormwood (1.50g), the acetone (40ml), according to the examples preparation title compound in the preparation 68.Produce yellow oil product (2.62g) thus.
1H?NMR(400MHz，DMSO-d
6)δ?ppm?1.20(t，3?H)，4.15(q，2H)，4.80(br，s，2?H)，7.15(s，1?H)，7.5(m，2?H)，7.61(m，1?H)，7.65(m，1H)
Preparation 110
(2-amino-6-bromo-3-nitro-pyridin-4-yl)-(3-cyano group-benzyl)-urethanum
Use (3-cyano group-benzyl)-(2,6-two bromo-3-nitro-pyridin-4-yls)-urethanum (2.32g), ammoniacal liquor (10.2ml) and 2-methyl-THF (10.2ml), according to the examples preparation title compound in the preparation 68.Produce the product (1.51g) of yellow solid thus.
1H?NMR(400MHz，DMSO-d
6)δ?ppm?1.20(t，3?H)，4.21(q，2H)，4.95(br，s，2?H)，6.35(br，s，2?H)，6.59(s，1?H)，7.5(m，1H)，7.6(m，3?H)
Preparation 111
(2-amino-3-nitro-6-oxazole-2-base-pyridin-4-yl)-(6-trifluoromethyl-pyridin-3-yl methyl)-urethanum
Shi Yong oxazole (30mg), (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-trifluoromethyl-pyridin-3-yl methyl)-urethanum (100mg) and two (triphenylphosphine) palladium chloride (30mg), according to the examples preparation title compound in the preparation 70, produce the product (61mg) of yellow solid.
1H NMR (400MHz, δ ppm 1.10-1.31 (m, the 3 H) 4.02-4.30 (m of chloroform-d), 2 H) 5.07 (s, 2 H) 6.39 (s, 2 H), 7.32 (s, 1 H) 7.35 (s, 1 H), 7.69 (d, J=7.82Hz, 1 H) 7.84 (s, 1 H) 8.01 (d, J=5.47Hz, 1 H), 8.70 (s, 1 H), LCMS R
t=3.02m/z 453[MH]
+
Preparation 112
[2-amino-6-(4-methyl-oxazoles-2-yl)-3-nitro-pyridin-4-yl]-(6-trifluoromethyl-pyridin-3-yl methyl)-urethanum
Use 4-methyl-oxazoles (36mg), (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-trifluoromethyl-pyridin-3-yl methyl)-urethanum (100mg) and two (triphenylphosphine) palladium chlorides (30mg), according to the examples preparation title compound in the preparation 70, produce the product (44mg) of yellow solid.
1H NMR (400MHz, δ ppm 1.10-1.25 (m, the 3 H) 2.28 (s of chloroform-d), 3 H) 4.09-4.25 (m, 2 H) 5.06 (s, 2 H) 6.41 (s, 2 H) 7.25 (s, 1 H), 7.55 (d, J=1.17Hz, 1 H) 7.69 (d, J=8.21Hz, 1 H), 8.01 (d, J=7.03Hz, 1H) 8.70 (s, 1 H), LCMS R
t=3.13m/z 467[MH]
+
Preparation 113
(2-amino-3-nitro-6-oxazole-2-base-pyridin-4-yl)-(3-cyano group-benzyl)-urethanum
Shi Yong oxazole (33mg), (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(3-cyano group-benzyl)-urethanum (100mg) and two (triphenylphosphine) palladium chlorides (33mg), according to the examples preparation title compound in the preparation 70, produce the product (67mg) of yellow solid.
1H NMR (400MHz, δ ppm 1.20 (t, the J=7.03Hz of chloroform-d), 3 H) 4.17 (s, 2 H) 4.99 (s, 2 H), 6.36 (s, 2 H) 7.26 (s, 1 H) 7.34 (s, 1 H), 7.46 (t, J=7.62Hz, 1 H) 7.59 (d, J=7.42Hz, 1 H) 7.62-7.68 (m, 2 H) 7.82 (s, 1 H), LCMSR
t=2.93m/z 409[MH]
+
Preparation 114
[2-amino-6-(4-methyl-oxazoles-2-yl)-3-nitro-pyridin-4-yl]-(3-cyano group-benzyl)-urethanum
Use 4-methyl-oxazoles (40mg), (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(3-cyano group-benzyl)-urethanum (100mg) and two (triphenylphosphine) palladium chlorides (30mg), according to the examples preparation title compound in the preparation 70, produce the product (65mg) of yellow solid.
1H NMR (400MHz, δ ppm 1.10-1.25 (m, the 3 H) 2.28 (s of chloroform-d), 3 H) 4.10-4.23 (m, 2 H) 4.99 (s, 2 H) 6.39 (s, 2 H) 7.20 (s, 1 H), 7.46 (t, J=7.62Hz, 1 H) 7.54 (d, J=1.17Hz, 1 H), 7.60 (d, J=7.42Hz, 1H) 7.63-7.69 (m, 2 H), LCMS R
t=3.04m/z 423[MH]
+
Preparation 115
4-amino-1-benzyl-6-bromo-1,3-dihydro-imidazol-is [4,5-c] pyridin-2-ones also
(50mg 0.13mmol) is dissolved among the AcOH (3ml) with (2-amino-6-bromo-3-nitro-pyridin-4-yl)-benzyl-urethanum.(43mg is 0.76mmol) and with mixture vigorous stirring 24 hours at room temperature to add iron powder.Reaction mixture is diluted with EtOAc (20ml) and water (10ml).Mixture is washed with diatomite filtration and with EtOAc (20ml).With each layer separation and with organic layer water (10ml), saturated NaHCO
3The aqueous solution (2 * 10ml) and salt solution (10ml) washing, use MgSO
4Dry also vacuum concentration.Thick material is ground in pentane, filter and in a vacuum, 40 ℃ of dryings to produce beige solid title compound (15mg).
1H NMR (d6-DMSO) δ 10.47 (br s, 1H), 7.36-7.26 (m, 5H), 6.70 (s, 1H), 6.05 (br s, 2H), 4.94 (s, 2H); LRMS (APCI and ES) m/z 319/321[MH]
+
Preparation 116
Benzyl-(2,3-diamino-6-pyrazol-1-yl-pyridin-4-yl)-urethanum
(65.4mg 0.171mmol) is dissolved in the methyl alcohol (5ml) and at room temperature, 80psi H with (2-amino-3-nitro-6-pyrazol-1-yl-pyridin-4-yl)-benzyl-urethanum
2Down through Raney nickel (25mg) hydrogenation 1 hour.Reaction mixture is evaporated filtrate to produce 58mg brown resistates shape title compound then in a vacuum with the short plug filtration of Arbocel.
1H?NMR(CDCl
3)δ?1.15(m，3H)，2.90(s?br，2H)，3.50(m，2H)，4.12(d，2H)，4.20(s?br，2H)，6.28(s?br，1H)，7.10(s?br，1H)，7.20-7.35(m，5H)，7.85(s，1H)，8.30(s，1H)；LRMS(ES
+)m/z?353(MH
+)。
Preparation 117
(2-amino-3-nitro-6-[1,2,4] triazol-1-yl-pyridin-4-yl)-benzyl-urethanum
Title compound is according to the preparation of the embodiment in the preparation 116.
1H NMR (CDCl
3) δ 1.20 (t, 3H), 4.19 (quartet, 2H), 5.00 (sbr, 2H), 6.37 (sbr, 2H), 7.09 (s, 1H), 7.27-7.37 (m, 5H), 8.03 (s, 1H), 9.00 (s, 1H); LRMS (ES
+) m/z 384 (MH
+).
Preparation 118
(ai) (2-amino-3-nitro-6-[1,2,3] triazole-2-base-pyridin-4-yl)-benzyl-urethanum and (bi) (2-amino-3-nitro-6-[1,2,3] triazol-1-yl-pyridin-4-yl)-benzyl-urethanum
With (2-amino-6-chloro-3-nitro-pyridin-4-yl)-benzyl-urethanum (100mg, 0.285mmol) be dissolved in add then in the acetonitrile (10ml) 1,2,3-triazoles (39.4mg, 0.570mmol), salt of wormwood (78.8mg, 0.570mmol).With yellow solution 70 ℃, under nitrogen atmosphere, stirred 18 hours.The dark orange reaction mixture of gained evaporated in a vacuum and be dissolved in resistates among the EtOAc and the water extraction.Organic extract is merged, by anhydrous magnesium sulfate drying and vacuum concentration.By automatic purifying (chiralpak post, 50:50 methyl alcohol: ethanol) 2 kinds of constitutional isomers are separated 48.1mg (ai) (the 2-amino-3-nitro-6-[1 that is yellow solid with generation, 2,3] triazole-2-base-pyridin-4-yl)-(bi) (2-amino-3-nitro-6-[1 of benzyl-urethanum and 34.9mg, 2,3] triazol-1-yl-pyridin-4-yl)-benzyl-urethanum.
1H?NMR(CDCl
3)(ai)δ?1.19(t，3H)，4.18(d，2H)，5.00(s?br，2H)，6.62(sbr，2H)，7.25-7.36(m，6H)，7.87(s，1H).LRMS(ES
+)m/z?384(MH
+)。
1H?NMR(CDCl
3)(bi)δ?1.21(t，3H)，4.20(q，2H)，5.02(s?br，2H)，6.35(sbr，2H)，7.24-7.40(m，6H)，7.77(s，1H)，8.40(d，1H).LRMS(ES
+)m/z384(MH
+)。
Preparation 119
[2-amino-6-(4-fluoro-pyrazol-1-yl)-3-nitro-pyridin-4-yl]-benzyl-urethanum
Under nitrogen atmosphere, with (2-amino-6-chloro-3-nitro-pyridin-4-yl)-benzyl-urethanum (100mg, 0.285mmol), 4-fluorine pyrazoles (24.5mg, 0.285mmol) and salt of wormwood (118mg 0.855mmol) places the 5ml acetonitrile to stir together.Reactant is heated to reflux temperature lasts 3 hours, be cooled to envrionment temperature then and spend the night.
With solvent evaporation and with 1% methanol-eluted fractions in the methylene dichloride soluble fractions usefulness methylene dichloride of resistates, by silicon-dioxide chromatography method purifying.To contain the elution fraction of pure material and 0.66 Rf merges in same elutriant and evaporates to produce yellow gluey title compound (106mg).
1H NMR (CDCl
3, 400MHz) δ 1.20 (wide unimodal, 3H), 4.17 (wide unimodal, 2H), 4.95 (wide bimodal, 2H) 6.38 (wide unimodal, 2H) 7.15 (s, 1H) 7.35 (m, 5H) 7.58 (d, 1H) 8.23 (d, 1H); LRMS (ES
+) m/z 401 (MH+)
Use and the following compound of method preparation identical described in the preparation 119.
Preparation 120
[2-amino-6-(3,5-dimethyl-pyrazol-1-yl)-3-nitro-pyridin-4-yl]-benzyl-urethanum
1H NMR (CDCl
3, 400MHz) δ 1.19 (wide unimodal, 3H), 2.24 (s, 3H) 2.62 (s, 3H) 4.16 (wide unimodal, 2H), 4.94 (wide bimodal, 2H) 5.98 (s, 1H) 6.36 (wide unimodal, 2H) 7.21 (s, 1H) 7.32 (m, 5H); LRMS (ES
+) m/z 411 (MH+).
Preparation 121
[2-amino-6-(4-methyl-pyrazol-1-yl)-3-nitro-pyridin-4-yl]-benzyl-urethanum
1H NMR (CDCl
3, 400MHz) δ 1.20 (wide unimodal, 3H), 2.14 (s, 3H) 4.16 (wide unimodal, 2H), 4.95 (wide bimodal, 2H) 6.39 (wide unimodal, 2H) 7.16 (s, 1H) 7.36 (m, 5H) .7.53 (s, 1H) 8.15 (s, 1H); LRMS (ES
+) m/z 397 (MH+)
Preparation 122
[2-amino-6-(3-trifluoromethyl-pyrazol-1-yl)-3-nitro-pyridin-4-yl]-benzyl-urethanum
1H NMR (CDCl
3, 400MHz) δ 1.22 (wide unimodal, 3H), 4.20 (wide unimodal, 2H), 5.00 (wide bimodal, 2H), 6.33 (wide unimodal, 2H) 6.69 (d, 1H), 7.22 (s, 1H), 7.35 (m, 5H), 8.45 (d, 1H); LRMS (ES
+) m/z451 (MH+).
Preparation 123
[2-amino-6-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-3-nitro-pyridin-4-yl]-benzyl-urethanum
1H NMR (CDCl
3, 400MHz) δ 1.22 (wide unimodal, 3H), 2.69 (s, 3H), 4.20 (wide unimodal, 2H), 5.00 (wide unimodal, 2H), 6.29 (wide unimodal, 2H), 6.41 (s, 1H), 7.19 (s, 1H), 7.33 (m, 5H); LRMS (ES
+) m/z 465 (MH+).
Preparation 124
2-amino-6-[4-(2-hydroxyl-ethyl)-pyrazol-1-yl]-3-nitro-pyridin-4-yl)-benzyl-urethanum
1H NMR (CDCl
3, 400MHz) δ 1.20 (broad peak, 3H), 2.78 (t, 2H), 3.85 (q, 2H) 4.18 (wide unimodal, 2H), 4.98 (wide unimodal, 2H), 6.37 (wide unimodal, 2H), 7.17 (s, 1H), 7.33 (m, 5H), 7.61 (s, 1H), 8.28 (s, 1H); LRMS (ES
+) m/w 427 (MH+)
Preparation 125
1-benzyl-4-benzylamino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-6-formic acid-(1-oximino-ethyl)-acid amides
In reaction flask, (52mg 0.32mmol) is added into 1-benzyl-4-benzylamino-2-oxo-2 with CDI, 3-dihydro-1H-imidazo [4,5-c] (80mg, 0.21mmol) (83 μ l are 0.64mmol) in the solution in dry DMF with Hunnigs alkali for pyridine-6-formic acid.At room temperature stirred 15 minutes with the bottle sealing and with mixture.(24mg 0.32mmol) and with mixture is heated to 60 ℃ in aluminium block to add the N-hydroxyl acetamidine.Mixture was stirred 3 hours in this temperature, then cooling and vacuum concentration.Between EtOAc (15ml) and water (5ml), divide resistates molten.Wash with salt solution (5ml) with each layer separation and with organic phase.At this moment, some solid precipitations are arranged, place in the separating funnel.With MeOH it is washed in the organic phase, then the organism drying (is used MgSO
4) and evaporate to produce the final product (120mg, 130%) of white solid.This material may contain inorganic substance, but can be used for next step with regard to purifying.
1H?NMR?CD3OD?δ?1.94(s，3H)4.54(s，2H)5.16(s，2H)7.16-7.46(m，11H)。
LCMS?R
t＝3.47m/z?431[MH]
+
Preparation 126
N2, N2-dibenzyl-6-bromo-3-nitro-pyridine-2,4-diamines
With 2,6-two bromo-4-amino-5-nitro-pyridine (3.52g) be dissolved among the 2-methyl THF (40ml) and solution in ice bath, be cooled to＜5 ℃.Dibenzylamine (2.39ml) and the solution of triethylamine (2.48ml) in 2-methyl THF (20ml) dropwise are added in the dibromo pyridine solution, and reaction mixture are heated stirred 16 hours to room temperature and under nitrogen atmosphere.Add dibenzylamine (684 μ l) and triethylamine (496 μ l) again, and with mixture restir 5 hours at room temperature, and then add dibenzylamine (684 μ l) and triethylamine (496 μ l), and with mixture restir 16 hours at room temperature.
Mixture is changed in the separating funnel, add water (60ml) then.Extract again with EtOAc (60ml) with each layer separation and with the aqueous solution.The organism drying that is merged (is used MgSO
4) and be evaporated to orange glue.Make this glue from MeOH: water (90:10 ,～200ml) in crystallization to produce solid, with its filtration and use MeOH: water (90:10) washing, the title compound (3.6g) of drying under vacuum then to produce orange crystalline solid.
1H?NMR(CDCl
3，400MHz)δ?4.45(s，4H)，5.95(br，s，2H)，6.22(s，1H)，7.05-7.15(m，4H)，7.21-7.35(m，6H)。LCMS?R
t＝3.73m/z?415[MH]
+
Preparation 127
N2, N2-dibenzyl-6-bromo-N4-(6-methyl-pyridin-3-yl methyl)-3-nitropyridine-2,4-diamines
Under nitrogen atmosphere, potassium tert.-butoxide (448mg) dropwise is added into N2, N2-dibenzyl-6-bromo-3-nitro-pyridine-2, (1500mg is 3.63mmol) in the cold soln in THF (40ml) (18 ℃-salt/ice bath) for the 4-diamines.After adding alkali, solution becomes scarlet/orange by yellow.Solution was stirred in cooling bath 5 minutes.
With 5-brooethyl-2-methyl-pyridine hydrobromide salt (1160mg) at saturated NaHCO
3Divide molten between solution (20ml) and the 2-Me THF (20ml).To respectively be separated and will have the aqueous solution with 2-MeTHF (20ml) extract again.The organism drying that is merged (is used MgSO
4), dropwise be added in aminopyridine and the KOtBu mixture with dropping funnel then.Color becomes yellow/orange by red/orange.Mixture is slowly heated in cooling bath to room temperature, then in room temperature, under nitrogen atmosphere, stirred 48 hours.Reaction mixture is cooled to-18 ℃ (ice/salt bath) again, adds KOtBu (102mg), four-normal-butyl iodate ammonium (670mg) then successively.Remove cooling bath and mixture is heated to room temperature, and then stirred 4 hours.The direct preadsorption of reaction mixture on silicon-dioxide, is used EtOAc then: the heptane wash-out, (80g Redisep) carries out column chromatography, increases to 80:20 through 10 column volume gradients by the 40:60 linearity by Isco Companion silica column.Required elution fraction merged and evaporation to produce the title compound (0.99g) of yellow solid.
1H?NMR(CDCl
3，400MHz)δ?2.58(s，3H)，4.38(d，2H)，4.45(s，4H)，6.19(s，1H)7.05-7.15(m，4H)，7.18(d，1H)，7.21-7.35(m，6H)，7.49(dd，1H)，7.99(t，1H)，8.42(d，1H)。LCMS?R
t＝3.12m/z?520[MH]
+
Preparation 128
N2, N2-dibenzyl-N4-(6-methyl-pyridin-3-yl methyl)-3-nitro-6-oxazole-2-base-pyridine-2,4-diamines
Dropwise Tian Jia is Zhi the solution that is stirred of oxazole (0.251ml) in THF (5ml)-78 ℃ (dry ice/acetone batch) with butyllithium (2.9ml), and maintenance is added speed so that temperature of reaction is no more than-60 ℃.Solution was stirred 10 minutes in this temperature, dropwise add the solution of zinc chloride (1.56g) in THF (7ml) then.Solution was stirred 15 minutes at-78 ℃, remove cooling bath then and reaction mixture is heated to room temperature.Be added into pre-sealed with syringe the aliquot sample (1.2ml) of Xin oxazole solution and by the microwave bottle (Biotage of purging with nitrogen gas, 0.5-2.0ml) in, this bottle contains N2, N2-dibenzyl-6-bromo-N4-(6-methyl-pyridin-3-yl methyl)-3-nitropyridine-2,4-diamines (90mg) and two (triphenylphosphine) palladium chloride (24mg).With this bottle under microwave irradiation (Biotage Initiator 8), 130 ℃ the heating 15 minutes.The nine parts of aliquot sample and the bromopyridine of Shi Xin oxazole solution react in microwave again with the same manner.
Merging all reaction mixtures also, vacuum concentration is a brown size.Between EtOAc (20ml) and 2M ammonia solution (20ml), divide glue molten.The aqueous solution is extracted with EtOAc (20ml) again, and the organism that is merged is washed with salt solution (20ml), drying (is used MgSO then
4) and be evaporated to brown size.With crude product EtOAc: the heptane wash-out, (120g carries out purifying on Redisep), increases to 100:0 through 6 column volume gradients by the 80:20 linearity, makes 18 column volumes at degree such as 100% EtOAc then at Isco Companion silica column.Required elution fraction merged and evaporation to produce yellow foaming solid title compound (0.43g).
1H?NMR(CDCl
3，400MHz)δ?2.60(s，3H)，4.55(d，2H)，4.60(s，4H)，6.99(s，1H)7.05-7.15(m，4H)，7.20-7.22(d，2H)，7.22-7.35(m，6H)，7.59(dd，1H)，7.79(s，1H)，8.09(t，1H)，8.55(d，1H)。LCMS?R
t＝2.87m/z?507[MH]
+
Preparation 129
N2, N2-dibenzyl-N4-(6-methyl-pyridin-3-yl methyl)-6-oxazole-2-base-pyridine-2,3,4-triamine
With N2, N2-dibenzyl-N4-(6-methyl-pyridin-3-yl methyl)-3-nitro-6-oxazole-2-base-pyridine-2,4-diamines (425mg) is dissolved among the THF (60ml), adds MeOH (60ml) then.With solution under nitrogen atmosphere (80psi) through Raney nickel (40mg) hydrogenation 1 hour.Reaction mixture is filtered with Celite pad, evaporate then to produce yellow thick gluey title compound, it can be directly used in next step.
LCMS?R
t＝2.42m/z?477[MH]
+。
Preparation 130
(2,6-two chloro-3-nitro-pyridin-4-yls)-urethanum
The solution of Vinyl chloroformate (2.75ml) in 2-methyl THF (10ml) dropwise is added into 2, in 6-two chloro-4-amino-5-nitro-pyridine (5.00g) and triethylamine (4.02ml) cold (ice bath) solution in 2-methyl THF (50ml).Adding speed should make temperature of reaction not rise to 5 ℃.After adding Vinyl chloroformate, form throw out.Suspension is heated to room temperature, under nitrogen atmosphere, stirred 16 hours then.Suspension is changed in the separating funnel, add water (50ml).Wash with salt solution (50ml) with each layer separation and with organism, drying (is used MgSO then
4) and be evaporated to orange glue, it is left standstill be cured as yellow solid.Make solid from MeOH: recrystallization in the water (70:30), produce the white needles title compound, it is collected (6.7g) by filtering.
1H?NMR(CDCl
3，400MHz)δ?1.25(t，3H)，4.31(q，2H)，8.10(br，s，1H)，8.40(s，1H)。LCMS?R
t＝4.16m/z?280[MH]
+
Preparation 131
Benzyl-(2,6-two chloro-3-nitro-pyridin-4-yls)-urethanum
Cylite (2.33ml) dropwise is added in (2,6-two chloro-3-nitro-pyridin-4-yls)-suspension that is stirred of urethanum (4.57g) in acetonitrile (40ml).With mixture under nitrogen atmosphere, at room temperature stirred 16 hours.Between EtOAc (50ml) and water (50ml), divide the mixture vacuum concentration molten then.With each layer separation and with the saturated NH of organism
4Cl (50ml), water (50ml) and salt solution (50ml) washing.The organism drying (is used MgSO
4) and be evaporated to yellow oil.With this material preadsorption on silicon-dioxide, use EtOAc then: heptane wash-out, at Isco Companion silica column (330g, Redisep) carry out column chromatography, make 1 column volume (CV) at degree such as 10:90, gradient increases to 30:70 through 6 CV by the 10:90 linearity then.Required elution fraction merged and evaporation to produce yellow oily title compound (6.05g).
1H?NMR(CDCl
3，400MHz)δ?1.25(t，3H)，4.19(q，2H)，4.81(s，2H)，6.88(s，1H)，7.20-7.28(m，2H)，7.30-7.40(m，3H)。LCMS?R
t＝3.62m/z372[MH]
+。
Preparation 132
(2-amino-6-chloro-3-nitro-pyridin-4-yl)-benzyl-urethanum
Benzyl-(2,6-two chloro-3-nitro-pyridin-4-yls)-urethanum (500mg) is dissolved among the THF (3ml) in the reaction flask.(7M 1ml), seals bottle, and reactant was at room temperature stirred 48 hours in MeOH to add ammonia.Then with the direct preadsorption of reaction mixture on silicon-dioxide, and use EtOAc: the heptane wash-out, (40g Redisep) carries out column chromatography, and gradient increases to 40:60 through 10 column volumes by the 10:90 linearity at Isco Companion silica column.Required elution fraction merged and evaporation to produce yellow gluey title compound, make it leave standstill curing (305mg).
1H?NMR(CDCl
3，400MHz)δ?1.05(t，3H)，4.02(q，2H)，4.87(br，s，2H)，6.58(s，1H)，7.20-7.36(m，5H)，7.61(br，s，1H)。LCMS?R
t＝3.24m/z351[MH]
+
Preparation 133
[2-amino-6-(2-methoxyl group-oxyethyl group)-3-nitro-pyridin-4-yl]-benzyl-urethanum
Sodium hydride (21mg) dropwise is added in the 2-methyl cellosolve (0.5ml).Gained solution dropwise is added in (2-amino-6-chloro-3-nitro-pyridin-4-yl)-solution of benzyl-urethanum (100mg) in THF (1.0ml).Reaction mixture is become dark red/orange solution by yellow solution, and it was at room temperature stirred 1 hour.With the orange mixture vacuum concentration, then at EtOAc (10ml) and saturated NH
4Divide molten between the Cl solution (10ml).With each layer separation and with organism water (10ml) and salt solution (10ml) washing, drying (is used MgSO then
4) and evaporate to produce the gelationus title compound of thick yellow (111mg).This thing can be directly used in next step and need not to be further purified.
LCMS?R
t＝3.13m/z?391[MH]
+
Preparation 134
4-benzylamino-3-nitro-pyridine-2-alcohol
With 4-chloro-3-nitro-2-pyrrole alkane ketone (5g 28.65mmol) is suspended in the 150ml acetonitrile, add successively then benzylamine (3.15ml, 28.65mmol), (4g's salt of wormwood 28.65mmol), and spends the night mixture 60 ℃ of stirrings.Remove solvent in a vacuum and resistates is suspended in the water (200ml).Adding 2M HCl solution is～6 until the pH value.Throw out is filtered also dry in a vacuum to produce 4.75g beige solid title compound.The 2nd results produce the 1.4g title compound in mother liquor.
1H NMR (d6 DMSO) δ: 11.20 (wide unimodal, 1H), 9.35 (t, 1H), 7.40-7.20 (m, 6H), 5.85 (d, 1H), 4.60 (d, 2H); LRMS (ES
+) m/z 246[MH]
+
Preparation 135
Benzyl-(2-chloro-3-nitro-pyridin-4-yl)-amine
With 4-benzylamino-3-nitro-pyridine-2-alcohol (6.15g 25.07mmol) is suspended in the 100ml acetonitrile, add successively then phosphoryl chloride (12ml, 125.40mmol), (4.15g's tetraethylammonium chloride 25.07mmol), and spends the night mixture 85 ℃ of stirrings.Remove solvent in a vacuum and be suspended in resistates in the water (300ml) and (2 * 200ml) extractions of usefulness methylene dichloride.Organic layer is removed to produce the title compound of 5.9g yellow solid in a vacuum with dried over mgso and with solvent.
1H NMR (CDCl
3) δ: 8.0 (d, 1H), 7.40-7.20 (m, 5H), 6.9 (wide unimodal, 1H), 6.60 (d, 1H), 4.5 (d, 2H); LRMS (ES
+) m/z 264[MH]
+
Preparation 136
N-2, N-2, N-4, tribenzyl-3-nitro-pyridine-2,4-diamines
With benzyl-(2-chloro-3-nitro-pyridin-4-yl)-amine (3.95g 14.99mmol) is suspended in the 50ml acetonitrile, add successively then dibenzylamine (2.9ml, 14.99mmol), (2g's salt of wormwood 14.99mmol), and spends the night mixture 80 ℃ of stirrings.Remove solvent in a vacuum and be suspended in resistates in the water (100ml) and (2 * 100ml) extractions of usefulness ethyl acetate.Organic layer is also removed solvent in a vacuum with dried over mgso.Use 15% ethyl acetate in the pentane, by the thick resistates of silica gel column chromatography purifying to produce 6g yellow oily title compound.
1H NMR (d6 DMSO) δ: 8.1 (the s broad peak, 1H), 7.9 (d, 1H), 7.40-7.10 (m, 15H), 6.10 (d, 1H), 4.55 (s, 4H), 4.5 (d, 2H); LRMS (ES
+) m/z 425[MH]
+
Preparation 137
N-2, N-2, N-4-tribenzyl-pyridine-2,3,4-triamine
With N-2, N-2, N-4, tribenzyl-3-nitro-pyridine-2, (6g 14.13mmol) is suspended in the 150ml ethanol 4-diamines, adds Raney nickel (1.2g, 20 weight %), then with mixture at room temperature, stirred 3 hours under 50psi hydrogen.After finishing, mixture is filtered and removes in a vacuum solvent to produce the gluey title compound of 5g lavender with Arbocel (lignocellulose).
1H NMR (CDCl
3) δ: 7.80 (d, 1H), 7.40-7.15 (m, 15H), 6.35 (d, 1H), 4.35 (d, 2H), 4.15 (s, 4H), 3.5-3.25 (wide unimodal, 2H); LRMS (ES
+) m/z 395[MH]
+
Preparation 138
1-benzyl-4-dibenzyl amino-1,3-dihydro-imidazol-be [4,5, c] pyridin-2-ones also
With N-2, N-2, N-4, tribenzyl-pyridine-2,3, (5g 12.67mmol) is dissolved in the 100ml acetonitrile 4-triamine, adds 1 then, and (3g's 1 '-carbonyl dimidazoles 19.701mol) and with reactant spends the night 80 ℃ of stirrings.Mixture is cooled to room temperature and throw out filtered and with the acetonitrile washing, dry in a vacuum then to produce 4.3g lilac solid title compound.
1H?NMR(d6?DMSO)δ：10.9(s，1H)，7.75(d，1H)，7.40-7.10(m，15H)，6.70(d，1H)，4.9(s，2H)，4.6(s，4H)；LRMS(ES
+)m/z?421[MH]
+。
Preparation 139
1-benzyl-7-bromo-4-dibenzyl amino-1, the 3-dihydro-imidazol-is [4,5, c] pyridin-2-ones also
With 1-benzyl-4-dibenzyl amino-1, the 3-dihydro-imidazol-also [4,5, c] pyridin-2-ones (1g 2.4mmol) is suspended in the 20ml acetate, dropwise add then sodium acetate (195mg, 2.4mmol), bromine (456mg, 2.85mmol).Mixture was at room temperature stirred 15 minutes.Form thick throw out.With mixture diluted in water (50ml) and with solid filtering and wash with water.Be diluted in then in the ethyl acetate (20ml), use dried over mgso, and remove solvent in a vacuum to produce 1.29g light orange solid title compound.
1H?NMR(d6?DMSO)δ：11.5(s，1H)，7.85(s，1H)，7.40-7.10(m，15H)，5.30(s，2H)，4.55(s，4H)；LRMS(ES
+)m/z?499，501[MH]
+
Preparation 140
1-benzyl-4-dibenzyl amino-2-oxo-2,3-dihydro-1H-imidazo [4,5, c] pyridine-7-methyl-formiate
With 1-benzyl-7-bromo-4-dibenzyl amino-1,3-dihydro-imidazol-also [4,5, c] (500mg 1mmol) is suspended in the 30ml methyl alcohol pyridin-2-ones, adds triethylamine (203mg then successively, 2mmol), (1,1 '-two (diphenylphosphino) ferrocene) the dichloro palladium (82mg, 0.1mmol), and with mixture 100 ℃, under 100psi CO, stir and spend the night.Mixture is cooled to room temperature, filters and use methanol wash with Arboce1.Remove solvent in a vacuum, use 1% methyl alcohol in the methylene dichloride, by silica gel column chromatography purifying resistates to produce the title compound of 21mg white solid.
1H NMR (CDCl
3) δ: 8.4 (s, 1H), 8.0 (wide unimodal, 1H), 7.40-7.00 (m, 15H), 5.45 (s, 2H), 4.80 (s, 4H), 3.7 (s, 3H); LRMS (ES
+) m/z 479[MH]
+
Preparation 141
1-benzyl-4-dibenzyl amino-2-oxo-2,3-dihydro-1H-imidazo [4,5, c] pyridine-7-formic acid cyclopropyl methyl nitrosourea
With 1-benzyl-4-dibenzyl amino-2-oxo-2, (50mg 0.1mmol) is suspended in 2ml (amino methyl) cyclopropane 3-dihydro-1H-imidazo [4,5, c] pyridine-7-methyl-formiate, and mixture is spent the night 120 ℃ of stirrings.Remove excessive amine and glue branch in water (20ml) and ethyl acetate (50ml) is molten in a vacuum, organic layer is separated, use MgSO
4The dry solvent that also removes in a vacuum.Use 5% methyl alcohol in the methylene dichloride, by silica gel column chromatography purifying resistates to produce the yellow gluey title compound of 10mg; LRMS (ES
+) m/z 518[MH]
+
Preparation 142
6-chloro-2,4-dihydroxyl-5-methyl-pyridine
(10g 71mmol) mixes with propionitrile (12ml) also at room temperature, stirred 16 hours under nitrogen atmosphere with malonyl chloride.The 50mL diox is added in the gained heterogeneous mixture, collects the gained throw out and use the washing of Leng diox by filtering.Collected solid is dissolved in several ml methanol and the Yong diox precipitates once more.By solid collected by filtration, the washing of Yong diox is also dry in a vacuum to produce the title compound (6g, 53%) of white solid; LRMS:(ES
+) m/z 160[MH]
+
Preparation 143
6-chloro-2,4-dihydroxyl-5-methyl-3-nitro-pyridine
With 6-chloro-2, (500mg 3.1mmol) is dissolved in the acetate (1ml) 4-dihydroxyl-5-methyl-pyridine, is cooled to 0 ℃, and under agitation dropwise adds nitric acid (4ml).After adding end, remove ice bath, reaction mixture is heated to room temperature through 16 hours.Ice is added into mixture to produce throw out, by filtering collection and dry in a vacuum to produce the title compound (180mg, 28%) of yellow solid; LRMS:(ES
+) m/z 205[MH]
+
Preparation 144
Diphenyl malonate
0 ℃, (11g, 106mmol) (20g 212mmol) mixes, and (11.5ml 123mmol) dropwise is added in the solid mixture with phosphoryl chloride with phenol to make propanedioic acid under nitrogen atmosphere.The gained mixture was stirred 5 minutes at 0 ℃,, make the solid fusion and form orange solution then reflux temperature heating 5 hours.Reactant is cooled to room temperature, pour into then at 100ml waterborne and with ether (3 * 75ml) extraction.With the organism that is merged salt water washing, use MgSO
4Drying, vacuum concentration are orange buttery title compound (27g, 99%).
1HNMR(CDCl
3，400MHz)3.86(s，2H)，7.17(m，4H)，7.27(m，2H)，7.41(m，4H)；LRMS(ES)m/z?257[MH]
+
Preparation 145
Cyclopentanone-uncle's fourth imines
(13.3ml, 150mmol) (47.4ml 450mmol) is mixed in the 110ml ether, is cooled to-55 ℃ then in dry ice/acetonitrile is bathed with TERTIARY BUTYL AMINE with cyclopentanone under nitrogen atmosphere.(8.2ml 75mmol) is dissolved in the 70ml pentane, dropwise is added into above-mentioned solution, notes making temperature maintenance at-40 ℃ with titanium tetrachloride.Then reactant was stirred 6 hours at-40 ℃, heat to ambient temperature overnight then.Reaction mixture is filtered and washs with ether with the short plug of diatomite.Filtrate is evaporated in a vacuum to produce the transparent buttery title product of 15.9g (76%).
1HNMR(CDCl
3，400MHz)1.26(s，9H)，1.67(m，2H)，1.82(m，2H)，2.29(t，2H)，2.36(t，2H)。
Preparation 146
6,7-dihydro-5H-[1] pyridine-2, the 4-glycol
(2.78g, 20mmol) (5.12g 20mmol) is mixed in the 40ml triglyme and 100 ℃ of heating 4 hours, then 200 ℃ of heating 2 hours with diphenyl malonate with cyclopentanone-uncle's fourth imines.Then reactant is cooled to room temperature, is poured into again in the 200ml ether and in sealed flask, in refrigerator and stored 4 days.Filter the gained throw out, with ether washing and dry in a vacuum to produce light brown solid title compound (1.45g, 50%).
1HNMR(CD
3OD，400MHz)2.12(m，2H)，2.70(t，2H)，2.82(t，2H)，5.64(s，1H)。
Preparation 147
5,6-dimethyl-pyridine-2,4-glycol
With 5, (10g 71mmol) is dissolved in the 0.88NH of 66ml diox and 33ml to 6-dimethyl-4-hydroxyl-2-oxo-2H-pyrans (J.Chem.Soc.PerkinTrans 1,1980,2272)
3In the solution, and with mixture backflow 3 hours.Then the gained suspension is cooled to ambient temperature overnight, solid collected by filtration, and dry in a vacuum to produce the title compound (6.5g) of white crystalline solid.The filtrate vacuum concentration to about 10ml, is collected the solid of gathering in the crops for the 2nd time (1.0g) by filtering.Twice cutting merging is used for next synthesis step.
1H?NMR(DMSO，400MHz)：δ?1.77(s，3H)，2.06(s，3H)，5.42(s，1H)；LRMSm/z(APCI
+)140[MH]
+。
Preparation 148
5,6-dimethyl-3-nitro-pyridine-2,4-glycol
With 5,6-dimethyl-pyridine-2, (6.5g 47mmol) places 30ml sulfuric acid to stir and is cooled to 0 ℃ at ice bath then the 4-glycol.Dropwise add nitrosonitric acid (10ml), after interpolation finishes mixture was stirred 1 hour.Reaction mixture is poured on trash ice and collect the gained yellow solid to obtain title compound (3.9g, 46%) by filtering.
1H?NMR(MeOD，400MHz)：δ?2.04(s，3H)，2.31(s，3H)；LRMS?m/z(APCI
+)185[MH]
+。
Preparation 149
2,4-two chloro-5,6-dimethyl-3-nitro-pyridine
With 5,6-dimethyl-3-nitro-pyridine-2, the 4-glycol (3.9g 21mmol) is dissolved in the acetonitrile (150ml), add then tetraethylammonium chloride (7.1g, 42mmol) and phosphoryl chloride (19.9ml, 210mmol), and with whole material 70 ℃ the heating 16 hours.Reaction mixture is poured in the trash ice also with DCM (2 * 30ml) extractions.With the extract MgSO that is merged
4Drying, filtration and vacuum concentration are to produce brown solid.This solid is dissolved among the 2ml DCM and use the 2:1 pentane: EtOAc wash-out, with the short plug filtration of silica gel.Evaporated filtrate is to produce light brown solid title compound (3.5g, 75%) then.
1H?NMR(CDCl
3，400MHz)：δ?2.61(s，3H)，2.41(s，3H)
Preparation 150
Benzyl-(2-chloro-5,6-dimethyl-3-nitro-pyridin-4-yl)-amine
With 2,4-two chloro-5,6-dimethyl-3-nitro-pyridine (2g, 9mmol) be dissolved in acetonitrile (100ml) and benzylamine (1.0ml, 9.5mmol) in.(1.3g 9.5mmol) adds with portion, and whole material was heated 16 hours at 55 ℃ with salt of wormwood.With reaction mixture with EtOAc dilution and use the 50ml water washing.The aqueous solution is extracted with EtOAc again, organism is merged use MgSO then
4Drying is evaporated to the garnet resistates.Use 8:1 pentane: EtOAc as elutriant, by this resistates of silica gel column chromatography purifying, to produce bright orange solid title compound (1.2g, 45%).
1H?NMR(CDCl
3，400MHz)：δ?2.09(s，3H)，2.47(s，3H)，4.25-4.27(d，2H)，4.52(bs，1H)，7.28-7.30(m，2H)，7.35-7.41(m，3H)LRMS?m/z(APCI
+)292[MH]
+。
Preparation 151
N2, N2-diallyl-N4-benzyl-5,6-dimethyl-3-nitro-pyridine-2,4-diamines
With benzyl-(2-chloro-5,6-dimethyl-3-nitro-pyridin-4-yl)-amine (1.2g 4.1mmol) is dissolved in the ethoxy ethanol (60ml), and with diisopropylethylamine (1.1ml, 6.2mmol) and diallylamine (0.76ml 6.2mmol) adds with portion.In sealed vessel, 100 ℃ of heated overnight, vacuum concentration is an orange residue then with reaction mixture.Use the pentane of gradient 8:1 → 1:1: EtOAc as elutriant, by this resistates of silica gel column chromatography direct purification to produce bright orange oily title compound (938mg, 65%).
1H?NMR(CDCl
3，400MHz)：δ?2.16(s，3H)，2.34(s，3H)，3.90-3.92(d，4H)，4.33-4.34(d，2H)，5.13-5.21(m，4H)，5.77-5.87(m，2H)，6.37-6.40(bt，1H)，7.35-7.28(m，5H)；LRMS?m/z(APCI
+)353[MH]
+
Preparation 152
N2, N2-diallyl-N4-benzyl-5,6-dimethyl-pyridine-2,3,4-triamine
With N2, N2-diallyl-N4-benzyl-5,6-dimethyl-3-nitro-pyridine-2, (828mg 2.4mmol) is dissolved among ethanol (15ml) and the 2N HCl (15ml) the 4-diamines, and (527mg 9.6mmol) adds with portion with iron powder.Reaction mixture 70 ℃ of heating 2 hours, is cooled to room temperature then and is poured in the 50ml water.With gained solution with the neutralization of 1N NaOH solution producing the sap green suspension, with it with EtOAc (2 * 25ml) extractions, and with the organism MgSO that is merged
4Drying, filtration and evaporation are to produce sap green oily title compound (559mg, 74%).
1H?NMR(CDCl
3，400MHz)：δ?1.95(s，3H)，2.32(s，3H)，3.73-3.74(d，4H)，4.21(s，2H)，5.07-5.23(m，4H)，5，86-5.96(m，2H)，7.26-7.32(m，5H)；LRMS?m/z(APCI
+)323[MH]
+
Preparation 153
1-benzyl-4-two allyl amino-6,7-dimethyl-1,3-dihydro-imidazol-are [4,5-c] pyridin-2-ones also
With N2, N2-diallyl-N4-benzyl-5,6-dimethyl-pyridine-2,3, (559mg 1.7mmol) is dissolved in the acetonitrile (50ml) the 4-triamine, and with 1, (2.8g 17mmol) adds with portion the 1-carbonyl dimidazoles, and whole material was refluxed 2 hours.Reaction mixture is cooled to room temperature, and vacuum concentration uses gradient 8:1 → 4:1 pentane: EtOAc as elutriant, by the silica gel column chromatography direct purification, to produce the title compound (258,59%) of white solid then.
1H?NMR(CDCl
3，400MHz)：δ?2.12(s，3H)，2.34(s，3H)，3.99-4.01(dt，4H)，5.25-5.28(m，4H)，5.34-5.40(d，2H)，6.01-6.10(m，2H)，7.11-7.13(d，2H)，7.24-7.32(m，3H)，7.66(bs，1H)；LRMS?m/z(ESCI
+)349[MH]
+
Preparation 154
4-methyl-3-oxo-valeric acid
(21g 132mmol) is dissolved in the 1.5M sodium hydroxide solution (15g is in 250ml water) and at room temperature stirred 16 hours with ethyl isobutyryl acetate.Solution is cooled to 0 ℃ is acidified to pH1-2 with the 35ml concentrated hydrochloric acid then in ice bath.With gained solution with sodium-chlor saturated use then ethyl acetate (3 * 300ml) extraction.With the extract that is merged dried over sodium sulfate after-filtration, and vacuum concentration is to produce transparent oily title compound (16.4g, 95%).
1HNMR (CDCl
3, 400MHz, about 4:1 mixture of ketone and enol tautomer) (main ketone form) 1.15-1.16 (d, 6H), 2.75-2.71 (m, 1H), 3.56 (s, 2H).
Preparation 155
4-hydroxyl-3-isobutyryl-6-sec.-propyl-pyran-2-one
(16.4g, 126mmol) at room temperature, be dissolved under nitrogen atmosphere among the THF (200ml), and with 1, (22.4g 138mmol) adds with portion the 1-carbonyl dimidazoles with 4-methyl-3-oxo-valeric acid.The gained yellow solution was at room temperature stirred 16 hours, then vacuum concentration and with resistates with DCM (200ml) dilution.Solution is washed and the aqueous solution is extracted with DCM (50ml) again with 2N HCl (100ml) and water (100ml).With the organism that is merged dried over sodium sulfate, vacuum concentration is to produce yellow oily title compound (11.7g, 80%) then.
1HNMR(CDCl
3，400MHz)δ?1.16-1.18(d，6H)，1.25-1.27(d，6H)，2.71-2.74(m，1H)，3.94-3.97(m，1H)，5.92(s，1H)；LRMS(APCI+)m/z225[MH]
+
Preparation 156
4-hydroxyl-6-sec.-propyl-pyran-2-one
(11.7g 52mmol) is dissolved in the vitriol oil (40ml) and stirred 15 minutes at 130 ℃ with 4-hydroxyl-3-isobutyryl-6-sec.-propyl-pyran-2-one.The black oil that is obtained is cooled to room temperature further in ice bath, is cooled to 0 ℃ then, under agitation add the 200ml trash ice again.With gained solution with ethyl acetate (3 * 200ml) extraction and with the organism that is merged dried over sodium sulfate, filter and be evaporated in a vacuum light brown oil, use pentane 3:1 → 30:70 gradient in the ethyl acetate as elutriant, be purified to produce light brown buttery title compound by column chromatography, it is left standstill curing (6.1g, 77%).
1HNMR(CDCl
3，400MHz)δ?1.20-1.22(d，6H，2.70-2.80(m，1H)，5.58(s，1H)，5.99(s，1H)；LRMS(APCI+)m/z?155[MH]
+
Preparation 157
Ethyl-2,4-diamino benzyl-6-methyl-3-manthanoate
With ethyl-2, (100mg 0.43mmol) is dissolved in the acetonitrile (2ml) 4-two chloro-6-methyl-3-manthanoate, use triethylamine (2401 then, 1.70mmol) and benzylamine (1121,1.02mmol) handle, and with reaction mixture 40 ℃, under nitrogen atmosphere, stirred 18 hours.After being cooled to room temperature, reactant poured in the entry and with mixture with ethyl acetate (3 * 5ml) extractions.The organism drying that is merged (is used MgSO
4) and evaporation to produce thick oil, use pentane: ethyl acetate 20:1-5:1 wash-out, pass through silica gel chromatography.Obtain transparent buttery title compound (98mg, 61%).
1H-NMR(CDCl
3，400MHz)：δ1.21(t，3H)，2.25(s，3H)，4.29(q，2H)，4.40，(d，2H)，4.78，(d，2H)，5.81(s，2H)，7.21-7.42(m，10H)，8.10(brs，1H)，8.30(brs，1H)；LRMSm/z(ESI)376[MH]
+
Preparation 158
2,4-diamino benzyl-6-methyl-3-formic acid
With ethyl-2,4-diamino benzyl-6-methyl-3-manthanoate (40mg 0.11mmol) is dissolved in the methyl alcohol (1ml), and with the 2N sodium hydroxide solution (601,0.12mmol) handle, and with reaction mixture 65 ℃, under nitrogen atmosphere, stirred 5 hours.After being cooled to room temperature, reactant is poured in the entry, use 2N hydrochloric acid with pH regulator to 6-7, and with mixture with ethyl acetate (3 * 5ml) extractions.The organism drying that is merged (is used MgSO
4) and the title compound (37mg, quantitative) of evaporation to produce pale solid.
1H-NMR(DMSO，400MHz)：δ2.22(s，3H)，4.59，(d，2H)，4.64，(d，2H)，6.20(s，2H)，7.20-7.39(m，10H)；LRMS?m/z(ESI)348[MH]
+，346[M-H]
-
Preparation 159
6-benzylamino-9-benzyl-2-methyl-8-oxo-8,9-dihydro-7H-purine and 4-benzylamino-9-benzyl-6-methyl-8-oxo-8,9-dihydro-7H-purine
With 2; 4-diamino benzyl-6-methyl-3-formic acid (30mg, 0.09mmol), the diphenylphosphine acyl azide (25mg, 0.09mmol) and triethylamine (141; 0.10mmol) be mixed in the toluene, and with reactant under nitrogen atmosphere, 111 ℃ the heating 16 hours.After being cooled to room temperature, reactant is poured in the entry, and (3 * 5ml) extract with ethyl acetate with mixture.The organism drying that is merged (is used MgSO
4) to produce thick oil, use pentane: ethyl acetate 1:1 wash-out, by the silica gel column chromatography purifying produces and is transparent buttery title compound (10mg (I), 11mg (II), 68% combination yield) separately.
1H-NMR(CDCl
3，400MHz)：(I)δ?2.39(s，3H)，4.7，(s，4H)，6.04(s，2H)，7.15-7.39(m，10H)；LRMS?m/z(ESI)354[MH]
+；(II)δ2.39(s，3H)，4.39，(d，2H)，5.01，(s，2H)，6.19(s，2H)，7.15-7.39(m，10H)。LRMS?m/z(ESI)354[MH]
+。
Preparation 160
1-benzyl-2-bromo-1H-imidazoles-5-iodo-4-formonitrile HCN
(50mg 0.18mmol) is dissolved in the methylene iodide (1ml) and with mixture heating up to 100 ℃ with 5-amino-1-benzyl-2-bromo-1H-imidazoles-4-formonitrile HCN.Then with syringe with Isopentyl nitrite (971,0.72mmol) dropwise be added in the reaction mixture that is heated.Observe gas evolution.After 30 minutes, reactant is cooled to room temperature and moves down and desolventize in high vacuum.With 100% pentane to the 7:3 pentane: eluent ethyl acetate, by the thick resistates of the remaining redness of silica gel column chromatography purifying.Produce yellow oily title compound (40mg, 60%) thus.
1H-NMR(CDCl
3，400MHz)：δ?5.22(s，2H)，6.71(s，2H)，7.09(m，2H)，7.28-7.40(m，3H)；LRMS?m/z(ESI)388/390[MH]
+
Preparation 161
1-benzyl-2-bromo-5-(4-hydroxyl fourth-1-alkynes)-1H-imidazoles-4-formonitrile HCN (I) and 2-(4-amino-1-benzyl-2-bromo-1H-imidazo [4,5-c] pyridine-6-yl)-ethanol (II)
With 1-benzyl-2-bromo-1H-imidazoles-5-iodo-4-formonitrile HCN (39mg, 0.1mmol) be dissolved in the acetonitrile (1ml) and with mixture with triethylamine (201,0.15mmol), Pd (PhCN)
2Cl
2(3.8mg, 0.01mmol) and fourth-1-alkynes-4-alcohol (91,0.12mmol) handle.Then with reactant in sealed tube, 100 ℃ the heating 2 hours.Reactant is cooled to room temperature and moves down and desolventize in vacuum.Then the ammonia solution in the 7N methyl alcohol is added into the residue thick brown resistates in, and with reactant in sealed tube, 120 ℃ the heating 18 hours.Under vacuum, remove volatile constituent then, produce thick brown oil.The LRMS of this material shows that main ingredient is cyclisation material (II), m/z (ESI) 347/349[MH]
+Then that this is oily with 10% pentane wash-out in the ethyl acetate, by the silica gel column chromatography purifying, the title compound (I) of generation yellow oily (6mg).Compound (II) can't reclaim in silicagel column.
1H-NMR(CDCl
3，400MHz)：(I)δ?2.75(t，2H)，3.79(t，2H)，5.2(s，2H)，7.18(m，2H)，7.22-7.38(m，3H)；LRMS?m/z(ESI)330/332[MH]
+
Preparation 162
1-benzyl-5-(Ding-4-hydroxyl-2-ketone-1-yl)-1H-imidazoles-2-methoxyl group-4-formonitrile HCN is with 1-benzyl-2-bromo-5-(4-hydroxyl fourth-1-alkynes)-1H-imidazoles-4-formonitrile HCN (6mg, 0.02mmol) be dissolved in the methyl alcohol (1ml) and with mixture with sodium methylate (5mg, * s) handle.Then reactant was heated 12 hours at 65 ℃.Reactant is cooled to room temperature and solvent is removed under vacuum.Then the 2N hydrochloric acid soln is added in the remaining thick resistates and with reactant and at room temperature stirred 2 hours.Under vacuum, remove volatile constituent then, produce the thick white solid that mainly contains title compound; LRMS m/z (ESI) 300[MH]
+
Preparation 163
2,6-two chloro-4-(N-nitro) amino-pyridine
0 ℃, under nitrogen atmosphere with 2,6-two chloro-4-aminopyridines (1.58g) are dissolved in the sulfuric acid (20ml), dropwise add nitric acid (2.5ml).After 30 minutes, reactant becomes orange and it slowly is poured in the frozen water.Throw out is filtered, wash with water then and be dissolved in the ethyl acetate.Then with organic solution MgSO
4Drying is filtered and is also evaporated in a vacuum to produce the title compound (1.7g) of yellow solid.
1H?NMR(CDCl
3，400MHz)δ?7.40(s，2H)，10.4(s，1H)。
Preparation 164
2,6-two chloro-4-amino-5-nitro-pyridines
With 2,6-two chloro-4-(N-nitro) amino-pyridines (1.7g) are dissolved in the sulfuric acid (10ml), and 90 ℃ of heating 30 minutes.Reaction mixture is cooled to room temperature, is poured into then in the frozen water to produce throw out.Yellow solid is leached, collects, is dissolved in the ethyl acetate, use Na then
2CO
3Solution washing.Then organism is used the salt water washing again, use MgSO
4Drying is filtered and is also evaporated in a vacuum to produce the title compound (1.45g) of yellow solid.
1H?NMR(CDCl
3，400MHz)δ?5.70(s，2H)，6.70(s，1H)；LRMS(ES
+)m/z?209[MH]
+
Preparation 165
2,6-two bromo-4-amino-5-nitro-pyridines
With 2,6-two chloro-4-amino-5-nitro-pyridine (2g) is dissolved in 33% solution of HBr in acetate (20mL), and 90 ℃, Teflon liner vessel in heating 72 hours.Reaction mixture is cooled to room temperature, is poured in the frozen water to produce throw out.The gained solid is leached, collects, is dissolved in the ethyl acetate, use Na then
2CO
3Solution washing.Then organism is used the salt water washing again, use MgSO then
4Drying is filtered and is also evaporated in a vacuum to produce the title compound (2g) of light yellow solid.
1H?NMR(CDCl
3，400MHz)δ?5.60(s，2H)，6.90(s，1H)；LRMS(ES
+)m/z295，297，299[MH]
+
Preparation 166
2,6-two bromo-4-chloro-5-nitro-pyridines
With 2,6-two bromo-4-amino-5-nitro-pyridine (3g) is dissolved in the concentrated hydrochloric acid (20ml), is cooled to 0 ℃.Add Sodium Nitrite (3.5g), and reaction mixture was stirred 1 hour at 0 ℃.Remove ice bath and reactant is heated to room temperature, then by adding ethyl acetate (50ml) and water (100ml) quenching through 3 hours.Organic layer is separated, use MgSO
4Dry and filtration also is evaporated to light yellow oil in a vacuum, uses 35:1 pentane: EtOAc as elutriant, by the column chromatography purifying it, to produce the title compound (2.2g) of white solid.
1H?NMR(CDCl
3，400MHz)δ?7.65(s，1H)。
Preparation 167
N-2, N-4-dibenzyl-6-bromo-3-nitro-pyridine-2,4-diamines
With 2,6-two bromo-4-amino-5-nitro-pyridine (1.53g) is dissolved among the THF (20ml), and each adds solid K with portion then
2CO
3(100mg) and benzylamine (1.1ml).Then reaction mixture was heated 16 hours at 70 ℃.Remove solvent in a vacuum, 10% ethyl acetate in the use pentane is as elutriant, by the title compound (1.2g) of the thick resistates of silica gel column chromatography purifying with the generation yellow oily.
1H?NMR(CDCl
3，400MHz)δ?4.45(d，2H)，4.78(d，2H)，6.20(s，1H)，7.20-7.41(m，10H)，9.41(s，1H)，9.50(s，1H)；LRMS(ES
+)m/z?413，415[MH]
+
Preparation 168
4,6-pair-benzylamino-5-nitro-pyridine-2-methyl-formiate
With N-2, N-4-dibenzyl-6-bromo-3-nitro-pyridine-2,4-diamines (1g) is dissolved in methyl alcohol and DMF (2:1, in mixture 15ml), add triethylamine (0.7ml), triphenylphosphine (30mg) and acid chloride (27mg) then, and with mixture heating 16 hours under 60 ℃ and 100psi carbon monoxide pressure.Reaction mixture is cooled to room temperature, filters with the short plug of Arbocel and also evaporate in a vacuum to produce yellow residue.8:1 → 2:1 pentane gradient in the use ethyl acetate is as elutriant, by the title compound (0.5g) of this resistates of silica gel column chromatography purifying with the generation light yellow solid.
1H?NMR(CDCl
3，400MHz)δ?3.91(s，2H)，4.58(s，1H)，4.85(d，2H)，6.85(s，1H)，7.05-7.25(m，10H)，9.3(t，1H)，9.55(t，1H)；LRMS(ES
+)m/z?393[MH]
+
Preparation 169
5-amino-4,6-benzylamino-pyridine-2-methyl-formiate
With 4,6-is two-benzylamino-5-nitro-pyridine-2-methyl-formiate (800mg) is dissolved in the methyl alcohol (30ml), and Raney nickel (80mg) is added with portion, and with mixture at room temperature, under the 60psi hydrogen pressure, stirred 3 hours.Reaction mixture is evaporated to produce the title compound (0.75g) of yellow residue shape in a vacuum with the short plug filtration of Arbocel and with filtrate, and it need not to be further purified just and can use; LRMS (ES
+) m/z 363[MH]
+
Preparation 170
1-benzyl-4-benzylamino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-6-methyl-formiate
With 5-amino-4,6-benzylamino-pyridine-2-methyl-formiate (0.75g) is dissolved in the acetonitrile (40ml), and with 1,1-carbonyl dimidazoles (500mg) adds with portion, and mixture was heated 6 hours at 80 ℃.Reaction mixture is evaporated in a vacuum to produce resistates, and the 1:1 pentane in the use ethyl acetate is as elutriant, by the silica gel column chromatography purifying, to produce the title compound (100mg) of white solid.
1H?NMR(d6-DMSO，400MHz)δ?3.75(s，3H)，4.45(d，2H)，4.98(s，2H)，6.48(t，1H)，7.18(s，1H)，7.22-7.47(m，10H)；LRMS(ES
+)m/z?389[MH]
+
Preparation 171
1-benzyl-4-benzylamino-2-oxo-2,3-dihydro [4,5-c] pyridine-6-formic acid
With 1-benzyl-4-benzylamino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-6-methyl-formiate (0.03g) is dissolved in methyl alcohol (1ml) and the 1N NaOH solution (2ml), and with mixture 40 ℃ of stirrings.After 2 hours, add the 2N HCl of 2ml, impel solid precipitation to separate out.This solid is leached and the dry in a vacuum title compound (25mg) with the generation white solid.
1H?NMR(CDCl
3，400MHz)δ?4.30(s，2H)，4.90(s，2H)，7.10-7.35(m，11H)，10.80(s，1H)；LRMS(ES
+)m/z?375[MH]
+
Preparation 172
1-benzyl-4-benzylamino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-6-formic acid cyclopropyl methyl nitrosourea
With 1-benzyl-4-benzylamino-2-oxo-2,3-dihydro-1H-imidazo [4,5-c] pyridine-6-methyl-formiate (0.05g) be dissolved in cyclopropyl-methylamine (1ml) and in reaction flask, 80 ℃ the heating 3 hours.Remove solvent in a vacuum, add ether, impel solid precipitation to separate out.This solid leached and dry in a vacuum to produce the 40mg white solid.The mixture that uses acetonitrile, water and diethylamine as elutriant, by preparation property HPLC with this solid purifying, with the title compound (18mg) of generation white solid.
1H?NMR(CDCl
3，400MHz)δ?0.22(q，2H)，0.55(q，2H)，1.05(m，1H)，3.22(t，2H)，4.35(d，2H)，4.90(s，2H)，5.90(t，1H)，7.10-7.35(m，11H)，7.85(t，1H)；LRMS(ES
+)m/z?428[MH]
+
Preparation 173
4-bromo-2-chloro-6-trifluoromethyl-pyridin-3-yl amine
(150g 925mmol) is suspended in the 500ml acetonitrile with 6-trifluoromethyl-pyridin-3-yl amine.With N-chlorosuccinimide (124g 925mmol) is added in this solution, and with mixture 80 ℃ of heating 2 hours, add then N-bromosuccinimide (165g, 925mmol) and with mixture 80 ℃ of reheat 3 hours.Reaction mixture is cooled to envrionment temperature, and vacuum concentration also grinds in the 100ml ether, removes throw out by filtration.With gained filtrate vacuum concentration, and use heptane: EtOAc 4:1 wash-out, by the silica column chromatogram purification, to produce garnet oily title compound (220g, 86%).
1H?NMR(CDCl
3)δ?4.90(bs，2H)，7.67(s，1H)；LRMS(ES)m/z?275/277[MH]
+
Preparation 174
N
*4
*-benzyl-2-chloro-6-trifluoromethyl-pyridine-3, the 4-diamines
Cesium fluoride (46.3g, 305mmol) and benzylamine (66.6ml 610mmol) exists down, and (84g 300mmol) places 500ml DMSO to stir with 4-bromo-2-chloro-6-trifluoromethyl-pyridin-3-yl amine.Gained brown suspension was heated 16 hours at 150 ℃.1500ml water is added in the suspension that is cooled and with mixture with 2 * 500ml extracted with diethyl ether.The organic extract drying that is merged (is used MgSO
4), vacuum concentration also use heptane: EtOAc 4:1-2:1 wash-out, pass through the silica column chromatography purification, to produce light brown solid title compound (15.8g, 17%).The non-required isomer of brown buttery is separated (51.0g, 48%) with the same manner.
1H?NMR(CDCl
3)δ?3.76(bs，2H)，4.39-4.41(d，2H)，4.53(bs，1H)，6.85(s，1H)，7.34-7.40(m，5H)；LRMS(ES)m/z?302[MH]
+。
Preparation 175
4,6-dihydroxyl-2-trifluoromethyl-Nikithan
In a three-necked bottle, (5.8g 51.9mmol) is suspended in the 100ml tetrahydrofuran (THF), slowly adds 1,3-acetonedicarboxylic acid diethyl ester (10g, 49.5mmol) solution in the 30ml tetrahydrofuran (THF) with potassium tert.-butoxide.Finish in case add, then mixture was at room temperature stirred 30 minutes.In second three-necked bottle of being furnished with the pneumatic outlet that is connected with first three-necked bottle, with 2,2, (11.2g 98.9mmol) is dissolved in the 80ml pyridine 2-trifluoroacetamide, slowly adds trifluoroacetic anhydride (TFAA) (20.8g, 98.9mmol) premixed solution in the 30ml pyridine, the gas that forms (2,2,2-trifluoromethyl acetonitrile) directly bubbling feeds first three-necked bottle.Finish in case add, the mixture in second three-necked bottle was at room temperature stirred 30 minutes, remove solvent then in a vacuum, and resistates is poured among the 4M HCl of 100ml.With mixture 150ml ethyl acetate extraction.Organic layer is separated, also remove solvent in a vacuum with dried over mgso.Resistates is ground in methylene dichloride, and throw out is filtered to produce 3g solid title compound.
1H NMR (MeOD): 12.5 (s, 1H), 12.4 (wide unimodal, 1H), 7.1 (s, 1H), 5.05 (q, 2H), 2.05 (t, 3H); LRMS (ES
+) m/z 252[MH]
+
Preparation 176
4,6-dihydroxyl-5-nitro-2-trifluoromethyl-Nikithan
With 4, (1g 3.9mmol) is dissolved in the 10ml vitriol oil 6-dihydroxyl-2-trifluoromethyl-Nikithan, and at room temperature dropwise adds the 2ml nitrosonitric acid.Finish in case add, then mixture was at room temperature stirred 30 minutes.Then mixture is poured in the trash ice, collects white depositions, be dissolved in the 50ml ethyl acetate,, also remove solvent in a vacuum to produce the title compound of 1.1g white solid with dried over mgso with 50ml water and the water washing of 50ml salt.
1H?NMR(d6?DMSO)：4.25(q，2H)，1.20(t，3H)。
Preparation 177
6-trifluoromethyl-pyridine-2, the 4-glycol
With 4, (15g 59.7mmol) is dissolved among the dense HCl of 250ml 6-dihydroxyl-2-trifluoromethyl-Nikithan, and mixture was stirred 3 days at 115 ℃.Mixture is cooled to 0 ℃, and adding 0.88 ammonia is～7 until the pH value.With formed solid filtering, wash with water, with methylbenzene azeotropic, and dry in a vacuum to produce the 9g title compound of white solid.
1H?NMR(d6?DMSO)：6.7(s，1H)，6.1(s，1H)；LRMS(ES
+)m/z?180[MH]
+
Preparation 178
(2-amino-3-nitro-6-vinyl-pyridin-4-yl)-(6-methyl-pyridin-3-yl methyl)-urethanum
With (2-amino-6-chloro-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-yl methyl)-urethanum (715mg/1.955mmol), vinyl three potassium fluoborates (415mg/3.098mmol), [1,1 '-two (diphenylphosphino) ferrocene] dichloro palladium (II) .CH
2Cl
2(90mg/0.11mmol) and triethylamine (0.28ml/2.0mmol) be mixed among the iPrOH (8.0ml), and 50 ℃, at N
2Heating is 24 hours under the atmosphere.Direct preadsorption is on silicon-dioxide and pass through the column chromatography purifying to produce the resinoid title compound of purple (270mg).
1H NMR (CD3OD, 400MHz) δ 1.15-1.20 (multiplet, 3H), 2.50 (s, 3H), 4.05-4.15 (multiplet, 2H), 4.90-4.95 (multiplet, 2H), 5.60 (d, 1H), 6.20-6.30 (multiplet, 1H); 6.55-6.65 (multiplet, 2H), 7.20-7.25 (d/1H), 7.70 (multiplet/1H), 8.35 (s/1H); LRMS (ES) m/z358[MH]
+
Preparation 179
(2-amino-6-formyl radical-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-yl methyl)-urethanum
(2-amino-3-nitro-6-vinyl-pyridin-4-yl)-(6-methyl-pyridin-3-yl methyl)-urethanum (270mg/0.755mmol) is dissolved in acetone (5ml)/water (5ml), add perosmic anhydride (2.5wt% in
tAmong the BuOH) (0.10ml/0.008mmol).Stir 5 minutes to produce brown solution, add sodium metaperiodate (500mg/3.47mmol) then, orange suspension was stirred 1 hour.(20wt% is in H with the Sulfothiorine pentahydrate at EtOAc (100ml)
2Among the O) divide between (50ml) molten.Collect organism, use the salt water washing, use Na
2SO
4Drying is filtered and the simmer down to brown resin.With the EtOAc wash-out, by column chromatography purifying generation yellow oily title compound (220mg).
1H NMR (CDCl3,400MHz) δ 1.15-1.20 (multiplet, 3H), 2.55 (s, 3H), 4.10-4.20 (multiplet, 2H), 4.95 (s, 2H), 6.06-6.15 (br s, 2H), 7.05 (s, 1H); 7.10-7.15 (d, 1H), 7.60 (d/1H), 8.35-8.40 (s/1H), 9.75 (s/1H); LRMS (AP) m/z 360[MH]
+
Preparation 180
(2-amino-3-nitro-6-oxazole-5-base-pyridin-4-yl)-(6-methyl-pyridin-3-yl methyl)-urethanum
(2-amino-6-formyl radical-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-yl methyl)-urethanum (190mg/0.529mmol) is dissolved among the MeOH (5ml).Add (4-tosyl group) methyl-isocyanide (124mg/0.634mmol), Anhydrous potassium carbonate (200mg/1.45mmol) successively.At N
2Stirred 1 hour under the atmosphere, then vacuum concentration.At EtOAc (100ml) and H
2Divide molten between the O (50ml).Collect organism, use the salt water washing, use Na
2SO
4Drying is filtered and the simmer down to black resin.Produce the title compound (135mg) of thick brown solid with 90:10 DCM/MeOH wash-out, by the column chromatography purifying; LRMS (ES) m/z399[MH]
+
Biological data
By the ability that PBL/HCV replicon biologic assay as detailed below comes affirmation formula (I) compound and pharmacy acceptable salt, solvate and polymorphic form adjusting TLR7 receptor active, wherein use following shortenings:
EMCV: encephalomyocarditis virus
IRES: internal ribosome entry site
Huh:Huh-7 people's hepatoma cell line 7 (being used to produce the parental cell of HCV replicon cell strain)
Luc: luciferase
Ubi: ubiquitin
Neo: Xin Meisu
ET: L-glutamic acid, Threonine (the cell cultures adaptive mutation of the replicon that is used for examining and determine)
RPMI-FCS:Roswell Park Memorial Institute (cell culture medium of PBL)-foetal calf serum
PBL: peripheral blood lymphocyte
PBL contains plasmocyte sample dendritic cell subgroup, and it is that natural interferon produces cell between period of infection, so it is a good model of describing interferon inducers.As a tetchy antiviral biological test, detect the antiviral activity of supernatant liquor in HCV replicon system of taking from PBL.Antiviral EC
50Value defined makes HCV replicon content reduce the concentration that was applied to the test compounds of PBL at 50% o'clock for after the PBL of predetermined amount substratum is passed to the cell strain that contains the HCV replicon.Although contain the cell of HCV replicon the PBL conditioned medium is responded fully, it does not directly respond thunderous Xi Mote of known TLR agonist (Resiquimod) and Imiquimod (Imiquimod).
The HCV replicon (Huh-5-2[I389luc-ubi-neo-NS3-3 '/ET]) be the external model that HCV duplicates, wherein the luciferase reporter molecule is integrated in the HCV sequence, and stably is retained among people's hepatoma cell line Huh-7.The Photinus pyralis LUC reporter molecule is expressed as luciferase-ubiquitin-neomycin phosphotransferase fusion rotein, and this fusion rotein can be divided by the host protein enzyme and discharge luciferase.This replicon also contains inner EMCV IRES, and it drives translating of HCVNS3-5B polymeric protein, and this albumen has cell cultures adaptive mutation ability to allow high cloning efficiency.Luciferase output shown with host cell in the content of the HCV RNA that exists directly be directly proportional.The Bright-Glo that the active Promega of use of Photinus pyralis LUC makes
TMThe luciferase detection system detects.
Specifically, the test compounds of 1-3mg is dissolved among 100% (v/v) DMSO, is generally 1,4 or 10mM or more than the 10mM to ultimate density, depend on required initial concentration in the test.The initial 3 times serial dilution series of preparation compound in 100% DMSO from mother liquor.Again this diluent series is further diluted 100 times with complete RPMI-FCS.Therefore, the final concentration of DMSO is that the final concentration of test compounds in 0.1%, the 100% DMSO diluent series is 1/1000 in the test.
PBL system is with 5 * 10
5/ hole/90 μ l are inoculated in the check-out console (96 holes bottom transparent TC level) of the compound that contains above-mentioned preparation and are prepared, and hatch 24 hours.
LucUbiNeo HCV replicon cell is with 10
4/ hole/90 μ l inoculation.It was hatched 24 hours.After 24 hours, from the PBL check-out console, get 10 μ l media transfer to HCV replicon check-out console and continued to hatch 48 hours.
| Embodiment No. | 1 | 2 | 3 | 4 | 12 | 15 | 16 | 17 | 18 | 19 | 20 | 21 | 22 |
| EC 50(nM) | 933 | 1540 | 266 | 497 | 240 | 252 | 104 | 955 | 107 | 355 | 700 | 215 | 450 |
| Embodiment No. | 23 | 24 | 25 | 26 | 27 | 31 | 32 | 34 | 36 | 37 | 38 | 39 | 40 |
| EC 50(nM) | 1080 | 1600 | 1000 | 926 | 453 | 3260 | 1710 | 1300 | 368 | 786 | 848 | 2200 | 427 |
| The embodiment numbering | 49 | 50 | 54 | 55 | 56 | 60 | 61 | 70 | 78 | 82 | 83 | 86 |
| EC 50(nM) | 2170 | 1970 | 302 | 2002 | 1300 | 445 | 1680 | 656 | 100 | 127 | 470 | 550 |
Compound advantageously of the present invention has at the TLR7 acceptor but not the selectivity of one or more other known Toll sample acceptor.Compound of the present invention also advantageously has at the TLR7 acceptor but not the selectivity of one or more cell kinases and/or one or more purinergic receptors such as adenosine or phosphodiester enzyme acceptor.
Embodiment 1,2,12 and 15 finds the TLR7 acceptor but not other all known Toll sample acceptors have selectivity through test.
In addition, embodiment 1,2,12 and 15 finds the TLR7 acceptor but not following target has selectivity: MEK (silk splits plain activated protein kinase/extracellular signal-regulated kinase), CDK1 (cyclin-dependent kinase-1), CDK2 (cyclin-dependent kinase-2), JNK (stress activated protein kinase), MSK (silk splits element and stress activated protein kinase), MSK-1, SGK, AMPK, MLCK, CHK-2 and phosphodiesterase PDE3, PDE4 and PDE5 through test.
In addition, embodiment 12 and 15 finds the TLR7 acceptor but not MAP (silk splits plain activated protein kinase) has selectivity through test.
In addition, embodiment 15 finds the TLR7 acceptor but not all known Adenosine Receptors A1, A2a, A2b and A3 have selectivity through test.
Claims (38)
1. the compound of formula (I),
The perhaps pharmacy acceptable salt of this compound or tautomer or solvate, wherein
(a) Y is a chemical bond, R
3Be selected from aryl, (C
1-C
6) alkyl and-(C
1-C
4) alkylidene group-O-(C
1-C
4) alkyl; Or
(b) Y is (C
1-4) alkylidene group, R
3Be selected from aryl, (C
3-C
7) cycloalkyl and 3-10 unit heterocyclic radical;
Z is oxygen or does not exist;
R
1Be selected from H, halogen, OH, CN, (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
6) alkoxyl group ,-NHSO
2R
6,-NR
6R
7,-C (O) R
6,-CO
2R
6,-C (O) NR
6R
7,-C (O) NR
6SO
2R
8, aryl and 3-10 unit heterocyclic radical;
R
2Be selected from H, halogen, OH, (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
6) alkoxyl group ,-NR
6R
7,-CO
2R
6,-C (O) NR
6R
7,-C (O) NR
6SO
2R
8With 3-10 unit heterocyclic radical; Or
R
1With R
2Can be connected to form (C
2-C
5) the alkylidene group connection, this connection is chosen wantonly and is incorporated 1 or 2 heteroatoms that is selected from independently of one another among N, O and the S into;
R
5Do not exist and R
4Be selected from H, (C
3-C
7) cycloalkyl, aryl ,-(CH
2) aryl ,-C (O) R
9,-CO
2R
9,-(C
1-C
6) alkylidene group-O-C (O) R
9,-(C
1-C
6) alkylidene group-O-CO
2R
9) ,-C (O) NR
9R
10,-(C
1-C
6) alkylidene group-O-C (O) NR
9R
10With-(C
1-C
6) alkylidene group-O-P (O) (OH)
2Or
R
4Do not exist and R
5Be selected from R
9,-C (O) R
9,-CO
2R
9,-(C
1-C
6) alkylidene group-O-C (O) R
9,-(C
1-C
6) alkylidene group-O-CO
2R
9,-C (O) NR
9R
10,-(C
1-C
6) alkylidene group-O-C (O) NR
9R
10With-(C
1-C
6) alkylidene group-O-P (O) (OH)
2
R
6And R
7Be selected from H, (C independently of one another
1-C
6) alkyl, (C
3-C
7) cycloalkyl and-(C
1-C
6) alkylidene group (C
3-C
7) cycloalkyl; Or R
6And R
7Form 3-6 unit saturated heterocyclic with the nitrogen that they connected, this saturated heterocyclic is chosen wantonly and is contained other 1 or 2 heteroatoms that is selected among N, O and the S;
R
8Be selected from (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl and phenyl;
R
9And R
10Be selected from H, (C independently of one another
1-C
6) alkyl, (C
3-C
7) cycloalkyl, aryl ,-(CH
2) aryl and 3-10 unit heterocyclic radical; Or R
9And R
10Form 3-10 unit heterocyclic radical with the nitrogen that they connected;
R
11And R
12Be independently selected from H and (C
1-C
6) alkyl; Or R
11And R
12Form 3-6 unit saturated heterocyclyl with the N that is connected, this saturated heterocyclyl is chosen wantonly and is contained other 1 or 2 heteroatoms that is selected among N, O and the S;
This alkyl, cycloalkyl, alkoxyl group, aryl and heterocyclic radical are optional to be independently selected from following atom or group replacement by one or more: halogen, OH, oxo, CF
3, CN, (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
6) alkoxyl group ,-(C
1-C
6) alkylidene group-O-(C
1-C
6) alkyl ,-(C
1-C
6) alkylidene group-OH ,-NR
11R
12,-(C
1-C
6) alkylidene group-NR
11R
12, aryl and 3-10 unit heterocyclic radical;
Its condition is, if R
1And R
2Be H and Z and R
5Do not exist, then:
(a) work as Y-R
3During for ethyl, R
4It is not methyl; And
(b) work as Y-R
3During for methyl, R
4Be not H or methyl.
2. compound as claimed in claim 1, wherein, R
1Be selected from
(a)H；
(b)CN；
(c) halogen
(d) optional (C that is replaced by 1-3 halogen atom
1-C
6) alkyl;
(e) tetrahydrofuran oxygen base;
(f) contained (C that 1-3 the first saturated heterocyclyl of heteroatomic 3-6 that is independently selected among N, O and the S replaces
1-C
6) alkyl, wherein this heterocyclic radical is optional is independently selected from CF by 1-3
3, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group and-(C
1-C
6) alkylidene group-O-(C
1-C
6) group in the alkyl replaces;
(g)-(C
1-C
4) alkylidene group-O-(C
1-C
6) alkyl;
(h)-(C
1-C
4) alkylidene group-N (H)-(C
1-C
4) alkylidene group-O-(C
1-C
4) alkyl;
(i) optional by the (C of OH or cyclopropyl replacement
1-C
6) alkoxyl group;
(j) (C
3-C
7) cycloalkyl;
(k)-(C
1-C
4) alkylidene group (C
3-C
7) cycloalkyl;
(l)-C(O)NR
6R
7；
(m)-CO
2R
6；
(n)-C(O)R
6；
(o) comprise (i) 1-4 nitrogen-atoms or (ii) 1-2 nitrogen-atoms and 1 Sauerstoffatom or sulphur atom or (iii) 5 yuan of aromatic heterocyclic radicals of 1 Sauerstoffatom or sulphur atom; 6 yuan of aromatic heterocyclic radicals that perhaps comprise 1-3 nitrogen-atoms, these 5 and 6 yuan of aromatic heterocyclic radicals are optional to be independently selected from halogen, OH, CF by 1-3
3, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group ,-(C
1-C
6) alkylidene group-O-(C
1-C
6) alkyl ,-(C
1-C
6) alkylidene group-OH ,-NR
11R
12With-(C
1-C
6) alkylidene group-NR
11R
12In atom or group replace;
(p) the optional phenyl that is replaced by 1-3 halogen atom;
(q)-NR
6R
7；
(r)-NH-(C
1-C
4) alkylidene group-O-(C
1-C
6) alkyl;
Wherein
R
6, R
7, R
11And R
12Such as claim 1 definition.
3. as the compound of claim 1 or 2, wherein, R
1Be selected from
(a)H；
(b)CN；
(c) halogen
(d) optional (C that is replaced by 1-3 halogen atom
1-C
6) alkyl;
(e) tetrahydrofuran oxygen base;
(f) chosen wantonly (the C that is replaced by 1 or 2 methyl substituted morpholine, piperazine or tetramethyleneimine
1-C
6) alkyl;
(h)-(C
1-C
4) alkylidene group-N (H)-(C
1-C
4) alkylidene group-O-(C
1-C
4) alkyl;
(i) optional by the (C of OH or cyclopropyl replacement
1-C
6) alkoxyl group;
(j) (C
3-C
7) cycloalkyl;
(k)-(C
1-C
4) alkylidene group (C
3-C
7) cycloalkyl;
(l)-C(O)NR
6R
7；
(m)-CO
2R
6；
(n)-C(O)R
6；
(o) comprise (i) 1-4 nitrogen-atoms or (ii) 1-2 nitrogen-atoms and 1 Sauerstoffatom or sulphur atom or (iii) 5 yuan of aromatic heterocyclic radicals of 1 Sauerstoffatom or sulphur atom; 6 yuan of aromatic heterocyclic radicals that perhaps comprise 1-3 nitrogen-atoms, these 5 and 6 yuan of aromatic heterocyclic radicals are optional to be independently selected from halogen, OH, CF by 1-3
3, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group ,-(C
1-C
6) alkylidene group-O-(C
1-C
6) alkyl ,-(C
1-C
6) alkylidene group-OH ,-NR
11R
12With-(C
1-C
6) alkylidene group-NR
11R
12In atom or group replace;
(p) the optional phenyl that is replaced by 1-3 halogen atom;
(q)-NR
6R
7；
(r)-NH-(C
1-C
4) alkylidene group-O-(C
1-C
6) alkyl;
Wherein,
R
6, R
7, R
11And R
12Such as claim 1 definition.
4. as the compound of above-mentioned each claim, wherein, R
1Be selected from: methyl that is replaced by 1-3 fluorine atom or ethyl, cyclopropyl ,-(C
1-C
2) alkylidene group-O-(C
1-C
2) alkyl, optional by the (C of OH or cyclopropyl replacement
1-C
4) alkoxyl group ,-COCH
3,-CH
2OCH
3, and-CO
2CH
3
5. as the compound of above-mentioned each claim, wherein, R
1Be cyclopropyl or CF
3
6. as each compound among the claim 1-3, wherein, R
1For comprising (i) 1-4 nitrogen-atoms or (ii) 1-2 nitrogen-atoms and 1 Sauerstoffatom or sulphur atom or (iii) 5 yuan of aromatic heterocyclic radicals of 1 Sauerstoffatom or sulphur atom, these 5 yuan of aromatic heterocyclic radicals are optional to be independently selected from following atom or group replaces: halogen, OH, CF by 1-3
3, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group ,-(C
1-C
3) alkylidene group-O-(C
1-C
4) alkyl ,-(C
1-C
4) alkylidene group-OH ,-NR
11R
12With-(C
1-C
3) alkylidene group-NR
11R
12, wherein, R
11And R
12Such as claim 1 definition.
7. compound as claimed in claim 6, wherein, R
1Be selected from imidazolyl, oxazolyl, oxadiazole base, triazole, pyrazoles and thiazole, they are all chosen wantonly by 1-3 and are independently selected from following atom or group replacement: halogen, OH, CF
3, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group ,-(C
1-C
3) alkylidene group-O-(C
1-C
4) alkyl ,-(C
1-C
4) alkylidene group-OH and-(C
1-C
3) alkylidene group-NR
11R
12, wherein, R
11And R
12Such as claim 1 definition.
8. compound as claimed in claim 7, wherein, R
1Being selected from not, Bei replaces De oxazolyl, triazole, pyrazoles and thiazole.
9. compound as claimed in claim 8, wherein, R
1The Wei oxazolyl.
10. as the compound of above-mentioned each claim 1, wherein, R
2Be selected from
(a)H；
(b) halogen;
(c) optional (C that is replaced by 1-3 halogen atom
1-C
6) alkyl;
(d) tetrahydrofuran oxygen base;
(e) contained (C that 1-3 the first saturated heterocyclyl of heteroatomic 3-6 that is independently selected among N, O and the S replaces
1-C
6) alkyl, wherein this heterocyclic radical is optional is independently selected from CF by 1-3
3, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group and-(C
1-C
6) alkylidene group-O-(C
1-C
6) group in the alkyl replaces;
(f)-(C
1-C
4) alkylidene group-O-(C
1-C
6) alkyl;
(g)-(C
1-C
4) alkylidene group-N (H)-(C
1-C
4) alkylidene group-O-(C
1-C
4) alkyl;
(h) optional by the (C of OH or cyclopropyl replacement
1-C
6) alkoxyl group;
(i) (C
3-C
7) cycloalkyl;
(j)-(C
1-C
4) alkylidene group (C
3-C
7) cycloalkyl;
(k)-C(O)NR
6R
7；
(l)-CO
2R
6；
(m)-C(O)R
6；
(n) comprise (i) 1-4 nitrogen-atoms or (ii) 1-2 nitrogen-atoms and 1 Sauerstoffatom or sulphur atom or (iii) 5 yuan of aromatic heterocyclic radicals of 1 Sauerstoffatom or sulphur atom; 6 yuan of aromatic heterocyclic radicals that perhaps comprise 1-3 nitrogen-atoms, these 5 and 6 yuan of aromatic heterocyclic radicals are optional to be independently selected from halogen, OH, CF by 1-3
3, (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group ,-(C
1-C
6) alkylidene group-O-(C
1-C
6) alkyl ,-(C
1-C
6) alkylidene group-OH ,-NR
11R
12With-(C
1-C
6) alkylidene group-NR
11R
12In atom or group replace;
(o) the optional phenyl that is replaced by 1-3 halogen atom;
(p)-NR
6R
7；
(q)-NH-(C
1-C
4) alkylidene group-O-(C
1-C
6) alkyl;
Wherein
R
6, R
7, R
11And R
12Such as claim 1 definition.
11. as the compound of above-mentioned each claim, wherein, R
2Be H or methyl.
12. as the compound of above-mentioned each claim, wherein, R
2Be H.
13. as the compound of above-mentioned each claim, wherein, Z does not exist.
14. as the compound of above-mentioned each claim, wherein, Y is a methylene radical; And R
3Be selected from: aryl; Comprise (i) 1-4 nitrogen-atoms or (ii) 1-2 nitrogen-atoms and 1 Sauerstoffatom or sulphur atom or (iii) 5 yuan of aromatic heterocyclic radicals of 1 Sauerstoffatom or sulphur atom; With 6 yuan of aromatic heterocyclic radicals that comprise 1-3 nitrogen-atoms; This aryl and aromatic heterocycle are optional to be independently selected from following atom or group replacement by 1-3: halogen, OH, oxo, CF
3, CN, (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
6) alkoxyl group ,-(C
1-C
6) alkylidene group-O-(C
1-C
6) alkyl ,-(C
1-C
6) alkylidene group-OH ,-NR
11R
12,-(C
1-C
6) alkylidene group-NR
11R
12, aryl and 3-10 unit heterocyclic radical, wherein, R
11And R
12Such as claim 1 definition.
15. as the compound of above-mentioned each claim, wherein, Y is a methylene radical; And R
3Be selected from phenyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl, its each optionally be independently selected from halogen, (C by 1-3
1-4) alkyl, (C
1-C
4) alkoxyl group and CF
3In atom or group replace.
16. as the compound of above-mentioned each claim, wherein, Y is a methylene radical; And R
3Be selected from phenyl, pyridin-3-yl and 6-methyl-pyridin-3-yl.
17. as the compound of above-mentioned each claim, wherein, R
5Do not exist; And
R
4Be selected from-(C
1-C
6) alkylidene group-O-C (O) R
9,-(C
1-C
6) alkylidene group-O-CO
2R
9,-(C
1-C
6) alkylidene group-O-C (O) NR
9R
10With-(C
1-C
6) alkylidene group-O-P (O) (OH)
2, wherein, R
9And R
10Such as claim 1 definition.
18. as the compound of above-mentioned each claim, wherein, R
4Be H and R
5Do not exist.
19. as each compound among the claim 1-16, wherein, R
4Do not exist; And R
5Be selected from-(C
1-C
6) alkylidene group-O-C (O) R
9,-(C
1-C
6) alkylidene group-O-CO
2R
9,-(C
1-C
6) alkylidene group-O-C (O) NR
9R
10With-(C
1-C
6) alkylidene group-O-P (O) (OH)
2, wherein, R
9And R
10Such as claim 1 definition.
20. compound as claimed in claim 1, wherein:
Y is a methylene radical;
R
1Be selected from CF
3, cyclopropyl is with oxazole;
R
2Be H;
R
3Be selected from phenyl, pyridin-3-yl and 6-methyl-pyridin-3-yl;
R
4Be H; And
R
5Do not exist.
21. the compound of formula (Ic),
Or its tautomer, the perhaps pharmacy acceptable salt of this compound or tautomer, solvate or polymorphic form,
Wherein,
Y is a methylene radical;
R
1And R
2Be selected from H, halogen, OH, (C independently of one another
1-C
6) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
6) alkoxyl group ,-NR
6R
7,-CO
2R
6,-C (O) NR
6R
7,-C (O) NR
6SO
2R
8, aryl and 3-10 unit heterocyclic radical; Or
R
1With R
2Can be connected to form (C
2-C
5) the alkylidene group connection, this connection is chosen wantonly and is incorporated 1 or 2 heteroatoms that is selected from independently of one another among N, O and the S into;
R
3Be selected from (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl, aryl and 3-10 unit heterocyclic radical;
R
4Be selected from R
9,-C (O) R
9,-CO
2R
9With-C (O) NR
9R
10, R
5Do not exist; Or
R
5Be selected from R
9,-C (O) R
9,-CO
2R
9With-C (O) NR
9R
10, R
4Do not exist;
R
6And R
7Be selected from H and (C independently of one another
1-C
6) alkyl;
R
8Be selected from (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl and phenyl;
R
9And R
10Be selected from H, (C independently of one another
1-C
6) alkyl, (C
3-C
7) cycloalkyl, aryl ,-(CH
2) aryl and 3-10 unit heterocyclic radical; Or
R
9And R
10Form 3-10 unit heterocyclic radical with the nitrogen that they connected;
Abovementioned alkyl, cycloalkyl, alkoxyl group, aryl and heterocyclic radical are optional to be replaced by one or more group that is independently selected from following group: halogen, OH, oxo, CF
3, CN, (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
6) alkoxyl group ,-(C
1-C
6) alkylidene group-O-(C
1-C
6) alkyl ,-NH (C
1-C
6) alkyl ,-N ((C
1-C
6) alkyl)
2, aryl and 3-10 unit heterocyclic radical;
Its condition is, if R
1And R
2Be H, Z and R
5Do not exist, then:
(a) work as Y-R
3During for ethyl, R
4It is not methyl; And
(b) work as Y-R
3During for methyl, R
4Be not H or methyl.
22. as the compound of claim 21, wherein, R
1And R
2Be selected from independently of one another: H, (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl ,-CO
2H ,-CO
2(C
1-C
6) alkyl and-C (O) NH (C
1-C
6) alkylidene group (C
3-C
7) cycloalkyl; Or R
1With R
2Can be connected to form (C
2-C
5) the alkylidene group connection.
23. as the compound of claim 22, wherein, R
1Be selected from H, methyl, n-propyl, sec.-propyl, cyclopropyl ,-CO
2H ,-CO
2CH
3With-C (O) NH (CH
2) cyclopropyl; And R
2Be selected from H and methyl; Or R
1With R
2Can be connected to form C
5-alkylidene group connects.
24. as the compound of claim 21-23, wherein, R
3Be aryl, it is chosen wantonly by one or more group that is independently selected from following group and replaces: halogen, OH, oxo, CF
3, CN, (C
1-C
6) alkyl, (C
3-C
7) cycloalkyl, (C
1-C
6) alkoxyl group, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl ,-NH (C
1-C
6) alkyl ,-N ((C
1-C
6) alkyl)
2, aryl and 3-10 unit heterocyclic radical.
25. as the compound of claim 24, wherein, R
3Be phenyl, it is chosen wantonly and is independently selected from halogen and CF by one or more
3In group replace.
26. formula as claimed in claim 1 (I) compound, it is selected from:
4-amino-1-benzyl-6-cyclopropyl-1,3-dihydro-imidazol-is [4,5-c] pyridin-2-ones also;
4-amino-1-benzyl-6-oxazole-2-base-1,3-dihydro-imidazol-is [4,5-c] pyridin-2-ones also; And
4-amino-1-benzyl-6-Trifluoromethyl-1,3-dihydro-imidazol-is [4,5-c] pyridin-2-ones also;
Or the pharmacy acceptable salt of this compound or solvate.
27. medicine merges thing, comprises formula (I) compound as above-mentioned each claim or pharmacy acceptable salt or solvate and one or more pharmaceutically acceptable vehicle of this compound.
28. the medicine as claim 27 merges thing, it comprises one or more other therapeutical agents.
29. the medicine as claim 28 merges thing, wherein above-mentioned one or more other therapeutic activity agent are selected from HCV NS3A albumen, HCV NS5A albumen, HCV NS4B albumen, HCV polysaccharase, HCV metalloprotease, HCV serine protease, HCV helicase and the proteic inhibitor of p7.
30. as each formula (I) compound or the pharmacy acceptable salt or the solvate of this compound among the claim 1-26, as medicine.
31., be used for the treatment of disease or the illness relevant with the adjusting of TLR7 acceptor as each formula (I) compound or the pharmacy acceptable salt or the solvate of this compound among the claim 1-26.
32. compound as claim 31, wherein, described disease or illness are to be selected from following each viral virus infection: adenovirus, simplexvirus, poxvirus, orthomyxovirus, Paramyxo virus, coronavirus, papovavirus, papillomavirus, hepadnavirus, flavivirus, retrovirus and inovirus.
33. as the compound of claim 31, wherein, described disease or illness are hepatitis C.
34. be used for the treatment of purposes in the medicine of disease relevant or illness in preparation with the adjusting of TLR7 acceptor as the pharmacy acceptable salt of each described formula (I) compound or this compound among the claim 1-26 or solvate.
35. the disease that treatment is relevant with the adjusting of TLR7 acceptor in Mammals or the method for illness are comprising the pharmacy acceptable salt or the solvate of each described formula (I) compound or this compound in the claim 1-26 of described Mammals drug treatment significant quantity.
36. the preparation method of the compound of formula (I),
Wherein, in each person of formula I, XVIII, XVIIIa, XIX, XIXa, XXa, XXb, XIV, XV, LIV and LXIII, Y-R
3Such as claim 14 definition, R
1Such as claim 2 definition, R
2Such as claim 10 definition, PG
1And PG
2Be nitrogen protective material and R
13Be (C
1-6) alkyl;
This method comprises:
(a) make the reaction of formula (XVIII) or compound (XVIIIa) and carbonyl supplying agent,
Forming corresponding formula (XIX) or (XIXa) compound,
Then, with formula (XIX) or compound deprotection (XIXa); Perhaps
(b) compound of formula (XXa) is reduced,
Forming the compound of formula (XXb),
Then by handle the compound cyclisation that makes formula (XXb) with protonic acid; Perhaps
(c) compound of formula (XIV) is reduced,
Forming the compound of formula (XV),
In the presence of carbonyl moiety, make the compound cyclisation of formula (XV) then; Perhaps
(e) in the presence of the diphenylphosphine acyl azide, the compound cyclisation that makes formula (LIV) is the compound of above-mentioned corresponding formula (XIXA), then with the amino protecting group deprotection,
Perhaps
(f) make the compound hydrolysis of formula (LXIII),
37. the compound of formula XVIII, XVIIIa, XIX, XIXa, XXa, XXb, XIV, XV, LIV and LXIII, wherein, Y-R
3Such as claim 14 definition, R
1Such as claim 2 definition, R
2Such as claim 10 definition, PG
1And PG
2Be nitrogen protective material and R
13Be (C
1-6) alkyl.
38. the compound of formula XVIII, XVIIIa, XIX, XIXa, XXa, XXb, XIV, XV, LIV and LXIII, wherein, Y-R
3As claim 15 or 16 definition, R
1As each defines among the claim 4-6, R
2Be H or methyl, PG
1And PG
2Be nitrogen protective material and R
13Be (C
1-6) alkyl.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US77458006P | 2006-02-17 | 2006-02-17 | |
| US60/774,580 | 2006-02-17 | ||
| US60/829,730 | 2006-10-17 | ||
| US60/870,020 | 2006-12-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101384593A true CN101384593A (en) | 2009-03-11 |
Family
ID=40463757
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800056096A Pending CN101384593A (en) | 2006-02-17 | 2007-02-05 | 3-deazapurine derivatives as tlr7 modulators |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN101384593A (en) |
| DO (1) | DOP2007000030A (en) |
| ZA (1) | ZA200806811B (en) |
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| CN107188891A (en) * | 2017-06-29 | 2017-09-22 | 天津药明康德新药开发有限公司 | A kind of synthetic method of 5 (tert-butyl carbonyl) 1 methylimidazoles and the carboxylic acid of pyridine 7 |
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| US10500209B2 (en) | 2013-07-31 | 2019-12-10 | Zenith Epigenetics Ltd. | Quinazolinones as bromodomain inhibitors |
| WO2020093905A1 (en) * | 2018-11-07 | 2020-05-14 | 四川科伦博泰生物医药股份有限公司 | Ring-fused compound, preparation method therefor and application thereof |
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| CN113750095A (en) * | 2021-03-10 | 2021-12-07 | 中国医学科学院医药生物技术研究所 | Application of compound containing cyclopropyl skeleton in preparation of medicine for treating and/or preventing coronavirus infection |
| WO2022111636A1 (en) * | 2020-11-26 | 2022-06-02 | 江苏恒瑞医药股份有限公司 | Fused tricyclic compound, preparation method therefor and application thereof in medicine |
-
2007
- 2007-02-05 CN CNA2007800056096A patent/CN101384593A/en active Pending
- 2007-02-13 DO DO2007000030A patent/DOP2007000030A/en unknown
-
2008
- 2008-08-06 ZA ZA200806811A patent/ZA200806811B/en unknown
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| WO2022111636A1 (en) * | 2020-11-26 | 2022-06-02 | 江苏恒瑞医药股份有限公司 | Fused tricyclic compound, preparation method therefor and application thereof in medicine |
| CN116490506A (en) * | 2020-11-26 | 2023-07-25 | 江苏恒瑞医药股份有限公司 | Fused tricyclic compounds, process for their preparation and their use in medicine |
| CN113750095A (en) * | 2021-03-10 | 2021-12-07 | 中国医学科学院医药生物技术研究所 | Application of compound containing cyclopropyl skeleton in preparation of medicine for treating and/or preventing coronavirus infection |
| CN113750095B (en) * | 2021-03-10 | 2023-07-04 | 中国医学科学院医药生物技术研究所 | Application of compound containing cyclopropyl skeleton in preparation of medicines for treating and/or preventing coronavirus infection |
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| Publication number | Publication date |
|---|---|
| DOP2007000030A (en) | 2007-09-15 |
| ZA200806811B (en) | 2010-01-27 |
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