CN102153538A - Benzocyclodirivative - Google Patents
Benzocyclodirivative Download PDFInfo
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- CN102153538A CN102153538A CN2011100369794A CN201110036979A CN102153538A CN 102153538 A CN102153538 A CN 102153538A CN 2011100369794 A CN2011100369794 A CN 2011100369794A CN 201110036979 A CN201110036979 A CN 201110036979A CN 102153538 A CN102153538 A CN 102153538A
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- 0 *c1c(*C([N+]2)=*)c2c(*2CCCCCCCCC2)c(*)c1* Chemical compound *c1c(*C([N+]2)=*)c2c(*2CCCCCCCCC2)c(*)c1* 0.000 description 4
- WFAFKYDHTCCWOQ-GFCCVEGCSA-N CC(C)(C)OC(N[C@H](CCC1)CN1c(cc(cc1NC)F)c1[N+]([O-])=O)=O Chemical compound CC(C)(C)OC(N[C@H](CCC1)CN1c(cc(cc1NC)F)c1[N+]([O-])=O)=O WFAFKYDHTCCWOQ-GFCCVEGCSA-N 0.000 description 1
- XIRRDAWDNHRRLB-UHFFFAOYSA-N Nc(c(Br)ccc1)c1Br Chemical compound Nc(c(Br)ccc1)c1Br XIRRDAWDNHRRLB-UHFFFAOYSA-N 0.000 description 1
- OPKZEDOPCBQRRH-UHFFFAOYSA-N O=Nc(c(Br)ccc1)c1Br Chemical compound O=Nc(c(Br)ccc1)c1Br OPKZEDOPCBQRRH-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention belongs to the technical field of medicaments, in particular relates to a benzocyclodirivative as shown in a general formula (I) as well as pharmaceutically acceptable salts, a hydras and an isomer thereof, wherein R1, R2, R3, R4, Q, X and Y are defined in the specification. The invention also relates to a preparation method of the compounds, a pharmaceutical composition containing the compounds and application of the compounds in preparing medicaments for treating and/or preventing non-insulin-dependent diabetes mellitus.
Description
1, technical field
The invention belongs to medical technical field, be specifically related to benzo ring derivatives, its pharmacy acceptable salt, its steric isomer or its solvate, the preparation method of these compounds, the pharmaceutical composition that contains these compounds, and these compounds treat and/or prevent application in the medicine of non-insulin-dependent diabetes mellitus (NIDDM) in preparation.
2, background technology
Diabetes are a kind of whole body chronic metabolic disease that normal level causes that exceed owing to blood sugar is out of control.Substantially be divided into four classes, comprise: I type (insulin-dependent), II type (non-insulin-depending type), other type and gestational diabetes.I type and type ii diabetes belong to primary diabetes mellitus, are modal two kinds of forms, are caused by the h and E factor interaction.The cause of disease of diabetes is very complicated, but is because Regular Insulin is absolute or relative the shortage after all, or insulin resistant.Its characteristics are because the absolute or relative deficiency of Regular Insulin and target cell to the susceptibility reduction of Regular Insulin, cause the metabolism disorder of carbohydrate, protein, fat, ionogen and water.
In recent years, because the rhythm of life that the change of growth in the living standard, dietary structure, day are becoming tight and few moving mode of life of sitting etc. all multifactor more, whole world onset diabetes rate increases rapidly, and diabetes have become the chronic disease of the third-largest serious threat human health after tumour, cardiovascular pathological changes.Present global diabetic subject has surpassed 1.2 hundred million people, China patient people the second in the world of living in groups.According to statistics, the diabetic subject that made a definite diagnosis of China reaches more than 4,000 ten thousand, and with annual 1000000 speed increase.Wherein, the type i diabetes patient accounts for 10%, and the type ii diabetes patient accounts for 90%.Diabetes have become the public health problem of people's growing interests.
The type i diabetes medicine mainly is insulin preparation and surrogate thereof at present; For the treatment of type ii diabetes, main medicine is an oral antidiabetic drug, roughly is divided into sulfourea, biguanides, Chinese medicine preparation, other antidiabetic drugs and adjuvant drug.Though it has good curative effect, medicine can not kept long-term efficacy aspect the hyperglycemia reducing, can not be at the cause of disease and effective mitigate the disease.Many antidiabetic medicines at first can fine controlling blood sugar, but along with the continuity of medication treatment then can not keep curative effect, Here it is, and people adopt conjoint therapy or use one of principal element of other different classes of medicines instead, and existing antidiabetic medicine to lack permanently effective major cause is because their mechanism of action is to increase target tissue to the susceptibility of insulin action or improve the activity that pancreas produces Regular Insulin, but the decay basic cause of disease of these diabetes of pancreatic beta cell function is lacked targeting.
Dipeptidase-IV (DPP-IV) extensively exists in vivo, it is a kind of cell surface protein that relates to the various biological function, the interior various active enzyme of the body of can degrading, as glucagon-like-peptide-1 (glucagons-like peptide 1, GLP-1), glucose pancreotropic hormone polypeptide (glucose-dependent insulinotropic polypeptide, GIP), neuropeptide, P material and chemokine etc.And the shortage of GLP-1, GIP all is the major cause of type ii diabetes (being non insulin dependent diabetes).The DPP-IV inhibitor is the medicine of a new generation's treatment diabetes.It has protected the activity of GLP-1 and GIP etc. by suppressing the DPP-IV activity, promotes insulin secretion, lowering blood glucose, and can not cause side effects such as hypoglycemia, weight increase, oedema.Its blood sugar reducing function no longer continues the performance blood sugar reducing function after reaching normal glucose level, the hypoglycemia situation can not occur, and life-time service, the function that can repair beta cell.
Sitagliptin (sitagliptin) is the DPP-IV inhibitor of first listing, becomes a cookle of Merck after the listing in 2006 rapidly.On July 31st, 2009, FDA ratifies Sha Gelieting (saxagliptin) listing of AstraZeneca and Bristol Myers Squibb exploitation again.Active and the selectivity of the SYR-322 of military field (Taketa) company all is better than sitagliptin and Sha Gelieting, be in registration at present before.In addition, also have 3 medicines to be in vast BI-1356 (linagliptin), the PF-734200 (gosogliptin) of Pfizer, the PHX1149 (dutogliptin) of phenomix company of phase III stage: Bo Mingge Yin Dynasty's lattice.The medicine that is in phase II has 9, is in have 7 of phase I.
Yet types of drugs is limited, can not meet clinical needs, and the medicine of being badly in need of the more DPP-IV inhibitor of exploitation satisfies clinical application.
3, summary of the invention
In order to address the above problem, further improve and optimize the DPP-IV inhibitor, the inventor provides a class new DPP-IV inhibitor through great deal of experimental.
Technical scheme of the present invention is as follows:
The invention provides the compound shown in the general formula (I), its pharmacy acceptable salt, its steric isomer or its solvated compounds:
Wherein: R
1Be the C that is not substituted or is replaced by halogen atom, hydroxyl, amino, carboxyl, formamyl or amino-sulfonyl
1-6Alkyl, C
3-6Thiazolinyl or C
2-6Alkynyl, or
The aromatic base C that is not substituted or is replaced by 1～5 substituting group V
1-6Alkyl, described substituting group V independently selected from halogen atoms, cyano group, cyano group C
1-6Alkyl, C
2-6Alkynyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, amino, amino C
1-6Alkyl, C
1-6Alkylamino, two (C
1-6Alkyl) amino, hydroxyl, hydroxyl C
1-6Alkyl, carboxyl, carboxyl C
1-6Alkyl, formamyl, C
1-6Alkyl-carbamoyl, C
1-6Alkyl amino sulfonyl, hydroxyl C
1-6Alkoxyl group, amino C
1-6Alkoxyl group or carboxyl C
1-6Alkoxyl group;
R
2, R
4Be hydrogen atom independently, halogen atom, cyano group, amino, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl or amino C
1-6Alkyl;
R
3Be hydrogen atom, halogen atom, cyano group, amino, hydroxyl, carboxyl, C
1-6Alkylamino, two (C
1-6Alkyl) amino, NR
9R
10C (O)-, NR
9R
10S (O)
2-, the C that is not substituted or is replaced by halogen atom, hydroxyl, amino, carboxyl, cyano group, formamyl, amino-sulfonyl
1-6Alkyl or C
1-6Alkoxyl group,
R
9, R
10Be hydrogen atom independently, be not substituted or by halogen atom, hydroxyl, amino, carboxyl, cyano group, formamyl, amino-sulfonyl, C
1-6Alkoxyl group, C
1-6Alkylamino, two (C
1-6Alkyl) amino, C
1-6Alkyl-carbamoyl, two (C
1-6Alkyl) formamyl, C
1-6Alkyl amino sulfonyl, two (C
1-6Alkyl) amino-sulfonyl, C
1-6Alkyl carbonylamino, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl, C
1-6Alkyl-carbonyl, C
1-6Alkyl carbonyl oxy, C
1-6The C that alkoxy carbonyl replaces
1-6Alkyl;
X is O, S, NR
5Or CR
6R
7,
R
5Be hydrogen atom, C
1-6Alkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl or C
3-6Cycloalkyl,
R
6, R
7Be hydrogen atom, halogen atom, C independently
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, amino C
1-6Alkyl or C
3-6Cycloalkyl, or R
6, R
7Form C with the carbon atom that links to each other
3-6The saturated Azacyclyl of cycloalkyl or 4-6 unit;
Y is O, S or NR
8, R
8Be hydrogen atom, formamyl, C
1-6Alkyl-carbonyl, C
3-6Cycloalkyl or the C that is not substituted or is replaced by halogen atom, hydroxyl, amino, carboxyl or formamyl
1-6Alkyl, C
1-6Alkoxyl group, aromatic base C
0-6Alkyl or aromatic base C
0-6Alkoxyl group;
4-7 the unit saturated or undersaturated heterocyclic radical that at least contain a nitrogen-atoms of Q for not being substituted or being replaced by 1～5 substituting group W,
Described substituting group W independently selected from halogen atoms, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, amino, amino C
1-6Alkyl, C
1-6Alkylamino, two (C
1-6Alkyl) amino, hydroxyl, hydroxyl C
1-6Alkyl, carboxyl, carboxyl C
1-6Alkyl, C
1-6Carbalkoxy, C
1-6Alkyl carbonyl oxy, formamyl, formamyl C
1-6Alkyl, C
1-6Alkyl-carbamoyl, C
1-6Alkyl carbonylamino, C
1-6Alkyl carbonylamino C
1-6Alkyl or iminomethyl.
Be preferably:
Wherein: R
1Be the C that is not substituted or is replaced by halogen atom, hydroxyl, amino, carboxyl, formamyl or amino-sulfonyl
1-6Alkyl, C
3-6Thiazolinyl or C
2-6Alkynyl, or
The aromatic base C that is not substituted or is replaced by 1～5 substituting group V
1-6Alkyl, described substituting group V independently selected from halogen atoms, cyano group, cyano group C
1-6Alkyl, C
2-6Alkynyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, amino, amino C
1-6Alkyl, C
1-6Alkylamino, two (C
1-6Alkyl) amino, hydroxyl, hydroxyl C
1-6Alkyl, carboxyl, carboxyl C
1-6Alkyl, formamyl, C
1-6Alkyl-carbamoyl, C
1-6Alkyl amino sulfonyl, hydroxyl C
1-6Alkoxyl group, amino C
1-6Alkoxyl group or carboxyl C
1-6Alkoxyl group;
R
2, R
3, R
4Be hydrogen atom independently, halogen atom, cyano group, amino, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl or amino C
1-6Alkyl;
X is O, S, NR
5Or CR
6R
7,
R
5Be hydrogen atom, C
1-6Alkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl or C
3-6Cycloalkyl,
R
6, R
7Be hydrogen atom, halogen atom, C independently
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, amino C
1-6Alkyl or C
3-6Cycloalkyl, or R
6, R
7Form C with the carbon atom that links to each other
3-6The saturated Azacyclyl of cycloalkyl or 4-6 unit;
Y is O, S or NR
8, R
8Be hydrogen atom, formamyl, C
1-6Alkyl-carbonyl, C
3-6Cycloalkyl or the C that is not substituted or is replaced by halogen atom, hydroxyl, amino, carboxyl or formamyl
1-6Alkyl, C
1-6Alkoxyl group, aromatic base C
0-6Alkyl or aromatic base C
0-6Alkoxyl group;
4-7 the unit saturated or undersaturated heterocyclic radical that at least contain a nitrogen-atoms of Q for not being substituted or being replaced by 1～5 substituting group W,
Described substituting group W independently selected from halogen atoms, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, amino, amino C
1-6Alkyl, C
1-6Alkylamino, two (C
1-6Alkyl) amino, hydroxyl, hydroxyl C
1-6Alkyl, carboxyl, carboxyl C
1-6Alkyl, C
1-6Carbalkoxy, C
1-6Alkyl carbonyl oxy, formamyl, formamyl C
1-6Alkyl, C
1-6Alkyl-carbamoyl, C
1-6Alkyl carbonylamino, C
1-6Alkyl carbonylamino C
1-6Alkyl or iminomethyl.
More preferably:
Wherein, R
1Be C
3-6Thiazolinyl, C
2-6Alkynyl, or the phenyl C that is not substituted or is replaced by 1～3 substituting group V
1-6Alkyl, described substituting group V independently selected from halogen atoms, cyano group, cyano group C
1-6Alkyl, C
2-6Alkynyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, amino, amino C
1-6Alkyl, C
1-6Alkylamino, two (C
1-6Alkyl) amino, hydroxyl, hydroxyl C
1-6Alkyl, carboxyl, carboxyl C
1-6Alkyl, formamyl, C
1-6Alkyl-carbamoyl or C
1-6Alkyl amino sulfonyl;
R
2, R
3, R
4Be hydrogen atom independently, halogen atom, cyano group, amino, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group or hydroxyl C
1-6Alkyl;
X is O, S, NR
5Or CR
6R
7,
R
5Be selected from hydrogen atom, C
1-6Alkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl or C
3-6Cycloalkyl,
R
6, R
7Be independently selected from hydrogen atom, halogen atom, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, amino C
1-6Alkyl or C
3-6Cycloalkyl, or R
6, R
7Form C with the carbon atom that links to each other
3-6The saturated Azacyclyl of cycloalkyl or 5-6 unit;
Y is O, S or NR
8, R
8Be hydrogen atom, C
3-6Cycloalkyl or the C that is not substituted or is replaced by halogen atom, hydroxyl, amino, carboxyl or formamyl
1-6Alkyl, C
1-6Alkoxyl group, phenyl C
0-6Alkyl or phenyl C
0-6Alkoxyl group;
5-6 the unit saturated or undersaturated heterocyclic radical that at least contain a nitrogen-atoms of Q for not being substituted or being replaced by 1～3 substituting group W,
Described substituting group W independently selected from halogen atoms, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, amino, amino C
1-6Alkyl, C
1-6Alkylamino, two (C
1-6Alkyl) amino, hydroxyl, hydroxyl C
1-6Alkyl, carboxyl, carboxyl C
1-6Alkyl, C
1-6Alkoxy carbonyl, C
1-6Alkyl carbonyl oxy, formamyl, formamyl C
1-6Alkyl, C
1-6Alkyl-carbamoyl, C
1-6Alkyl carbonylamino, C
1-6Alkyl carbonylamino C
1-6Alkyl or iminomethyl.
Be preferably again:
Wherein, R
1Be C
3-4Thiazolinyl, C
2-4Alkynyl, or the phenyl C that is not substituted or is replaced by 1～3 substituting group V
1-4Alkyl, described substituting group V independently selected from halogen atoms, cyano group, cyano group C
1-4Alkyl, C
2-4Alkynyl, C
1-4Alkyl, halo C
1-4Alkyl, C
1-4Alkoxyl group, halo C
1-4Alkoxyl group, amino, amino C
1-4Alkyl, C
1-4Alkylamino, two (C
1-4Alkyl) amino, hydroxyl, hydroxyl C
1-4Alkyl, formamyl, C
1-4Alkyl-carbamoyl or C
1-4Alkyl amino sulfonyl;
R
2, R
3, R
4Be hydrogen atom independently, halogen atom, cyano group, C
1-4Alkyl, halo C
1-4Alkyl, C
1-4Alkoxyl group, halo C
1-4Alkoxyl group or hydroxyl C
1-4Alkyl;
X is O, S, NR
5Or CR
6R
7,
R
5Be selected from hydrogen atom, C
1-4Alkyl, halo C
1-4Alkyl, C
2-4Thiazolinyl or C
3-6Cycloalkyl,
R
6, R
7Be independently selected from hydrogen atom, halogen atom, C
1-4Alkyl, halo C
1-4Alkyl, C
1-4Alkoxyl group, halo C
1-4Alkoxyl group, hydroxyl C
1-4Alkyl, amino C
1-4Alkyl or C
3-6Cycloalkyl, or R
6, R
7Form C with the carbon atom that links to each other
3-6The saturated Azacyclyl of cycloalkyl or 5-6 unit;
Y is O, S or NR
8, R
8Be hydrogen atom or C
1-4Alkyl;
5-6 the unit saturated or undersaturated heterocyclic radical that at least contain a nitrogen-atoms of Q for not being substituted or being replaced by 1～3 substituting group W,
Described substituting group W independently selected from halogen atoms, C
1-4Alkyl, halo C
1-4Alkyl, C
1-4Alkoxyl group, halo C
1-4Alkoxyl group, amino, amino C
1-4Alkyl, C
1-4Alkylamino, hydroxyl, hydroxyl C
1-4Alkyl, carboxyl C
1-4Alkyl, C
1-4Alkoxy carbonyl, C
1-4Alkyl carbonyl oxy, formamyl, formamyl C
1-4Alkyl, C
1-4Alkyl-carbamoyl, C
1-4Alkyl carbonylamino, C
1-4Alkyl carbonylamino C
1-4Alkyl or iminomethyl.
More preferably:
Wherein, R
1Be propenyl, proyl, or the phenyl C that is not substituted or is replaced by 1～3 substituting group V
1-4Alkyl, described substituting group V be independently selected from fluorine atom, chlorine atom, cyano group, cyano methyl, ethynyl, methyl, trifluoromethyl, methoxyl group, trifluoromethoxy, amino, aminomethyl, methylamino-, dimethylamino, methylol, hydroxyethyl, formamyl, methylamino formyl radical or methylamino alkylsulfonyl;
R
2, R
3, R
4Be hydrogen atom independently, fluorine atom, chlorine atom, cyano group, methyl, trifluoromethyl, methoxyl group, trifluoromethoxy or methylol;
X is O, S, NR
5Or CR
6R
7,
R
5Be selected from hydrogen atom, methyl, ethyl, sec.-propyl, trifluoromethyl, vinyl or cyclopropane base,
R
6, R
7Be independently selected from hydrogen atom, fluorine atom, methyl, ethyl, methyl fluoride, trifluoromethyl, methoxyl group, methylol or aminomethyl, or R
6, R
7Form cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl or piperidyl with the carbon atom that links to each other;
Y is O, S or NR
8, R
8Be hydrogen atom or methyl;
Pyrrolidyl, pyrryl, imidazolidyl, the pyrazolyl, 4 of Q for not being substituted or being replaced by 1～2 substituting group W, 5-pyrazoline base, pyrazolidyl, 1,2,4-triazolyl, 1,4-
Piperazine base, piperidyl, piperazinyl or morpholinyl,
Described substituting group W be independently selected from fluorine atom, chlorine atom, methyl, methyl fluoride, methoxyl group, amino, aminomethyl, methylamino-, hydroxyl, methylol, carboxymethyl, methoxycarbonyl, acetoxyl group, formamyl, carbamyl ylmethyl, methylamino formyl radical, kharophen, acetylamino methyl or iminomethyl.
Further be preferably:
Wherein, R
1Be the benzyl that is not substituted or is replaced by 1～3 substituting group V, described substituting group V is independently selected from fluorine atom, cyano group, ethynyl, methyl, trifluoromethyl, methoxyl group, trifluoromethoxy or methylamino-;
R
2, R
3, R
4Be hydrogen atom independently, fluorine atom or methoxyl group;
X is O, S, NR
5Or CR
6R
7,
R
5Be selected from hydrogen atom, methyl, ethyl or sec.-propyl,
R
6, R
7Be independently selected from hydrogen atom, methyl, or R
6, R
7Form cyclopropane base, pentamethylene base or piperidyl with the carbon atom that links to each other;
Y is O;
Pyrrolidyl, imidazolidyl, piperidyl or the piperazinyl of Q for not being substituted or being replaced by 1～2 substituting group W,
Described substituting group W is independently selected from amino, methylamino-, hydroxyl, methylol or formamyl.
" halogen atom " of the present invention comprises fluorine atom, chlorine atom, bromine atoms, iodine atom.
" C of the present invention
1-6Alkyl " hydrocarbon that refers to contain 1～6 carbon atom partly removes the alkyl of a hydrogen atom deutero-straight or branched; as methyl; ethyl; n-propyl; sec.-propyl; normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, the 2-methyl butyl, 1, the 1-dimethyl propyl, 1, the 2-dimethyl propyl, neo-pentyl, the 1-ethyl propyl, n-hexyl, isohexyl, the 2-methyl amyl, the 3-methyl amyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 2-dimethylbutyl, 2, the 3-dimethylbutyl, 3, the 3-dimethylbutyl, the 1-ethyl-butyl, the 2-ethyl-butyl, 1,1,2-trimethylammonium propyl group, 1,2,2-trimethylammonium propyl group, 1-ethyl-1-methyl-propyl and 1-ethyl-2-methyl-propyl.Term " C
1-4Alkyl " refer to the specific examples that contains 1～4 carbon atom in the above-mentioned example.
" C of the present invention
1-6Alkoxyl group " refer to term " C
1-6Alkyl " group that is connected with other structures by Sauerstoffatom, as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, pentyloxy, neopentyl oxygen, hexyloxy etc.Term " C
1-4Alkoxyl group " refer to term " C
1-4Alkyl " group that is connected with other structures by Sauerstoffatom.
" halo C of the present invention
1-6Alkyl, halo C
1-4Alkyl, halo C
1-6Alkoxyl group, halo C
1-4Alkoxyl group " in " halo " be meant C
1-6Alkyl, C
1-4Alkyl, C
1-6Alkoxyl group, C
1-4One or more hydrogen atom on the carbon atom in the alkoxyl group is replaced by halogen atom.
" C of the present invention
3-6Cycloalkyl " refer to that the paraffin section of 3～6 carbon atoms removes a hydrogen atom deutero-cyclic alkyl, cyclopropyl, cyclobutyl, 1-methyl cyclobutyl, cyclopentyl, cyclohexyl etc.
" C of the present invention
3-6Thiazolinyl " be meant that the carbonatoms that contains two keys is 3～6 straight or branched or cyclic thiazolinyl, as 1-propenyl, 2-propenyl, 1-butylene base, crotyl, 1-pentenyl, pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, cyclopropenyl radical, cyclopentenyl, cyclohexenyl etc." C of the present invention
3-4Thiazolinyl " be meant that the carbonatoms that contains two keys is 3～4 the straight or branched or the example of cyclic thiazolinyl.
" C of the present invention
2-6Alkynyl " be meant and contain the alkynyl that the triple-linked carbonatoms is 2～6 straight or branched, as ethynyl, proyl, 2-butyne base, valerylene base, 3-pentynyl, 2-hexin base, 3-hexin base etc." C of the present invention
2-4Alkynyl " be meant that the carbonatoms that contains two keys is the example of the alkynyl of 2～4 straight or branched.
" aromatic base " of the present invention be meant aromatic ring for example phenyl, replacement phenyl and thick and aromatic nucleus (for example naphthyl) etc.
The specific examples of " the saturated or undersaturated heterocyclic radical that contains a nitrogen-atoms at least of 4-7 unit " of the present invention has azetidinyl, 1,2-diazetidine base, azete base, 1,2-diazetine base, pyrryl, pyrrolin base, pyrrolidyl, imidazolyl, 4,5-glyoxalidine base, imidazolidyl, pyrazolyl, 4,5-pyrazoline base, pyrazolidyl, 1,2,3-triazoles base, 1,2,4-triazolyl, tetrazyl,
Azoles base, 4, the 5-dihydro
Azoles base, different
Azoles base, 4, the 5-dihydro is different
Azoles base, 2, the 3-dihydro is different
Azoles base, 1,2,3-
Di azoly, 1,2,5-
Di azoly, thiazolyl, 4,5-dihydro-thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, pyridyl, piperidyl, pyridazinyl, pyrimidyl, pyrazinyl, piperazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazine base, 2H-1,2-
Piperazine base, 4H-1,2-
Piperazine base, 6H-1,2-
Piperazine base, 2H-1,3-
Piperazine base, 4H-1,3-
Piperazine base, 5,6-dihydro-4H-1,3-
Piperazine base, 6H-1,3-
Piperazine base, 2H-1,4-
Piperazine base, 4H-1,4-
Piperazine base, 2H-1,3-thiazinyl, 4H-1,3-thiazinyl, 5,6-dihydro-4H-1,3-thiazinyl, 6H-1,3-thiazinyl, 2H-1,4-thiazinyl, 4H-1,4-thiazinyl, morpholinyl, azatropylidene base, 1,4-Diazesuberane base etc." 5-6 unit the saturated or undersaturated heterocyclic radical that contains a nitrogen-atoms at least " of the present invention refers to that annular atoms number in the above-mentioned example is 5 or 6 specific examples.
The specific examples of " the saturated Azacyclyl of 4-6 unit " of the present invention has azetidinyl, pyrrolidyl, imidazolidine, pyrazolidine, piperidyl, piperazinyl etc." 5-6 unit saturated Azacyclyl " of the present invention refers to that annular atoms number in the above-mentioned example is 5 or 6 specific examples.
Further preferred compound is as follows:
The present invention also provides the preparation method of above-claimed cpd, but is not limited only to following method.
X is CR
6R
7, and R
6, R
7When being methyl, can prepare compound by following preparation method:
Reaction equation:
Reactions steps:
(1) preparation of intermediate 1
With raw material 1, metachloroperbenzoic acid joins in the methylene dichloride, reacts under the room temperature, filters, and gets intermediate 1.
(2) preparation of intermediate 2
Under the room temperature, intermediate 1 is dissolved in Glacial acetic acid and H
2O
2In, add HNO
3, temperature reaction adds entry, filters, and gets intermediate 2.
(3) preparation of intermediate 3
Intermediate 2, raw material 2 are dissolved among the DMA, add amine (including but not limited to DIEA), reaction mixture is poured in the water 120-160 ℃ of reaction down, uses ethyl acetate extraction, drying revolve desolventize intermediate 3.
(4) preparation of intermediate 4
Intermediate 3 and zinc powder are joined in the alcohol (including but not limited to methyl alcohol, ethanol), add hydrazine hydrate and formic acid solution, at room temperature; nitrogen protection is stirred down, filters, and organic layer concentrates; solid is dissolved in methylene dichloride and the saturated NaCl solution, dry, concentrate intermediate 4.
(5) preparation of intermediate 5
Under the ice-water bath, in the dichloromethane solution of intermediate 4, stir adding methacrylic chloride down, under the room temperature, reaction mixture stirs, and reaction mixture is concentrated, and adds ethyl acetate, uses saturated NaHCO
3Solution washing gets intermediate 5.
(6) preparation of intermediate 6
Intermediate 5, palladium, triphenylphosphine, etamon chloride and sodium formiate are joined among the DMSO, under the nitrogen protection, be heated with stirring to 80-120 ℃, TLC monitors to raw material reaction complete, cooling, filtration, concentrating under reduced pressure, and remnants get intermediate 6 through column chromatography.
(7) preparation of formula I ' compound
Intermediate 6 and raw material 3 are dissolved among the DMF, add K under the room temperature
2CO
3, after reaction is spent the night, add the entry extraction, the organic layer concentrating under reduced pressure, remaining through purification by silica gel column chromatography, get formula I ' compound.
R in the above reaction equation
1, R
2, R
3, R
4With Q as mentioned before.
X is CR
6R
7, and R
6, R
7The formation C that is connected with it
3-6During cycloalkyl, can prepare compound by following preparation method:
Reaction equation:
Reactions steps:
(1) preparation of intermediate 1 '
In the DMF of raw material 4 and diethyl malonate solution, add K
2CO
3, stirring reaction spends the night, and reaction is cooled to room temperature after finishing, and adds frozen water, and the reaction mixture ethyl acetate extraction merges organic layer and washes MgSO with salt
4Drying is filtered, and vacuum concentration gets intermediate 1 '.
(2) preparation of intermediate 2 '
The mixture backflow of intermediate 1 ' and HCl is spent the night, show that up to LC-MS intermediate 1 ' reaction finishes, leach the solid of generation, washing is dissolved in solid in the ethyl acetate, with salt washing, MgSO
4Drying is filtered, and vacuum concentration obtains intermediate 2 '.
(3) preparation of intermediate 3 '
In the methanol solution of intermediate 2 ', add H at leisure
2SO
4, the mixed solution reaction is spent the night, and after reaction finishes, transfers pH with the NaOH aqueous solution, uses ethyl acetate extraction, and organic layer is washed with salt, MgSO
4Drying is filtered, and vacuum concentration gets intermediate 3 '.
(4) preparation of intermediate 4 '
In ice bath, the exsiccant THF solution of intermediate 3 ' slowly is added drop-wise in the exsiccant solution of NaH, after mixed solution stirs, drip the exsiccant THF solution of raw material 5, continue the stirring at room reaction, after the LC-MS monitoring reaction finishes, add frozen water, ethyl acetate extraction, organic layer is washed with salt, MgSO
4Drying is filtered, vacuum concentration, and silica gel column chromatography gets intermediate 4 '.
(5) preparation of intermediate 5 '
In the alcoholic solution of intermediate 4 ' and triethylamine, add raw material 2 in batches, reaction mixture refluxed, after the LC-MS monitoring reaction finished, vacuum concentration joined resistates in the frozen water, ethyl acetate extraction, organic layer is washed with salt, Na
2SO
4Drying is filtered, and vacuum concentration obtains intermediate 5 '.
(6) preparation of intermediate 6 '
With intermediate 5 ' and Pd (OH)
2/ C joins in the methyl alcohol, and under nitrogen atmosphere, stirring at room leaches solid, uses methanol wash, merging filtrate and washings, and vacuum concentration gets intermediate 6 '.
(7) preparation of intermediate 7 '
With intermediate 6 ' and K
2CO
3Join in the methyl alcohol, reflux, after the LC-MS monitoring reaction finishes, with the reaction mixture vacuum concentration, add frozen water, use ethyl acetate extraction, organic layer is washed with salt, Na
2SO
4Drying is filtered, vacuum concentration, and purification by silica gel column chromatography gets intermediate 7 '.
(8) formula I " preparation of compound
With intermediate 7 ', K
2CO
3Join among the DMF with raw material 3, reacting by heating is spent the night, and after reaction finishes, adds frozen water, uses ethyl acetate extraction, and organic layer is washed with salt, MgSO
4Drying is filtered, and vacuum concentration gets formula I " compound.
R in the above reaction equation
1, R
2, R
3, R
4With Q as mentioned before, the integer of n=1-4.
X is NR
5The time, can prepare compound by following preparation method:
Reaction equation:
Reactions steps:
(1) intermediate 1 " preparation
In the exsiccant reaction flask, add raw material 4, raw material 2, triethylamine, polar solvent (including but not limited to methyl alcohol, ethanol, Virahol), stirring reaction (temperature range be room temperature-100 ℃), the reaction solution underpressure distillation, column chromatography purification obtains intermediate 1 ".
(2) intermediate 2 " preparation
In the exsiccant reaction flask, add intermediate 1 ", be dissolved in the alcohol (as ethanol, butanols), add the ethanolic soln of raw material 6,30-120 ℃ of following stirring reaction, reaction solution drying under reduced pressure, column chromatography purification get intermediate 2 ".
(3) intermediate 3 " preparation
In the exsiccant reaction flask, add intermediate 2 ", be dissolved in the polar solvent (including but not limited to methyl alcohol, ethanol, Virahol), add Pd/C under the room temperature, feed hydrogen, stir, filter, vacuum-drying, column chromatography purification gets intermediate 3 ".
(4) intermediate 4 " preparation
In the exsiccant reaction flask, add triphosgene, triethylamine is dissolved in the tetrahydrofuran (THF), certain temperature (20 ℃ to-5 ℃) adds down intermediate 3 " tetrahydrofuran solution; stirring reaction, reaction solution add entry and ethyl acetate, the reaction solution ethyl acetate extraction; with saturated sodium carbonate solution and salt water washing; the organic layer anhydrous sodium sulfate drying, and column chromatography purification must intermediate 4 ".
(5) formula I " ' preparation of compound
In the exsiccant reaction flask, add intermediate 4 "; salt of wormwood, be dissolved in DMF, splash into the DMF solution of raw material 3 under the certain temperature (20 ℃ to-5 ℃); stirring reaction under the room temperature; reaction solution ethyl acetate extraction, the saturated nacl aqueous solution washing, organic layer anhydrous sodium sulfate drying; column chromatography purification gets formula I " ' compound.
R in the above reaction equation
1, R
2, R
3, R
4, R
5With Q as mentioned before.
The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention is meant by the salt of pharmaceutically acceptable, non-toxic bases or acid preparation, comprises organic acid salt, inorganic acid salt, organic alkali salt, inorganic base salts.Organic acid comprises formic acid, acetate, trifluoroacetic acid, Phenylsulfonic acid, phenylformic acid, tosic acid, (2R, 3R)-2,3-dyhydrobutanedioic acid, camphorsulfonic acid, citric acid, methylsulfonic acid, ethyl sulfonic acid, propanesulfonic acid, fumaric acid, glyconic acid, L-glutamic acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, glactaric acid, pamoic acid, pantothenic acid, succsinic acid, tartrate etc., preferred especially trifluoroacetic acid, phenylformic acid, Phenylsulfonic acid, tosic acid, citric acid, toxilic acid, fumaric acid, tartrate.Mineral acid comprises Hydrogen bromide, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid etc., preferred especially Hydrogen bromide, hydrochloric acid, sulfuric acid, phosphoric acid.Organic bases comprises primary, the second month in a season and tertiary amine, be substituted amine and comprise naturally occurring replacement amine, cyclammonium and basic ion exchange resin, be selected from arginine, trimethyl-glycine, caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, 2-diethylaminoethanol, the 2-dimethylaminoethanol, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, meglumine, glucosamine, Histidine, Hai Baming, isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, Trometamol etc.Mineral alkali comprises the basic cpd of ammonium and lithium, sodium, potassium, calcium, magnesium, zinc, barium, aluminium, iron, ketone, ferrous, manganese, bivalent manganese etc., the basic cpd of preferred especially ammonium and lithium, sodium, potassium, calcium, magnesium, zinc, barium.The salt that is solid form can exist with more than one crystalline structure, also can be the form of hydrate.
The compounds of this invention contains one or more asymmetric centers, thereby can be used as racemic modification and racemic mixture, single enantiomer, non-enantiomer mixture and single diastereomer.The compounds of this invention has asymmetric center, and each will independently produce two optical isomers this class asymmetric center, and scope of the present invention comprises all possible optical isomer and non-enantiomer mixture and pure or partial-purified compound.The present invention includes all stereoisomeric forms in any ratio of these compounds.
Compound of the present invention unless stated otherwise, the present invention includes cis-isomeride and trans-isomer(ide) if contain olefinic double bonds.
Compound of the present invention can exist with tautomeric forms, and it has the tie point of different hydrogen by one or more double-bond shifts.For example, ketone and its enol form are the keto-enol tautomerism bodies.Each tautomer and composition thereof all is included in the compound of the present invention.
Compound shown in the general formula (I), its pharmacy acceptable salt, its steric isomer can be solvate forms.Solvate is under the situation of hydrate, and hydration can be finished in preparation process or can be utilized the water absorbability of original anhydrous product to carry out gradually.
Compound of the present invention can be united with one or more other medicines, and is more safer or more effective than single medicine.Can be with these other medicines and formula (I) compound simultaneously or in succession by a kind of approach and with its usual amounts administration.During administration simultaneously, be preferably the medicinal compositions of the unit dosage form that contains described other medicines and formula (I) compound.Can with formula (I) compound drug combination or respectively administration or in same medicinal compositions other activeconstituents of administration include, but are not limited to:
(a) other pepx IV inhibitor;
(b) insulin sensitisers comprises: (i) PPAR gamma agonist, as glitazones (as troglitazone, pioglitazone, englitazone, MCC-555, Rosiglitazone etc.) and other PPAR part, comprise PPAR α/γ economic benefits and social benefits agonist, as KRP-297 and PPAR alfa agonists such as Fenofibric Acid derivative (gemfibrozil, clofibrate, fenofibrate and bezafibrate); (ii) biguanides is as N1,N1-Dimethylbiguanide and phenformin; (iii) albumen network propylhomoserin phosphoesterase-1B (PTP-1B) inhibitor;
(c) Regular Insulin or insulin-mimickers;
(d) sulfonylurea and other Regular Insulin succagoga are as tolbutamide and Glipizide, meglitinide and related drugs;
(e) alpha-glucosidase inhibitor (as acarbose)
(f) glucagon receptor antagonist;
(g) GLP-1, GLP-1 stand-in and GLP-1 receptor stimulant;
(h) GLP and GLP stand-in and GLP receptor stimulant;
(i) PACAP, PACAP stand-in and PACAP acceptor 3 agonists;
(j) cholesterol reducing agent, as (i) HMG-CoA reductase inhibitor (lovastatin, Simvastatin, Pravastatin, fluvastatin, Ah appropriate cuts down his spit of fland, rivastatin, itavastatin, superstatin and other statins), (ii) inner complex (Colestyramine, the dialkyl aminoalkyl derivative of colestipol and crosslinked dextran), (iii) nicotinic alcohol, nicotinic acid or other salt, (iv) PPAR alfa agonists, as Fenofibric Acid derivative (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) PPAR α/γ economic benefits and social benefits agonist is as KRP-297; (vi) cholesterol absorption inhibitor, as β-Gu Zaichun and ezetimibe, (vii) ethanoyl CoA, chole-sterol acyltransferase inhibitor is as avasimibe with (viii) antioxidant is as probucol;
(k) PPAR delta agonists;
(l) anti-obesity compound, for example Phenfluoramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y 5 inhibitor and beta 3 adrenoreceptor agonists;
(m) ileal bile acid transfer protein inhibitor; With
(n) be used for the medicine of inflammation, for example acetylsalicylic acid, non-steroidal anti-inflammatory drug, glucocorticosteroid, sulphur nitrogen sulphur pyridine and epoxidase II select inhibitor.
Above-mentioned unite comprise compound of the present invention not only with a kind of other active compound and also with the associating of two or more other active compounds.Non-limiting example comprises that the have formula compound of (I) and two or more are selected from the associating of the active compound of biguanides, sulfonylurea, HMG-CoA reductase inhibitor, PPAR agonist, PTP-1B inhibitor, other DPP-IV inhibitor and anti-obesity compound.
The weight ratio of The compounds of this invention and second kind of activeconstituents can change, and it depends on the effective dose of various compositions.In general, with the effective dose that adopts separately.Therefore for example when compound of the present invention and other medicines drug combination, the weight ratio of The compounds of this invention and other medicines generally between about 1000: 1 to about 1: 1000, is preferably between about 200: 1 to about 1: 200.The drug combination of The compounds of this invention and other activeconstituents generally also can be in above-mentioned scope, but under each situation, should use the effective dose of each activeconstituents.
The present invention is claimed arbitrary compound recited above, its pharmacy acceptable salt, its steric isomer or its solvated compounds of comprising further; with the pharmaceutical composition of one or more pharmaceutical carriers and/or thinner, for clinically or pharmaceutically acceptable arbitrary formulation.Wherein contain the compound 1mg～100mg shown in the general formula (I) of physiology significant quantity, can be described activeconstituentss such as 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 50mg, 75mg, 100mg.Can be by 1～4 time arrangement every day, give described compound 1～2 time preferred every day.
The arbitrary compound of the present invention, its pharmacy acceptable salt, its steric isomer or its solvated compounds can oral mode be applied to the patient who needs this treatment.Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule means medicine or is added with the auxiliary material filling in Capsules or be sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable auxiliary material uniform mixing, and the spherical or near-spherical solid preparation so that proper method is made comprises dripping pill, sugar-pill, piller etc.Granule means that medicine and suitable auxiliary material make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral clarified liq preparation in suitable solvent.Oral suspensions means the insoluble solid pharmaceutical, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspensoid or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Typical binders comprises Xylo-Mucine, PVP-K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dry starch, polyvinylpolypyrrolidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.
Dipeptidase-IV (DPP-IV) is a kind of cell surface protein that relates to the various biological function.It has tissue distribution (intestines, kidney, liver, pancreas, placenta, thymus gland, spleen, epithelial cell, blood vessel endothelium, lymph and myelocyte, serum) and tissue and cell type expression level widely clearly.DPP-IV is confirmed as T type cell-stimulating mark CD26, and it can be at immunoregulatory in a large number, the endocrine and neurologic peptide of external cracking.This shows that there is the effect of diving in this peptase in the various diseases process of human body or other animal.
Pharmacological evaluation proves that the DPP-IV inhibitor can significantly suppress the DPP-IV activity, and protection GLP-1 activity promotes insulin secretion, reduces hyperglycemic-glycogenolytic factor after the meal, and lowering blood glucose improves anti-sugar amount; And have the active effect of protection GIP, can improve the concentration of GIP, strengthen the effect of its insulin secretion accelerating; The DPP-IV inhibitor can also improve glycolipid metabolism, prevents weight increase.
The present invention also provides new DPP-IV inhibitor to be used for the treatment of and/or to prevent purposes in the medicine of following disease in preparation.
Type ii diabetes and relative disease, now full confirmation GLP-1 and GIP can be by DPP-IV quick inactivatings in vivo, therefore DPP-IV inhibitor of the present invention can be used for treating a large amount of illnesss that type ii diabetes and treatment and prevention are followed type ii diabetes, comprises metabolic syndrome X, reactive hypoglycemia and glycosuria sexual abnormality lipidemia.Following disease, illness is relevant with type ii diabetes with symptom, therefore can treat by the methods of treatment that adopts The compounds of this invention, control or prevention in some cases: (1) hyperglycemia, (2) low dextrose tolerance, (3) insulin resistance, (4) obesity, (5) matter fat disease, (6) unusual lipidemia, (7) hyperlipidaemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high HDL level, (12) atherosclerosis and sequela thereof, (13) vascular restenosis, (14) irritable bowel syndrome, (15) enteritis comprises crohnShi disease and ulcerative colitis, (16) retinopathy, (21) ephrosis, (22) neuropathy, (23) X syndromes, the hyperandrogenism (polycystic ovary syndrome) of (24) ovary and the disease of other tool insulin resistance; And the growth hormone deficiency disease, damage of intestines, immunosuppressive action, HIV infects, hemopoietic, neuronal disease, brain tumor is invaded and is shifted benign prostatauxe, seminal fluid motility, oulitis, osteoporosis etc.
DPP-IV inhibitor of the present invention compared with prior art has the following advantages:
(1) The compounds of this invention can suppress the activity of DPP-IV preferably, makes the interior GLP-1 level of body more stable;
(2) DPP-IV inhibitor of the present invention is effective, and clinical consumption is few, saves cost;
(3) DPP-IV inhibitor of the present invention has good security and tolerance in vivo, and incidence rate of adverse reaction reduces more;
(4) DPP-IV inhibitor preparation technology of the present invention is simple, and medicine purity height, yield height, steady quality are easy to carry out large-scale commercial production.
Below further set forth the beneficial effect of The compounds of this invention by external pharmacological evaluation, but this should be interpreted as that The compounds of this invention only has following beneficial effect.
The external pharmacologically active of experimental example The compounds of this invention
Trial-product: part of compounds of the present invention, self-control, its chemical name and structural formula are as mentioned before.
Experimental technique:
The preparation DPPIV-Glo of reaction solution
TMDamping fluid needs to melt in advance, and the freeze-drying fluorescein needs to put to room temperature from taking out in the refrigerator in advance.With DPPIV-Glo
TMSubstrate is dissolved into the water mesoscale eddies mixing of 110 μ L as mother liquor (concentration is 10mM), fluorescein is put into filled 50mL DPPIV-Glo
TMIn the damping fluid ampoule.Then 100 μ L are contained DPPIV-Glo
TMThe solution of substrate and 50mL contain the DPPIV-Glo of fluorescein
TMThe damping fluid mixing obtains reaction solution.Reaction solution need be preserved at-20 ℃ of refrigerators.
1, fluorescent method detects the restraining effect to DPP-IV:
The total volume in every hole is 25 μ L in the mensuration of DPP-IV enzyme, comprise 12 μ L solution (66pM DPP-4 is dissolved in the 10mM tris buffer, pH=7.5), the compound of 0.5 μ L (dissolving), the reaction solution of 12.5 μ L with DMSO.All compounds need ten times of dilutions with DMSO before experiment, each compound need dilute 8 concentration.The solution and the compound that at first contain the DPP-IV enzyme before the test were hatched in RT 10 minutes, and then the adding reaction solution was hatched 30 minutes.Not enzyme-added in the negative control group.Measure fluorescent signal after 30 minutes, all compounds need be measured twice.
2, the fluorescent method detection compound is to the restraining effect of DPP-8:
The total volume in every hole is 25 μ L in the mensuration of DPP-8 enzyme, comprise 12 μ L solution (111.9pM DPP-8 is dissolved in the 10mM tris buffer, pH=7.5), the compound of 0.5 μ L (dissolving), the reaction solution of 12.5 μ L with DMSO.All compounds need ten times of dilutions with DMSO before experiment, each compound need dilute 8 concentration.The solution and the compound that at first contain the DPP-8 enzyme before the test were hatched in RT 10 minutes, and then the adding reaction solution was hatched 30 minutes.Not enzyme-added in the negative control group.Measure fluorescent signal after 30 minutes, all compounds need be measured twice.
3, the fluorescent method detection compound is to the restraining effect of DPP-9:
The total volume in every hole is 25 μ L in the mensuration of DPP-9 enzyme, comprise 12 μ L solution (26pM DPP-9 is dissolved in the 10mM tris buffer, pH=7.5), the compound of 0.5 μ L (dissolving), the reaction solution of 12.5 μ L with DMSO.All compounds need ten times of dilutions with DMSO before experiment, each compound need dilute 8 concentration.The solution and the compound that at first contain the DPP-9 enzyme before the test were hatched in RT 10 minutes, and then the adding reaction solution was hatched 30 minutes.Not enzyme-added in the negative control group.Measure fluorescent signal after 30 minutes, all compounds need be measured twice.
Experimental result and conclusion:
Table 1 The compounds of this invention is to the activity of DPP-IV
By table 1 as seen, The compounds of this invention all has excellent inhibition activity to DPP-IV, to DPP-8, DPP-9 unrestraint activity, DPP-IV is had higher selectivity.The compounds of this invention is safe and effective.
4, embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
For the purpose of convenience, what obtain among the following embodiment of the present invention all is the form of the salt of compound, and in deprotection (tertbutyloxycarbonyl (Boc)), can obtain the form of different salt with different acid (hydrochloric acid, trifluoroacetic acid etc.).Under the condition of alkalescence, can obtain the form of compound.
Among the embodiment, being abbreviated as m-CPBA is metachloroperbenzoic acid; DMA is a N,N-dimethylacetamide; DIEA is a diisopropylethylamine; DMF is N, dinethylformamide; THF is a tetrahydrofuran (THF); DMSO is a dimethyl sulfoxide (DMSO); LC-MS is the logotype of liquid matter; TLC is a tlc; Pre-HPLC is a preparative high-performance liquid chromatographic; TFA is a trifluoroacetic acid; TEA is a triethylamine; Boc
2O is a tert-Butyl dicarbonate; Me is a methyl; Et is an ethyl.
Embodiment 1 (R)-2-[[7-(3-amino piperidine-1-yl)-3,3-dimethyl-2-oxoindoline-1-yl] methyl] cyanobenzene (change
Compound 1) preparation of hydrochloride
The preparation of (1) 1,3-two bromo-2-nitrosobenzenes
With 2,6-dibromo aniline 9.8g (39mmol), 80% metachloroperbenzoic acid 30g (139mmol) joins in the 500mL methylene dichloride, and reaction is 3 hours under the room temperature, gets product 7.24g, yield: 70.0%.
The preparation of (2) 1,3-two bromo-2-oil of mirbane
Under the room temperature, with 1,3-two bromo-2-nitrosobenzene 1.23g (4.64mmol) are dissolved in Glacial acetic acid (25mL) and H
2O
2(25mL), add HNO
3(0.83mL), be warming up to 90 ℃, reaction 2h adds 50mL water, filters, and gets product 0.67g, yield: 51.4%.
(3) (R)-preparation of 1-(3-bromo-2-nitrophenyl) piperidines-3-aminocarbamic acid tert-butyl ester
With 1,3-two bromo-2-oil of mirbane 8.4g (30.0mmol), (R)-piperidines-3-aminocarbamic acid tert-butyl ester 3.2g (16mmol) are dissolved among the DMA (20mL), add DIEA4.3mL (26mmol), reaction mixture reacted 10 hours down at 150 ℃, pour in the water, use ethyl acetate extraction, drying revolve desolventize oily matter, get product 5.58g through column chromatography purification, yield: 87.3%.
(4) (R)-preparation of 1-(2-amino-3-bromophenyl) piperidines-3-aminocarbamic acid tert-butyl ester
(R)-1-(3-bromo-2-nitrophenyl) piperidines-3-aminocarbamic acid tert-butyl ester 0.2g (0.5mmol) and zinc powder 0.065g (1mmol) are joined in the methyl alcohol (3mL); formic acid solution (the 2mL that adds hydrazine hydrate and 85%; v/v=1); at room temperature; nitrogen protection was stirred 5 hours down, filtered, and organic layer concentrates; solid is dissolved in methylene dichloride and the saturated NaCl solution, dry, concentrate crude product 0.19g.
(5) (R)-preparation of 1-(3-bromo-2-methacrylamido phenyl) piperidines-3-aminocarbamic acid tert-butyl ester
Under the ice-water bath, in the dichloromethane solution of (R)-1-(2-amino-3-bromophenyl) piperidines-3-aminocarbamic acid tert-butyl ester 0.37g (1.0mmol), stir adding methacrylic chloride 0.13g (1.2mmol) down, add in 30 minutes.Under the room temperature, reaction mixture stirred 2 hours.Reaction mixture is concentrated, add ethyl acetate (90mL), use saturated NaHCO
3Solution washing gets crude product 0.45g, is directly used in next step without purification.
(6) (R)-preparation of 1-(3,3-dimethyl-2-oxoindoline-7-yl) piperidines-3-aminocarbamic acid tert-butyl ester
(R)-1-(3-bromo-2-methacrylamido phenyl) piperidines-3-aminocarbamic acid tert-butyl ester 0.44g (1.0mmol), palladium 0.116g (0.2mmol), triphenylphosphine 50mg (0.2mmol), etamon chloride 260mg (2mmol) and sodium formiate 68mg (1.0mmol) are joined among the DMSO (2mL); under the nitrogen protection; be heated with stirring to 100 ℃, TLC monitors to raw material reaction complete.Cooling, filtration, concentrating under reduced pressure, remnants get the 0.23g yield through column chromatography: 63.7%.
(7) (R)-and 1-[1-(2-cyano group benzyl)-3,3-dimethyl-2-oxoindoline-7-yl] preparation of piperidines-3-aminocarbamic acid tert-butyl ester
(R)-1-(3,3-dimethyl-2-oxoindoline-7-yl) piperidines-3-aminocarbamic acid tert-butyl ester 3.6g (10mmol) and 2-(brooethyl) cyanobenzene 2.16g (11mmol) are dissolved among the DMF (20mL), add K under the room temperature
2CO
31.66g (12mmol), after reaction is spent the night, add the extraction of 200mL water, the organic layer concentrating under reduced pressure, remaining through purification by silica gel column chromatography, get product 3.12g, yield: 65.6%.
(8) (R)-and 2-[[7-(3-amino piperidine-1-yl)-3,3-dimethyl-2-oxoindoline-1-yl] methyl] preparation of cyanobenzene hydrochloride
With (R)-1-[1-(2-cyano group benzyl)-3,3-dimethyl-2-oxoindoline-7-yl] piperidines-3-aminocarbamic acid tert-butyl ester 200mg (0.4mmol) is dissolved in the ethyl acetate (20mL), feeds HCl gas, reacted 30 minutes.Filter, (2 * 100mL) wash solid, and drying under reduced pressure gets solid product 135mg, yield 78.0% with ethyl acetate.
Molecular formula: C
23H
27ClN
4O molecular weight: 410.94 mass spectrums (M+H): 375.2
1H-NMR(CDCl
3，600MHz)：δ8.19(s，3H)，7.66(d，1H)，7.52(t，1H)，7.26(d，1H)，7.16(d，1H)，7.14(d，1H)，7.07(t，1H)，6.92(d，1H)，5.45(dd，2H)，2.99(s，1H)，2.73(s，1H)，2.58～2.54(m，2H)，2.48(s，1H)，2.09(m，1H)，1.56(d，1H)，1.47(s，3H)，1.45(s，3H)，1.42～1.40(m，1H)，1.14～1.13(m，1H).
Embodiment 2 (R)-2-[[7 '-(3-amino piperidine-1-yl)-2 '-oxo spiral shell [cyclopropane-1,3 '-indoline]-1 '-yl] methyl] benzene
The preparation of formonitrile HCN (compound 2) hydrochloride
(1) preparation of 2-(3-fluoro-2-nitrophenyl) diethyl malonate
To 1, add K in DMF (20mL) solution of 3-two fluoro-2-oil of mirbane 17.0g (0.107mol) and diethyl malonate 18.8g (0.117mol)
2CO
326.7g (0.193mol), 60 ℃ of following stirring reactions spend the night.Reaction is cooled to room temperature after finishing, and adds frozen water.Reaction mixture with ethyl acetate (3 * 50mL) extractions, merge organic layer with the salt washing (2 * 100mL), MgSO
4Drying is filtered, and vacuum concentration gets faint yellow oily product 26.8g, and yield 83.8% is directly used in the next step without being further purified.
(2) preparation of 2-(3-fluoro-2-nitrophenyl) acetate
The mixture backflow of 2-(3-fluoro-2-nitrophenyl) diethyl malonate 26.8g (0.896mol) and HCl 200mL (6N) is spent the night, show that up to LC-MS the reaction of 2-(3-fluoro-2-nitrophenyl) diethyl malonate finishes.Leach the solid of generation, (5 * 100mL) wash water.Solid is dissolved in the ethyl acetate (50mL), with salt washing (2 * 100mL), MgSO
4Drying is filtered, and vacuum concentration obtains white solid 15.0g, and yield 84.1% is directly used in the next step without being further purified.
(3) preparation of 2-(3-fluoro-2-nitrophenyl) methyl acetate
In methyl alcohol (50mL) solution of 2-(3-fluoro-2-nitrophenyl) acetate 15.0g (0.075mol), add con.H at leisure
2SO
4(0.5mL), the mixed solution reaction is spent the night.After reaction finishes, transfer pH to 8 with the 10%NaOH aqueous solution, (2 * 50mL) extractions, (2 * 100mL) wash organic layer, MgSO with salt solution with ethyl acetate
4Drying is filtered, and vacuum concentration gets yellow solid 15.0g, and yield 93.4% is directly used in the next step without being further purified.
(4) preparation of 1-(3-fluoro-2-nitrophenyl) ethylene-acetic acid methyl esters
In ice bath, exsiccant THF (1mL) solution of 2-(3-fluoro-2-nitrophenyl) methyl acetate 2.01g (9.4mmol) slowly is added drop-wise in exsiccant THF (20mL) solution of NaH 564mg (23.5mmol).Mixed solution stirred after 30 minutes, dripped exsiccant THF (1mL) solution of glycol dibromide 7.06g (37.6mmol).Continue stirring at room reaction 4 hours, the LC-MS monitoring.After reaction finishes, add frozen water, (3 * 10mL) extractions, (2 * 50mL) wash organic layer ethyl acetate, MgSO with salt solution
4Drying is filtered, vacuum concentration, silica gel column chromatography (ethyl acetate: sherwood oil=1: 20) get faint yellow solid 1.26g, yield 55.9%.
(5) (R)-and 1-[3-(3-azido-piperidines-1-yl)-2-nitrophenyl] preparation of ethylene-acetic acid methyl esters
In ethanol (10mL) solution of 1-(3-fluoro-2-nitrophenyl) ethylene-acetic acid methyl esters 1.26g (5.27mmol) and triethylamine 2.406g (23.78mmol), add (R)-3-azido-piperazine hydrochloride 2.58g (15.87mmol) in batches.Reaction mixture refluxed 72 hours, the LC-MS monitoring.After reaction finishes, vacuum concentration.Resistates is joined in the frozen water, ethyl acetate extraction, organic layer is washed with salt, Na
2SO
4Drying is filtered, and vacuum concentration obtains pale solid crude product 1.56g, is directly used in the next step without being further purified.
(6) (R)-and 1-[2-amino-3-(3-amino piperidine-1-yl) phenyl] preparation of ethylene-acetic acid methyl esters
With (R)-1-[3-(3-azido-piperidines-1-yl)-2-nitrophenyl] ethylene-acetic acid methyl esters 1.56g (4.52mmol) and Pd (OH)
2/ C (0.2g) joins in the methyl alcohol (20mL), at 1～2 atmospheric H
2Down, stirring at room 50 minutes.Go out solid with diatomite filtration, with methyl alcohol (2x10mL) washing, merging filtrate and washings, vacuum concentration get brown oil 1.7g, are directly used in the next step without being further purified.
(7) (R)-and 1-[2-amino-3-[3-(t-butoxycarbonyl amino) piperidines-1-yl] phenyl] preparation of ethylene-acetic acid methyl esters
Under the room temperature, with Boc
2O 1.4g (6.415mmol) joins (R)-1-[2-amino-3-(3-amino piperidine-1-yl) phenyl] ethylene-acetic acid methyl esters 1.7g (5.875mmol) and K
2CO
31.2g in the mixture of tetrahydrofuran (THF) (8.68mmol) (3mL), reaction is stirred and is spent the night.Reaction mixture is concentrated, pour frozen water into, use ethyl acetate extraction.Organic layer is washed with salt, Na
2SO
4Drying is filtered, and vacuum concentration gets thick product.Purification by silica gel column chromatography (ethyl acetate: sherwood oil=1: 20) get faint yellow solid 747mg, yield 32.6%.
(8) (R)-1-(preparation of 2 '-oxo spiral shell [cyclopropane-1,3 '-indoline]-7 '-yl) piperidines-3-aminocarbamic acid tert-butyl ester
With (R)-1-[2-amino-3-[3-(t-butoxycarbonyl amino) piperidines-1-yl] phenyl] ethylene-acetic acid methyl esters 747mg (1.92mmol) and K
2CO
3929mg (6.72mmol) joins in the methyl alcohol (2mL), refluxes the LC-MS monitoring.After reaction finishes, with the reaction mixture vacuum concentration, add frozen water, use ethyl acetate extraction, organic layer is washed with salt, Na
2SO
4Drying is filtered vacuum concentration.Purification by silica gel column chromatography (ethyl acetate: sherwood oil=1: 20) get faint yellow solid 350mg, yield 51.1%.
(9) (R)-and 1-[1 '-(2-cyano group benzyl)-2 '-oxo spiral shell [cyclopropane-1,3 '-indoline]-7 '-yl] preparation of piperidines-3-aminocarbamic acid tert-butyl ester
With (R)-1-(2 '-oxo spiral shell [cyclopropane-1,3 '-indoline]-7 '-yl) piperidines-3-aminocarbamic acid tert-butyl ester 350mg (0.98mmol), K
2CO
3203mg (1.47mmol) and 2-(brooethyl) cyanobenzene 288mg (1.47mmol) join among the DMF (3mL), are heated to 65 ℃ of reactions and spend the night.After reaction finishes, add frozen water, with ethyl acetate (3x10mL) extraction, organic layer is washed MgSO with salt solution (2x50mL)
4Drying is filtered, and vacuum concentration gets crude product, purification by silica gel column chromatography (ethyl acetate: sherwood oil=1: 20) get faint yellow solid 360mg, yield 77.8%.
(10) (R)-and 2-[[7 '-(3-amino piperidine-1-yl)-2 '-oxo spiral shell [cyclopropane-1,3 '-indoline]-1 '-yl] methyl] preparation of cyanobenzene hydrochloride
With (R)-1-[1 '-(2-cyano group benzyl)-2 '-oxo spiral shell [cyclopropane-1,3 '-indoline]-7 '-yl] piperidines-3-aminocarbamic acid tert-butyl ester 360mg (0.762mmol) is dissolved in 1 of saturated HCl, in 4-dioxane (5mL) solution, stir the TLC monitoring.After reaction finishes, the reaction mixture vacuum concentration, it is inferior to give a baby a bath on the third day after its birth with ether, and vacuum-drying gets faint yellow solid 260mg, yield 83.5%.Product can be further purified through Pre-HPLC.
Molecular formula: C
23H
25ClN
4O molecular weight: 408.92 mass spectrums (M+H): 373.2
1H-NMR(DMSO+D
2O，300MHz)：δ7.92(d，1H)，7.62(t，1H)，7.46(t，1H)，7.18(d，1H)，7.08(t，1H)，6.98-6.89(m，2H)，5.49-5.33(m，2H)，2.93-2.91(m，1H)，2.56-2.44(m，4H)，1.90-1.86(m，1H)，1.74-1.63(m，4H)，1.57-1.52(m，1H)，1.23-1.20(m，1H)，1.11-0.99(m，1H).
Embodiment 3 (R)-2-[[7-(3-amino piperidine-1-yl)-3-methyl-2-oxo-2,3-dioxy-1H-benzo [d] imidazoles-1-yl] first
Base] preparation of cyanobenzene (compound 5) trifluoroacetate
(1) (R)-preparation of 1-(3-fluoro-2-nitrophenyl) piperidines-3-aminocarbamic acid tert-butyl ester
In the exsiccant reaction flask, add ethanol 6mL, 1,3-two fluoro-2-oil of mirbane 0.21mL (2.0mmol), (R)-and piperidines-3-aminocarbamic acid tert-butyl ester 480mg (2.4mmol), triethylamine 0.5mL is heated to 100 ℃ and stirred 12 hours, the reaction solution decompression, separate out yellow liquid, get crude product 0.7g, be directly used in the next step.
(2) (R)-and 1-[3-(methylamino-)-2-nitrophenyl] preparation of piperidines-3-aminocarbamic acid tert-butyl ester
In the exsiccant reaction flask, add (R)-1-(3-fluoro-2-nitrophenyl) piperidines-3-aminocarbamic acid tert-butyl ester 0.7g (2.1mmol), be dissolved in the 8mL butanols, the methylethylolamine solution 6mL of adding 27%, 110 ℃ were stirred 48 hours down, and the reaction solution drying under reduced pressure is separated out red solid, get crude product 0.7g, be directly used in the next step.
(3) (R)-and 1-[2-amino-3-(methylamino-) phenyl] preparation of piperidines-3-aminocarbamic acid tert-butyl ester
In the exsiccant reaction flask, add (R)-1-[3-(methylamino-)-2-nitrophenyl] piperidines-3-aminocarbamic acid tert-butyl ester 0.75g (2.1mmol), be dissolved in the 10mL methyl alcohol, add 10%Pd/C 0.07g under the room temperature, feed hydrogen, stirred 3 hours, reacting liquid filtering, vacuum-drying is by column chromatography purification (ethyl acetate: sherwood oil=1: 3), get white solid 0.5g, three step yields 78.0%.
(4) (R)-preparation of 1-(1-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazol-4 yl) piperidines-3-aminocarbamic acid tert-butyl ester
In the exsiccant reaction flask, add triphosgene 359mg (1.2mmol), 0.77mL triethylamine (5.3mmol), be dissolved in the 40mL tetrahydrofuran (THF), under-10 ℃, add (R)-1-[2-amino-3-(methylamino-) phenyl] tetrahydrofuran (THF) (5mL) solution of piperidines-3-aminocarbamic acid tert-butyl ester 0.35g (1.1mmol), stirred 0.5 hour, the reaction solution ethyl acetate extraction, with saturated sodium carbonate solution and salt water washing, organic layer anhydrous sodium sulfate drying, column chromatography purification (ethyl acetate: sherwood oil=1: 2), get white powder 370mg, yield 97.8%.
(5) (R)-and 1-[3-(2-cyano group benzyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazol-4 yl] preparation of piperidines-3-aminocarbamic acid tert-butyl ester
In the exsiccant reaction flask, add (R)-1-(1-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazol-4 yl) piperidines-3-aminocarbamic acid tert-butyl ester 370mg (1.1mmol), be dissolved in 2mL DMF, splash into 2-(brooethyl) cyanobenzene 259mg (1.3mmol) under-10 ℃, salt of wormwood 304mg (2.2mmol), stirring reaction is 2 hours under the room temperature, the reaction solution ethyl acetate extraction, the saturated nacl aqueous solution washing, organic layer anhydrous sodium sulfate drying, column chromatography purification (sherwood oil: ethyl acetate=3: 1), get white powder 390mg, yield 79.1%.
(6) (R)-and 2-[[7-(3-amino piperidine-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazoles-1-yl] methyl] preparation of cyanobenzene trifluoroacetate
In the exsiccant reaction flask, adding (R)-1-[3-(2-cyano group benzyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazol-4 yl] piperidines-3-aminocarbamic acid tert-butyl ester 320mg (0.69mmol) is dissolved in 24mL CH
2Cl
2, 0 ℃ splashes into trifluoroacetic acid 4.8mL, stirs 1 hour under the room temperature, and the reaction solution evaporate to dryness with small amount of methanol and ether dissolution, is separated out white solid, gets product 230mg, yield 69.8%.
Molecular formula: C
23H
24F
3N
5O
3Molecular weight: 475.46 mass spectrums (M+H): 362.2
1H-NMR(CDCl
3+D
2O，300MHz)：δ7.69(d，1H)，7.43(t，1H)，7.29(t，1H)，7.10(t，1H)，6.95(d，1H)，6.85(t，2H)，5.66(d，2H)，3.47(s，3H)，3.04(d，1H)，2.74(t，2H)，2.37-2.52(m，1H)，2.17-2.29(m，1H)，1.86(t，1H)，1.55(t，1H)，1.34(m，1H)，0.94(m，1H).
Embodiment 4 (R)-2-[[7-(3-amino piperidine-1-yl)-5-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazoles-1-
Base] methyl] preparation of cyanobenzene (compound 6) trifluoroacetate
(1) (R)-preparation of 1-(3,5-two fluoro-2-nitrophenyls) piperidines-3-aminocarbamic acid tert-butyl ester
In the exsiccant reaction flask, with (R)-piperidines-3-aminocarbamic acid tert-butyl ester 3.9g (19.5mmol), triethylamine 4.18mL is dissolved in the 45mL ethanol, is added drop-wise to 75mL ethanol and 1.75mL (15.0mmol) 1,3 under the room temperature, in the mixture of 5-three fluoro-2-oil of mirbane, stirring at room 3 days, the reaction solution drying under reduced pressure is by column chromatography purification (ethyl acetate: sherwood oil=1: 7), get yellow solid 5.012g, yield 93.5%.
(2) (R)-and 1-[5-fluoro-3-(methylamino-)-2-nitrophenyl] preparation of piperidines-3-aminocarbamic acid tert-butyl ester
In the exsiccant reaction flask, add (R)-1-(3,5-two fluoro-2-nitrophenyls) piperidines-3-aminocarbamic acid tert-butyl ester 1.964g (5.5mmol), be dissolved in the 100mL ethanol, add 27% methylethylolamine solution 6.64g, 40 ℃ were stirred 16 hours down, the reaction solution drying under reduced pressure, by column chromatography purification (ethyl acetate: sherwood oil=1: 8), get yellow solid 1.361g, yield 67.2%.
(3) (R)-and 1-[2-amino-5-fluoro-3-(methylamino-) phenyl] preparation of piperidines-3-aminocarbamic acid tert-butyl ester
In the exsiccant reaction flask, add (R)-1-[5-fluoro-3-(methylamino-)-2-nitrophenyl] piperidines-3-aminocarbamic acid tert-butyl ester 1.361g (3.694mmol), be dissolved in the 30mL methyl alcohol, add 10%Pd/C 0.283g under the room temperature, feed hydrogen, stirred 16 hours, reacting liquid filtering, vacuum-drying gets pale solid 1.25g, yield 100%.
(4) (R)-preparation of 1-(6-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazol-4 yl) piperidines-3-aminocarbamic acid tert-butyl ester
In the exsiccant reaction flask, add triphosgene 0.873g (2.942mmol), 1.49mL triethylamine (10.703mmol), be dissolved in the 60mL tetrahydrofuran (THF), under-12 ℃, with (R)-1-[2-amino-5-fluoro-3-(methylamino-) phenyl] the 20mL tetrahydrofuran solution of piperidines-3-aminocarbamic acid tert-butyl ester 0.904g (2.671mmol) is added drop-wise in the system, stirred 2 hours, reaction solution adds entry and ethyl acetate, ethyl acetate extraction, merge organic phase, the saturated common salt water washing, organic layer anhydrous sodium sulfate drying, column chromatography purification, get pale powder 0.816g, yield 83.8%.
(5) (R)-and 1-[3-(2-cyano group benzyl)-6-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazol-4 yl] preparation of piperidines-3-aminocarbamic acid tert-butyl ester
In the exsiccant reaction flask, add (R)-1-(6-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazol-4 yl) piperidines-3-aminocarbamic acid tert-butyl ester (0.793g, 2.176mmol), salt of wormwood 0.601g (4.348mmol), be dissolved in 8mL DMF,-10 ℃ add 2-(brooethyl) cyanobenzene 0.448g (2.285mmol) down, and stirring reaction is 2.5 hours under the room temperature, the reaction solution ethyl acetate extraction, organic phase washes with water, the saturated nacl aqueous solution washing, organic layer anhydrous sodium sulfate drying, column chromatography purification (ethyl acetate: sherwood oil=1: 2), get white powder 0.871g, yield 83.5%.
(6) (R)-and 2-[[7-(3-amino piperidine-1-yl)-5-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazoles-1-yl] methyl] preparation of cyanobenzene trifluoroacetate
In the exsiccant reaction flask, adding (R)-1-[3-(2-cyano group benzyl)-6-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazol-4 yl] piperidines-3-aminocarbamic acid tert-butyl ester 0.871g (1.816mmol) is dissolved in 70mL CH
2Cl
2,-15 ℃ splash into trifluoroacetic acid 12.5mL, stirred 2 hours under the room temperature, and the reaction solution evaporate to dryness, residue is separated out the white powder solid with small amount of methanol and ether dissolution, gets product 0.65g, yield 72.5%.
Molecular formula: C
23H
23F
4N
5O
3Molecular weight: 493.45 mass spectrums (M+H): 380.2
1H-NMR(d
6-DMSO+D
2O，400MHz)：δ7.84(d，1H)，7.58(t，1H)，7.45(t，1H)，7.03(dd，1H)，6.88(d，1H)，6.80(dd，1H)，5.49(d，1H)，5.40(d，1H)，3.37(s，3H)，3.05-3.03(m，1H)，2.85(br?s，1H)，2.68-2.65(m，1H)，2.62-2.54(m，2H)，1.96-1.93(m，1H)，1.63-1.60(m，1H)，1.32-1.25(m，1H)，1.21-1.18(m，1H).
Embodiment 5 (R)-2-[[7-(3-amino piperidine-1-yl)-5-methoxyl group-3-methyl-2-oxo-2,3-dihydro-1H-benzo [d] miaow
Azoles-1-yl] methyl] preparation of cyanobenzene (compound 7) trifluoroacetate
The preparation of (1) 1,3-two fluoro-5-methoxyl group-2-oil of mirbane
In the exsiccant reaction flask, 7mL methyl alcohol is added drop-wise in the sodium hydride of 0.226g (5.65mmol) 60% under the room temperature, adds the dilution of 8mL methyl alcohol then.-29 ℃ are added to 0.66mL (5.65mmol) 1 with the drips of solution that makes, 3, in 5-three fluoro-2-oil of mirbane and the 15mL carbinol mixture, stirring at room 4 days, concentrating under reduced pressure, residue adds entry and ethyl acetate, and ethyl acetate extraction merges organic phase, use the saturated common salt water washing, the organic phase anhydrous sodium sulfate drying filters, and concentrating under reduced pressure gets faint yellow solid 1.065g.Dichloromethane solution with 1.25mL boron tribromide (13.27mmol) under the dry ice bath is added drop-wise in the above-mentioned 1.065g faint yellow solid, stirring at room 24 hours, in reaction solution, add frozen water and ethyl acetate, ethyl acetate extraction, merge organic phase, the organic phase anhydrous sodium sulfate drying, filter, concentrating under reduced pressure gets faint yellow oily thing, adds acetic acid ethyl dissolution, with the washing of 2N sodium hydroxide solution, the organic phase anhydrous sodium sulfate drying, filter, concentrating under reduced pressure gets faint yellow solid 0.27g, yield 25.3%.
(2) (R)-preparation of 1-(3-fluoro-5-methoxyl group-2-nitrophenyl) piperidines-3-aminocarbamic acid tert-butyl ester
With (R)-piperidines-3-aminocarbamic acid tert-butyl ester 0.206g (1.03mmol), triethylamine 0.18mL is dissolved in the 8mL ethanol, be added drop-wise to 7mL ethanol and 1 under the room temperature, in the mixture of 3-two fluoro-5-methoxyl groups-2-oil of mirbane 0.163g (0.862mmol), 40 ℃ were stirred 24 hours down, and the reaction solution drying under reduced pressure gets crude product yellow oil 0.426g.
(3) (R)-and 1-[5-methoxyl group-3-(methylamino-)-2-nitrophenyl] preparation of piperidines-3-aminocarbamic acid tert-butyl ester
In the exsiccant reaction flask, add crude product (R)-1-(3-fluoro-5-methoxyl group-2-nitrophenyl) piperidines-3-aminocarbamic acid tert-butyl ester 0.426g (0.862mmol), be dissolved in the 15mL ethanol, the methylethylolamine solution 1.185g of adding 27%, 50 ℃ were stirred 24 hours, and the reaction solution drying under reduced pressure obtains crude product red solid 0.423g.
(4) (R)-and 1-[2-amino-5-methoxyl group-3-(methylamino-) phenyl] preparation of piperidines-3-aminocarbamic acid tert-butyl ester
In the exsiccant reaction flask, add crude product (R)-1-[5-methoxyl group-3-(methylamino-)-2-nitrophenyl] piperidines-3-aminocarbamic acid tert-butyl ester 0.423g (0.862mmol), be dissolved in the 10mL methyl alcohol, add 10%Pd/C 0.033g under the room temperature, feed hydrogen, stirred 3.5 hours, reacting liquid filtering, vacuum-drying gets crude product brown solid 0.386g.
(5) (R)-preparation of 1-(6-methoxyl group-1-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazol-4 yl) piperidines-3-aminocarbamic acid tert-butyl ester
In the exsiccant reaction flask, add triphosgene 0.281g (0.947mmol), 0.48mL triethylamine, be dissolved in the 15mL tetrahydrofuran (THF), under-20 ℃, add (R)-1-[2-amino-5-methoxyl group-3-(methylamino-) phenyl] piperidines-3-aminocarbamic acid tert-butyl ester 0.386g (1.101mmol), be dissolved in the 20mL tetrahydrofuran (THF), stirred 0.5 hour, reaction solution adds entry and ethyl acetate, ethyl acetate extraction, merge organic phase, the saturated common salt water washing, organic layer anhydrous sodium sulfate drying, concentrating under reduced pressure get red solid 0.244g.
(6) (R)-and 1-[3-(2-cyano group benzyl)-6-methoxyl group-1-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazol-4 yl] preparation of piperidines-3-aminocarbamic acid tert-butyl ester
In the exsiccant reaction flask, add (R)-1-(6-methoxyl group-1-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazol-4 yl) piperidines-3-aminocarbamic acid tert-butyl ester 0.576g (1.530mmol), salt of wormwood 0.422g (3.053mmol), be dissolved in 9mL DMF, splash into DMF (9mL) solution of 2-(brooethyl) cyanobenzene 0.406g (2.071mmol) under-10 ℃, stirring reaction is 2 days under the room temperature, the reaction solution ethyl acetate extraction, organic phase washes with water, the saturated nacl aqueous solution washing, the organic layer anhydrous sodium sulfate drying, column chromatography purification (ethyl acetate: sherwood oil=1: 3), get white powder 0.125g with ethyl acetate and normal hexane recrystallization then, yield 16.6%.
(7) (R)-and 2-[[7-(3-amino piperidine-1-yl)-5-methoxyl group-3-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazoles-1-yl] methyl] preparation of cyanobenzene trifluoroacetate
In the exsiccant reaction flask, adding (R)-1-[3-(2-cyano group benzyl)-6-methoxyl group-1-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazol-4 yl] piperidines-3-aminocarbamic acid tert-butyl ester 0.125g (0.254mmol) is dissolved in 10mL CH
2Cl
2,-7 ℃ splash into trifluoroacetic acid 1.75mL, stirred 1 hour under the room temperature, and the reaction solution evaporate to dryness, residue is separated out the white powder solid with small amount of methanol and ether dissolution, gets product 50mg, yield 38.9%.
Molecular formula: C
24H
26O
3N
5O
4Molecular weight: 505.49 mass spectrums (M+H): 392.2
1H-NMR(d
6-DMSO，400MHz)：δ7.89(d，1H)，7.58(t，1H)，7.45(t，1H)，6.78(d，2H)，6.50(s，1H)，5.43(d，1H)，5.33(d，1H)，3.77(s，3H)，3.38(s，3H)，2.97(d，1H)，2.73(br?s，1H)，2.57-2.50(m，3H)，1.90(d，1H)，1.56(d，1H)，1.09(m，2H).
With reference to above-mentioned preparation method, can also prepare following compound:
Claims (10)
1. the compound shown in the general formula (I), its pharmacy acceptable salt, its steric isomer or its solvate:
Wherein: R
1Be the C that is not substituted or is replaced by halogen atom, hydroxyl, amino, carboxyl, formamyl or amino-sulfonyl
1-6Alkyl, C
3-6Thiazolinyl or C
2-6Alkynyl, or
The aromatic base C that is not substituted or is replaced by 1～5 substituting group V
1-6Alkyl, described substituting group V independently selected from halogen atoms, cyano group, cyano group C
1-6Alkyl, C
2-6Alkynyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, amino, amino C
1-6Alkyl, C
1-6Alkylamino, two (C
1-6Alkyl) amino, hydroxyl, hydroxyl C
1-6Alkyl, carboxyl, carboxyl C
1-6Alkyl, formamyl, C
1-6Alkyl-carbamoyl, C
1-6Alkyl amino sulfonyl, hydroxyl C
1-6Alkoxyl group, amino C
1-6Alkoxyl group or carboxyl C
1-6Alkoxyl group;
R
2, R
4Be hydrogen atom independently, halogen atom, cyano group, amino, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl or amino C
1-6Alkyl;
R
3Be hydrogen atom, halogen atom, cyano group, amino, hydroxyl, carboxyl, C
1-6Alkylamino, two (C
1-6Alkyl) amino, NR
9R
10C (O)-, NR
9R
10S (O)
2-, the C that is not substituted or is replaced by halogen atom, hydroxyl, amino, carboxyl, cyano group, formamyl, amino-sulfonyl
1-6Alkyl or C
1-6Alkoxyl group,
R
9, R
10Be hydrogen atom independently, be not substituted or by halogen atom, hydroxyl, amino, carboxyl, cyano group, formamyl, amino-sulfonyl, C
1-6Alkoxyl group, C
1-6Alkylamino, two (C
1-6Alkyl) amino, C
1-6Alkyl-carbamoyl, two (C
1-6Alkyl) formamyl, C
1-6Alkyl amino sulfonyl, two (C
1-6Alkyl) amino-sulfonyl, C
1-6Alkyl carbonylamino, C
1-6Alkyl sulfonyl amino, C
1-6Alkyl sulphonyl, C
1-6Alkyl-carbonyl, C
1-6Alkyl carbonyl oxy, C
1-6The C that alkoxy carbonyl replaces
1-6Alkyl;
X is O, S, NR
5Or CR
6R
7,
R
5Be hydrogen atom, C
1-6Alkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl or C
3-6Cycloalkyl,
R
6, R
7Be hydrogen atom, halogen atom, C independently
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, amino C
1-6Alkyl or C
3-6Cycloalkyl, or R
6, R
7Form C with the carbon atom that links to each other
3-6The saturated Azacyclyl of cycloalkyl or 4-6 unit;
Y is O, S or NR
8, R
8Be hydrogen atom, formamyl, C
1-6Alkyl-carbonyl, C
3-6Cycloalkyl or the C that is not substituted or is replaced by halogen atom, hydroxyl, amino, carboxyl or formamyl
1-6Alkyl, C
1-6Alkoxyl group, aromatic base C
0-6Alkyl or aromatic base C
0-6Alkoxyl group;
4-7 the unit saturated or undersaturated heterocyclic radical that at least contain a nitrogen-atoms of Q for not being substituted or being replaced by 1～5 substituting group W,
Described substituting group W independently selected from halogen atoms, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, amino, amino C
1-6Alkyl, C
1-6Alkylamino, two (C
1-6Alkyl) amino, hydroxyl, hydroxyl C
1-6Alkyl, carboxyl, carboxyl C
1-6Alkyl, C
1-6Carbalkoxy, C
1-6Alkyl carbonyl oxy, formamyl, formamyl C
1-6Alkyl, C
1-6Alkyl-carbamoyl, C
1-6Alkyl carbonylamino, C
1-6Alkyl carbonylamino C
1-6Alkyl or iminomethyl.
2. compound as claimed in claim 1, its pharmacy acceptable salt, its steric isomer or its solvate:
Wherein: R
1Be the C that is not substituted or is replaced by halogen atom, hydroxyl, amino, carboxyl, formamyl or amino-sulfonyl
1-6Alkyl, C
3-6Thiazolinyl or C
2-6Alkynyl, or
The aromatic base C that is not substituted or is replaced by 1～5 substituting group V
1-6Alkyl, described substituting group V independently selected from halogen atoms, cyano group, cyano group C
1-6Alkyl, C
2-6Alkynyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, amino, amino C
1-6Alkyl, C
1-6Alkylamino, two (C
1-6Alkyl) amino, hydroxyl, hydroxyl C
1-6Alkyl, carboxyl, carboxyl C
1-6Alkyl, formamyl, C
1-6Alkyl-carbamoyl, C
1-6Alkyl amino sulfonyl, hydroxyl C
1-6Alkoxyl group, amino C
1-6Alkoxyl group or carboxyl C
1-6Alkoxyl group;
R
2, R
3, R
4Be hydrogen atom independently, halogen atom, cyano group, amino, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl or amino C
1-6Alkyl;
X is O, S, NR
5Or CR
6R
7,
R
5Be hydrogen atom, C
1-6Alkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl or C
3-6Cycloalkyl,
R
6, R
7Be hydrogen atom, halogen atom, C independently
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, amino C
1-6Alkyl or C
3-6Cycloalkyl, or R
6, R
7Form C with the carbon atom that links to each other
3-6The saturated Azacyclyl of cycloalkyl or 4-6 unit;
Y is O, S or NR
8, R
8Be hydrogen atom, formamyl, C
1-6Alkyl-carbonyl, C
3-6Cycloalkyl or the C that is not substituted or is replaced by halogen atom, hydroxyl, amino, carboxyl or formamyl
1-6Alkyl, C
1-6Alkoxyl group, aromatic base C
0-6Alkyl or aromatic base C
0-6Alkoxyl group;
4-7 the unit saturated or undersaturated heterocyclic radical that at least contain a nitrogen-atoms of Q for not being substituted or being replaced by 1～5 substituting group W,
Described substituting group W independently selected from halogen atoms, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, amino, amino C
1-6Alkyl, C
1-6Alkylamino, two (C
1-6Alkyl) amino, hydroxyl, hydroxyl C
1-6Alkyl, carboxyl, carboxyl C
1-6Alkyl, C
1-6Carbalkoxy, C
1-6Alkyl carbonyl oxy, formamyl, formamyl C
1-6Alkyl, C
1-6Alkyl-carbamoyl, C
1-6Alkyl carbonylamino, C
1-6Alkyl carbonylamino C
1-6Alkyl or iminomethyl.
3. compound as claimed in claim 2, its pharmacy acceptable salt, its steric isomer or its solvate:
Wherein, R
1Be C
3-6Thiazolinyl, C
2-6Alkynyl, or the phenyl C that is not substituted or is replaced by 1～3 substituting group V
1-6Alkyl, described substituting group V independently selected from halogen atoms, cyano group, cyano group C
1-6Alkyl, C
2-6Alkynyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, amino, amino C
1-6Alkyl, C
1-6Alkylamino, two (C
1-6Alkyl) amino, hydroxyl, hydroxyl C
1-6Alkyl, carboxyl, carboxyl C
1-6Alkyl, formamyl, C
1-6Alkyl-carbamoyl or C
1-6Alkyl amino sulfonyl;
R
2, R
3, R
4Be hydrogen atom independently, halogen atom, cyano group, amino, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group or hydroxyl C
1-6Alkyl;
X is O, S, NR
5Or CR
6R
7,
R
5Be selected from hydrogen atom, C
1-6Alkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl or C
3-6Cycloalkyl,
R
6, R
7Be independently selected from hydrogen atom, halogen atom, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, hydroxyl C
1-6Alkyl, amino C
1-6Alkyl or C
3-6Cycloalkyl, or R
6, R
7Form C with the carbon atom that links to each other
3-6The saturated Azacyclyl of cycloalkyl or 5-6 unit;
Y is O, S or NR
8, R
8Be hydrogen atom, C
3-6Cycloalkyl or the C that is not substituted or is replaced by halogen atom, hydroxyl, amino, carboxyl or formamyl
1-6Alkyl, C
1-6Alkoxyl group, phenyl C
0-6Alkyl or phenyl C
0-6Alkoxyl group;
5-6 the unit saturated or undersaturated heterocyclic radical that at least contain a nitrogen-atoms of Q for not being substituted or being replaced by 1～3 substituting group W,
Described substituting group W independently selected from halogen atoms, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, amino, amino C
1-6Alkyl, C
1-6Alkylamino, two (C
1-6Alkyl) amino, hydroxyl, hydroxyl C
1-6Alkyl, carboxyl, carboxyl C
1-6Alkyl, C
1-6Alkoxy carbonyl, C
1-6Alkyl carbonyl oxy, formamyl, formamyl C
1-6Alkyl, C
1-6Alkyl-carbamoyl, C
1-6Alkyl carbonylamino, C
1-6Alkyl carbonylamino C
1-6Alkyl or iminomethyl.
4. compound as claimed in claim 3, its pharmacy acceptable salt, its steric isomer or its solvate:
Wherein, R
1Be C
3-4Thiazolinyl, C
2-4Alkynyl, or the phenyl C that is not substituted or is replaced by 1～3 substituting group V
1-4Alkyl, described substituting group V independently selected from halogen atoms, cyano group, cyano group C
1-4Alkyl, C
2-4Alkynyl, C
1-4Alkyl, halo C
1-4Alkyl, C
1-4Alkoxyl group, halo C
1-4Alkoxyl group, amino, amino C
1-4Alkyl, C
1-4Alkylamino, two (C
1-4Alkyl) amino, hydroxyl, hydroxyl C
1-4Alkyl, formamyl, C
1-4Alkyl-carbamoyl or C
1-4Alkyl amino sulfonyl;
R
2, R
3, R
4Be hydrogen atom independently, halogen atom, cyano group, C
1-4Alkyl, halo C
1-4Alkyl, C
1-4Alkoxyl group, halo C
1-4Alkoxyl group or hydroxyl C
1-4Alkyl;
X is O, S, NR
5Or CR
6R
7,
R
5Be selected from hydrogen atom, C
1-4Alkyl, halo C
1-4Alkyl, C
2-4Thiazolinyl or C
3-6Cycloalkyl,
R
6, R
7Be independently selected from hydrogen atom, halogen atom, C
1-4Alkyl, halo C
1-4Alkyl, C
1-4Alkoxyl group, halo C
1-4Alkoxyl group, hydroxyl C
1-4Alkyl, amino C
1-4Alkyl or C
3-6Cycloalkyl, or R
6, R
7Form C with the carbon atom that links to each other
3-6The saturated Azacyclyl of cycloalkyl or 5-6 unit;
Y is O, S or NR
8, R
8Be hydrogen atom or C
1-4Alkyl;
5-6 the unit saturated or undersaturated heterocyclic radical that at least contain a nitrogen-atoms of Q for not being substituted or being replaced by 1～3 substituting group W,
Described substituting group W independently selected from halogen atoms, C
1-4Alkyl, halo C
1-4Alkyl, C
1-4Alkoxyl group, halo C
1-4Alkoxyl group, amino, amino C
1-4Alkyl, C
1-4Alkylamino, hydroxyl, hydroxyl C
1-4Alkyl, carboxyl C
1-4Alkyl, C
1-4Alkoxy carbonyl, C
1-4Alkyl carbonyl oxy, formamyl, formamyl C
1-4Alkyl, C
1-4Alkyl-carbamoyl, C
1-4Alkyl carbonylamino, C
1-4Alkyl carbonylamino C
1-4Alkyl or iminomethyl.
5. compound as claimed in claim 4, its pharmacy acceptable salt, its steric isomer or its solvate:
Wherein, R
1Be propenyl, proyl, or the phenyl C that is not substituted or is replaced by 1～3 substituting group V
1-4Alkyl, described substituting group V be independently selected from fluorine atom, chlorine atom, cyano group, cyano methyl, ethynyl, methyl, trifluoromethyl, methoxyl group, trifluoromethoxy, amino, aminomethyl, methylamino-, dimethylamino, methylol, hydroxyethyl, formamyl, methylamino formyl radical or methylamino alkylsulfonyl;
R
2, R
3, R
4Be hydrogen atom independently, fluorine atom, chlorine atom, cyano group, methyl, trifluoromethyl, methoxyl group, trifluoromethoxy or methylol;
X is O, S, NR
5Or CR
6R
7,
R
5Be selected from hydrogen atom, methyl, ethyl, sec.-propyl, trifluoromethyl, vinyl or cyclopropane base,
R
6, R
7Be independently selected from hydrogen atom, fluorine atom, methyl, ethyl, methyl fluoride, trifluoromethyl, methoxyl group, methylol or aminomethyl, or R
6, R
7Form cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl or piperidyl with the carbon atom that links to each other;
Y is O, S or NR
8, R
8Be hydrogen atom or methyl;
Pyrrolidyl, pyrryl, imidazolidyl, the pyrazolyl, 4 of Q for not being substituted or being replaced by 1～2 substituting group W, 5-pyrazoline base, pyrazolidyl, 1,2,4-triazolyl, 1,4-
Piperazine base, piperidyl, piperazinyl or morpholinyl,
Described substituting group W be independently selected from fluorine atom, chlorine atom, methyl, methyl fluoride, methoxyl group, amino, aminomethyl, methylamino-, hydroxyl, methylol, carboxymethyl, methoxycarbonyl, acetoxyl group, formamyl, carbamyl ylmethyl, methylamino formyl radical, kharophen, acetylamino methyl or iminomethyl.
6. compound as claimed in claim 5, its pharmacy acceptable salt, its steric isomer or its solvate:
Wherein, R
1Be the benzyl that is not substituted or is replaced by 1～3 substituting group V, described substituting group V is independently selected from fluorine atom, cyano group, ethynyl, methyl, trifluoromethyl, methoxyl group, trifluoromethoxy or methylamino-;
R
2, R
3, R
4Be hydrogen atom independently, fluorine atom or methoxyl group;
X is O, S, NR
5Or CR
6R
7,
R
5Be selected from hydrogen atom, methyl, ethyl or sec.-propyl,
R
6, R
7Be independently selected from hydrogen atom, methyl, or R
6, R
7Form cyclopropane base, pentamethylene base or piperidyl with the carbon atom that links to each other;
Y is O;
Pyrrolidyl, imidazolidyl, piperidyl or the piperazinyl of Q for not being substituted or being replaced by 1～2 substituting group W,
Described substituting group W is independently selected from amino, methylamino-, hydroxyl, methylol or formamyl.
7. compound as claimed in claim 6, its pharmacy acceptable salt, its steric isomer or its solvate:
(R)-and 2-[[7-(3-amino piperidine-1-yl)-3,3-dimethyl-2-oxoindoline-1-yl] methyl] cyanobenzene,
(R)-and 2-[[7 '-(3-amino piperidine-1-yl)-2 '-oxo spiral shell [cyclopropane-1,3 '-indoline]-1 '-yl] methyl] cyanobenzene,
(R)-and 2-[[7 '-(3-amino piperidine-1-yl)-2 '-oxo spiral shell [pentamethylene-1,3 '-indoline]-1 '-yl] methyl] cyanobenzene,
(R)-and 2-[[7-(3-amino piperidine-1-yl)-2-oxo spiral shell [indoline-3,4 '-piperidines]-1-yl] methyl] cyanobenzene,
(R)-and 2-[[7-(3-amino piperidine-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazoles-1-yl] methyl] cyanobenzene,
(R)-and 2-[[7-(3-amino piperidine-1-yl)-5-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazoles-1-yl] methyl] cyanobenzene,
(R)-and 2-[[7-(3-amino piperidine-1-yl)-5-methoxyl group-3-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazoles-1-yl] methyl] cyanobenzene,
(R)-1-methyl-4-[3-(methylamino-) piperidines-1-yl]-3-(3,4,5-trimethoxy benzyl)-1H-benzo [d] imidazoles-2 (3H)-ketone,
3-(2, the 5-difluorobenzyl)-4-(3-hydroxyl pyrrolidine-1-yl)-1-methyl isophthalic acid H-benzo [d] imidazoles-2 (3H)-ketone,
(R)-2-[[4-(3-amino piperidine-1-yl)-2-oxo benzo [d]
Azoles-3 (2H)-yl] methyl] cyanobenzene,
4-[3-[3-(methylamino-) benzyl]-2-oxo-2,3-dihydrobenzo [d]
Azoles-4-yl] piperazine-1-methane amide,
(R)-and 2-[[4-(3-amino piperidine-1-yl)-2-oxo benzo [d] thiazole-3 (2H)-yl] methyl] cyanobenzene,
4-[3-(methylol) imidazolidine-1-yl]-3-[3-(trifluoromethoxy) benzyl] benzo [d] thiazole-2 (3H)-ketone.
8. as the described compound of the arbitrary claim of claim 1～7, its pharmacy acceptable salt, its steric isomer or its solvate, it is characterized in that its pharmacy acceptable salt is benzoate, benzene sulfonate, tosilate, Citrate trianion, maleate, fumarate, tartrate, trifluoroacetate, hydrobromate, hydrochloride, vitriol, nitrate, phosphoric acid salt, arginic acid salt, meglumine salt, glucosamine salt or ammonium salt, lithium salts, sodium salt, sylvite, calcium salt, magnesium salts, zinc salt, barium salt.
9. as the pharmaceutical composition of the described compound of the arbitrary claim of claim 1～7, its pharmacy acceptable salt, its steric isomer or its solvate and one or more pharmaceutical carriers and/or thinner, be pharmaceutically acceptable arbitrary formulation.
As the described compound of the arbitrary claim of claim 1～7, its pharmacy acceptable salt, its steric isomer or its solvate in the application that is used for preparing the medicine that treats and/or prevents non-insulin-dependent diabetes mellitus (NIDDM).
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| WO2005044793A2 (en) * | 2003-10-31 | 2005-05-19 | Takeda Pharmaceutical Company Limited | Nitrogen-containing fused heterocyclic compounds |
| CN1745080A (en) * | 2002-12-04 | 2006-03-08 | 卫材株式会社 | 1,3-dihydroimidazole fused-ring compound |
| CN101166729A (en) * | 2005-04-27 | 2008-04-23 | 武田药品工业株式会社 | Fused heterocyclic compounds |
| CN101263136A (en) * | 2005-07-13 | 2008-09-10 | 弗·哈夫曼-拉罗切有限公司 | Benzimidazole derivatives as 5-HT6, 5-HT24 |
| WO2009058728A1 (en) * | 2007-10-29 | 2009-05-07 | Schering Corporation | Thiazole derivatives as protein kinase inhibitors |
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| CN1745080A (en) * | 2002-12-04 | 2006-03-08 | 卫材株式会社 | 1,3-dihydroimidazole fused-ring compound |
| WO2005044793A2 (en) * | 2003-10-31 | 2005-05-19 | Takeda Pharmaceutical Company Limited | Nitrogen-containing fused heterocyclic compounds |
| CN101166729A (en) * | 2005-04-27 | 2008-04-23 | 武田药品工业株式会社 | Fused heterocyclic compounds |
| CN101263136A (en) * | 2005-07-13 | 2008-09-10 | 弗·哈夫曼-拉罗切有限公司 | Benzimidazole derivatives as 5-HT6, 5-HT24 |
| WO2009058728A1 (en) * | 2007-10-29 | 2009-05-07 | Schering Corporation | Thiazole derivatives as protein kinase inhibitors |
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