CN102372701A - Azabicyclo hexane derivative, preparation method, and application of azabicyclo hexane derivative in medicine - Google Patents

Azabicyclo hexane derivative, preparation method, and application of azabicyclo hexane derivative in medicine Download PDF

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Publication number
CN102372701A
CN102372701A CN2010102496200A CN201010249620A CN102372701A CN 102372701 A CN102372701 A CN 102372701A CN 2010102496200 A CN2010102496200 A CN 2010102496200A CN 201010249620 A CN201010249620 A CN 201010249620A CN 102372701 A CN102372701 A CN 102372701A
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general formula
alkyl
compound
aryl
heterocyclic radical
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邓炳初
杨方龙
范江
关东亮
沈光远
王阳
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention relates to a azabicyclo hexane derivative, a preparation method, and an application of the azabicyclo hexane derivative in medicine, specifically to a new azabicyclo hexane derivative represented by a general formula (I), a preparation method, a drug composition containing the derivative, a use of the derivative as a therapeutic agent, especially a GPR119 agonist, and a use of the derivative in preparing drugs for treating diabetes, metabolic disorders, and other diseases. Various substituents in the formula (I) are the same as the definitions in the instruction.

Description

Azabicyclohexane analog derivative, its preparation method and in pharmaceutically application
Technical field
The pharmaceutical composition that the present invention relates to a kind of new azabicyclohexane analog derivative, its preparation method and contain this verivate with and as therapeutical agent particularly as the GPR119 agonist with in the purposes of the medicine of diseases such as preparation treatment anti-diabetic and metabolic disorder.
Background technology
A classical symptom of type ii diabetes is the Regular Insulin that pancreatic beta cell can't secrete q.s when following the patient to show insulin resistant.Can the medicine of treating type ii diabetes clinically be divided into two types based on this point, a kind of is the medicine that is used for improving the insulin resistant symptom of organ-tissues such as liver, muscle; Second kind is to act on the medicine that pancreatic beta cell promotes its excreting insulin.At present; Develop multiple medicine and be used for realizing this purpose; Like glucagon kind polypeptide-1 analogue (GLP-1 mimetics); Because its mechanism of action is the glucose dependency, maybe not can in the clinical treatment use makes the patient hypoglycemic symptom occur, thereby become the ideal medicine simultaneously.On to GLP-1 research basis, developed DPP IV (DPPIV) suppressor factor again, also success becomes the medicine for treatment of novel I type i diabetes.Along with further going deep into of research,, make a kind of g protein coupled receptor GPR119 become the novel targets of a potential type ii diabetes treatment especially to the research of pancreatic beta cell excreting insulin process.
G protein coupled receptor 119 (GPR119) is a kind of orphan receptor of finding through the Human genome sequencing analysis, and its assignment of genes gene mapping mainly is expressed in beta Cell of islet and intestinal cell in the pancreatic tissue in X chromosome.Through further research, find that Oleoyl monoethanolamide (OEA) and derivative of fatty acid oleoyl SUNLECITHIN A are the endogenic ligands of GPR119.Exciting GPR119 can improve the intracellular cyclic monophosphate of β (cAMP) concentration through combine also with GPR119, and the stimulus-secretion coupling in the activated cell promotes flow of calcium ions, thereby promotes the Regular Insulin vesicle secretion outside born of the same parents.
Histocyte expression characteristic and the function of GPR119 are all pointed out, and activate this receptor and can promote GLP-1 and insulin secretion, help glycemic control.This notion has been used in the pharmaceutical research relevant with mellitus.In the isolated perfusion test to the isolated from rat pancreas islet, the GPR119 agonist can stimulate to be secreted with second o'clock in first o'clock of Regular Insulin mutually mutually, and this promoting insulin secretion has the glucose dependency.In addition, the GPR119 agonist also can promote mouse intestinal L clone secretion GLP-1.The GPR119 agonist has obtained demonstration to the treatment of diabetes effect in experimentation on animals.Can significantly improve Regular Insulin, GLP-1 and GIP level in the blood circulation for the oral GPR119 agonist of rat, reduce the blood sugar concentration of rat after accepting carbohydrate tolerance test simultaneously.Give diabetes rat 4 weeks of oral GPR119 agonist continued treatment (ZDF rat) every day; Its fasting blood glucose level obviously reduces, and the tolerance of carbohydrate tolerance test significantly improves, and the glycolated hemoglobin level is significantly improved; Significantly increase with insulin content simultaneously, the prompting islet function makes moderate progress.Above-mentioned test-results all shows, uses the diabetic symptom that the GPR119 agonist can improve experimental animal.
As the new formulation of treatment type ii diabetes, the main advantage of GPR119 agonist is that secretin's (comprising GLP-1 and GIP) and pancreas islet are have multiple secretomotor effect.This characteristic is that the GLP-1 analogue and the DPP-4 suppressor factor of anti-DPP-4 degraded is not available.In addition, the animal experiment prompting, the GPR119 agonist also has the potential of management of body weight.This novel mechanism of action possibly bring renewal, stronger hypoglycemic effect for treating diabetes, thereby helps to increase the variety of diabetes drug treatment, to satisfy requirement of different patients.
The patented claim of a series of GPR119 agonist is disclosed at present, comprising WO2005061489, WO2007116229 and WO2008083238.
Although disclose the GPR119 agonist of diseases such as a series of treatment mellitus and metabolic disease at present; But still need the new compound of exploitation with better drug effect; Through continuous effort; The compound that the present invention's design has the structure shown in the general formula (I), and find that the compound with this class formation shows excellent effect and effect.
Summary of the invention
The object of the present invention is to provide the compound shown in a kind of general formula (I), and their tautomer, enantiomorph, diastereomer, raceme and pharmaceutically useful salt, and meta-bolites and metabolic precursor thereof or prodrug.
Wherein:
Ar is selected from aryl or heteroaryl, wherein said aryl or heteroaryl optional further by one or more be selected from halogen, cyanic acid, nitro, alkyl, thiazolinyl, alkynyl, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-OR 6,-S (O) mR 6,-C (O) R 6,-C (O) OR 6,-NR 6R 7,-C (O) NR 6R 7,-NR 6C (O) R 7,-NR 6S (O) mR 7Or-SO 2NR 6R 7Substituting group replace, wherein said alkyl, thiazolinyl, alkynyl, naphthenic base, heterocyclic radical, aryl or heteroaryl independently optional separately further by one or more be selected from alkyl, halogen, haloalkyl, oxo, thiazolinyl, alkynyl, nitro, cyanic acid, alkoxyl group, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-OR 6,-S (O) mR 6,-C (O) R 6,-C (O) OR 6,-NR 6R 7,-C (O) NR 6R 7,-NR 6C (O) R 7,-NR 6S (O) mR 7Or-SO 2NR 6R 7Substituting group replace;
D, E and G are selected from O, N, N (R independently of one another 8), S or C (R 8), simultaneously, have at least one to be selected from O, N, N (R among D, E and the G 8) or S;
L is selected from-(CH 2) n-, wherein at least one CH 2By O, N (R 9), S, S (O) or S (O) 2Substitute all the other CH 2Choose wantonly and further replaced by one or two substituting group that is selected from halogen, alkyl or haloalkyl;
R 1Be selected from alkyl, thiazolinyl, alkynyl, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-A-C (O) R 6,-A-C (O) OR 6,-A-C (O) NR 6R 7With-SO 2R 6, wherein said alkyl, naphthenic base, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from alkyl, halogen, haloalkyl, oxo, thiazolinyl, alkynyl, nitro, cyanic acid, alkoxyl group, naphthenic base ,-OR 6,-S (O) mR 6,-C (O) R 6,-C (O) OR 6,-NR 6R 7,-C (O) NR 6R 7,-NR 6C (O) R 7,-NR 6S (O) mR 7Or-SO 2NR 6R 7Substituting group replace;
A be selected from a key ,-C (O)-,-C (O)-or-(CH 2) 1-4-, wherein-(CH 2) 1-4-optional further replaced by one or more substituting groups that are selected from halogen, alkyl or haloalkyl;
R 2, R 3, R 4And R 5Be selected from independently of one another Wasserstoffatoms, alkyl, halogen, haloalkyl, thiazolinyl, alkynyl, nitro, cyanic acid, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-OR 6,-S (O) 2R 6,-C (O) R 6,-C (O) OR 6,-NR 6R 7,-C (O) NR 6R 7,-NR 6C (O) R 7Or-SO 2NR 6R 7Perhaps R 2And R 3, R 4And R 5Form oxo together;
R 6And R 7Be selected from Wasserstoffatoms, alkyl, thiazolinyl, alkynyl, naphthenic base, heterocyclic radical, aryl or heteroaryl independently of one another, wherein said alkyl, thiazolinyl, alkynyl, naphthenic base, heterocyclic radical, aryl or heteroaryl independently optional separately further by one or more be selected from alkyl, halogen, haloalkyl, oxo, thiazolinyl, alkynyl, nitro, cyanic acid, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-OR 10,-S (O) mR 10,-C (O) R 10,-C (O) OR 10,-NR 10C (O) OR 11,-NR 10R 11,-C (O) NR 10R 11,-NR 10S (O) 2NR 10R 11,-NR 10S (O) 2R 11,-NR 10C (O) R 11Or-SO 2NR 10R 11Substituting group replace;
Simultaneously, R 6And R 7Form heterocyclic radical with the nitrogen-atoms that is connected, wherein said heterocyclic radical contains one or more N, O or S (O) mHeteroatoms, and said heterocyclic radical optional further by one or more be selected from alkyl, halogen, haloalkyl, oxo, thiazolinyl, alkynyl, nitro, cyanic acid, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-OR 10,-S (O) mR 10,-C (O) R 10,-C (O) OR 10,-NR 10C (O) OR 11,-NR 10R 11,-C (O) NR 10R 11,-NR 10S (O) 2NR 10R 11,-NR 10S (O) 2R 11,-NR 10C (O) R 11Or-SO 2NR 10R 11Substituting group replace;
R 8Be selected from Wasserstoffatoms, alkyl, halogen, haloalkyl, naphthenic base or-OR 6
R 9Be selected from-R 6,-C (O) R 6Or-S (O) 2R 6
R 10And R 11Independently be selected from Wasserstoffatoms, alkyl, haloalkyl, naphthenic base, heterocyclic radical, aryl or heteroaryl separately;
M is 0,1 or 2; And
N is 2,3 or 4.
Preferred compound of the present invention, the described compound of a kind of general formula (I) or its pharmaceutically useful salt, comprising the compound shown in a kind of general formula (II) or its pharmaceutically useful salt:
Figure BSA00000223622300031
Wherein Ar, D, E, G, L, R 1～R 5Definition such as general formula (I) described in.
Preferred compound of the present invention, the described compound of a kind of general formula (I) or its pharmaceutically useful salt, wherein Ar is an aryl, is preferably phenyl, said aryl is optional further by one or more-S (O) mR 6Replace.
Preferred compound of the present invention, the described compound of a kind of general formula (I) or its pharmaceutically useful salt, wherein L is-CH 2-O-.
Preferred compound of the present invention, the described compound of a kind of general formula (I) or its pharmaceutically useful salt, wherein R 1For-C (O) OR 6
Preferred compound of the present invention, the described compound of a kind of general formula (I) or its pharmaceutically useful salt, wherein R 2, R 3, R 4And R 5Be Wasserstoffatoms.
Typical compound of the present invention includes, but are not limited to:
Figure BSA00000223622300041
Or its pharmaceutically useful salt.
The present invention relates to the described compound of a kind of general formula (IA) or its pharmaceutically useful salt, this method comprises:
Figure BSA00000223622300042
With general formula (IA) compound and Ar-OH reaction, obtain general formula (I) compound;
Wherein: X is selected from halogen;
D, E, G, L, Ar and R 1～R 5Definition such as general formula (I) described in.
The present invention relates to a kind of general formula (IA) compound or its pharmaceutically useful salt:
Figure BSA00000223622300043
Wherein:
X is selected from halogen;
D, E and G are selected from O, N, N (R independently of one another 8), S or C (R 8), simultaneously, have at least one to be selected from O, N, N (R among D, E and the G 8) or S;
L is selected from-(CH 2) n-, wherein at least one CH 2By O, N (R 9), S, S (O) or S (O) 2Substitute all the other CH 2Choose wantonly and further replaced by one or two substituting group that is selected from halogen, alkyl or haloalkyl;
R 1Be selected from alkyl, thiazolinyl, alkynyl, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-A-C (O) R 6,-A-C (O) OR 6,-A-C (O) NR 6R 7With-SO 2R 6, wherein said alkyl, naphthenic base, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from alkyl, halogen, haloalkyl, oxo, thiazolinyl, alkynyl, nitro, cyanic acid, alkoxyl group, naphthenic base ,-OR 6,-S (O) mR 6,-C (O) R 6,-C (O) OR 6,-NR 6R 7,-C (O) NR 6R 7,-NR 6C (O) R 7,-NR 6S (O) mR 7Or-SO 2NR 6R 7Substituting group replace;
A be selected from a key ,-C (O)-,-C (O)-or-(CH 2) 1-4-, wherein-(CH 2) 1-4-optional further replaced by one or more substituting groups that are selected from halogen, alkyl or haloalkyl;
R 2, R 3, R 4And R 5Be selected from independently of one another Wasserstoffatoms, alkyl, halogen, haloalkyl, oxo, thiazolinyl, alkynyl, nitro, cyanic acid, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-OR 6,-S (O) 2R 6,-C (O) R 6,-C (O) OR 6,-NR 6R 7,-C (O) NR 6R 7,-NR 6C (O) R 7Or-SO 2NR 6R 7, perhaps R 2And R 3, R 4And R 5Form oxo together;
R 6And R 7Be selected from Wasserstoffatoms, alkyl, thiazolinyl, alkynyl, naphthenic base, heterocyclic radical, aryl or heteroaryl independently of one another, wherein said alkyl, thiazolinyl, alkynyl, naphthenic base, heterocyclic radical, aryl or heteroaryl independently optional separately further by one or more be selected from alkyl, halogen, haloalkyl, oxo, thiazolinyl, alkynyl, nitro, cyanic acid, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-OR 10,-S (O) mR 10,-C (O) R 10,-C (O) OR 10,-NR 10C (O) OR 11,-NR 10R 11,-C (O) NR 10R 11,-NR 10S (O) 2NR 10R 11,-NR 10S (O) 2R 11,-NR 10C (O) R 11Or-SO 2NR 10R 11Substituting group replace;
Simultaneously, R 6And R 7Form heterocyclic radical with the nitrogen-atoms that is connected, wherein said heterocyclic radical contains one or more N, O or S (O) mHeteroatoms, and said heterocyclic radical optional further by one or more be selected from alkyl, halogen, haloalkyl, oxo, thiazolinyl, alkynyl, nitro, cyanic acid, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-OR 10,-S (O) mR 10,-C (O) R 10,-C (O) OR 10,-NR 10C (O) OR 11,-NR 10R 11,-C (O) NR 10R 11,-NR 10S (O) 2NR 10R 11,-NR 10S (O) 2R 11,-NR 10C (O) R 11Or-SO 2NR 10R 11Substituting group replace;
R 8Be selected from Wasserstoffatoms, alkyl, halogen, haloalkyl, naphthenic base or-OR 6
R 9Be selected from-R 6,-C (O) R 6Or-S (O) 2R 6
R 10And R 11Independently be selected from Wasserstoffatoms, alkyl, haloalkyl, naphthenic base, heterocyclic radical, aryl or heteroaryl separately;
M is 0,1 or 2; And
N is 2,3 or 4.
The present invention relates to the preparation method of a kind of general formula (IA) compound, this method comprises:
Figure BSA00000223622300061
General formula (ID) compound through reduction reaction, is obtained general formula (IE) compound;
Figure BSA00000223622300062
General formula (IE) compound deaminize protection base, the general formula that obtains (IF) compound;
Figure BSA00000223622300063
General formula (IF) compound is converted into general formula (IG) compound;
Figure BSA00000223622300064
General formula (IG) compound is oxidized to carboxylic acid general formula (IH) compound;
Figure BSA00000223622300065
General formula (IH) compound changes into acid amides general formula (IJ) compound;
Figure BSA00000223622300066
General formula (IJ) compound further is converted into general formula (IB) compound;
Figure BSA00000223622300071
General formula (IB) compound and the reaction of general formula (IC) compound obtain general formula (IA) compound;
Wherein:
R is selected from hydroxyl, alkoxy or halogen;
X is selected from halogen, and D is selected from carbon atom, and E is selected from nitrogen-atoms, and G is selected from the S atom;
PG is an amino protecting group, preferred benzyl;
L and R 1～R 5Definition such as general formula (IA) described in.
Another aspect of the present invention relates to The compounds of this invention or the purposes of its pharmaceutically useful salt in the medicine of preparation GPR119 agonist.
Another aspect of the present invention relates to The compounds of this invention or its pharmaceutically useful salt medicine as the GPR119 agonist.
The invention still further relates to The compounds of this invention or its pharmaceutically useful salt in the medicine of the disease of preparation treatment mellitus and metabolic syndrome purposes.
Further, another aspect of the present invention relates to a kind of pharmaceutical composition, and it contains The compounds of this invention or its pharmaceutically useful salt and the pharmaceutically useful carrier or the vehicle of treating effective dose.This pharmaceutical composition is as the medicine of GPR119 agonist.The purposes of this pharmaceutical composition in the medicine of preparation treatment GPR119 agonist.
Another aspect of the present invention relates to a kind of method of treating the disease of mellitus and metabolic syndrome, and this method comprises The compounds of this invention or its pharmaceutically useful salt of the effective therapeutic dose of patient that needs treatment.
Another aspect of the present invention relates to The compounds of this invention or its pharmaceutically useful salt as the medicine of the disease of treatment mellitus and metabolic syndrome.
Another aspect of the present invention relates to a kind of method of regulating Regular Insulin, and this method comprises The compounds of this invention or its pharmaceutically useful salt of the effective therapeutic dose of patient of needs treatment.
Another aspect of the present invention relates to The compounds of this invention or its pharmaceutically useful salt as the medicine of regulating Regular Insulin.
Detailed description of the invention
Only if the phase counter-statement is arranged, otherwise the following term that is used in specification sheets and claims has following implication.
" alkyl " refers to saturated aliphatic hydrocarbon group, comprises the straight chain and the branched group of 1 to 20 carbon atom.The alkyl that preferably contains 1 to 12 carbon atom, non-limiting example comprise methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec.-butyl, n-pentyl, 1,1-dimethyl propyl, 1; 2-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl propyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl-propyl, 1,1; 2-trimethylammonium propyl group, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2; 2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethyl-butyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2,3-dimethylbutyl, n-heptyl, 2-methyl hexyl, 3-methyl hexyl, 4-methyl hexyl, 5-methyl hexyl, 2; 3-dimethyl-amyl group, 2,4-dimethyl-amyl group, 2,2-dimethyl-amyl group, 3; 3-dimethyl-amyl group, 2-ethyl pentyl group, 3-ethyl pentyl group, n-octyl, 2,3-dimethyl-hexyl, 2,4-dimethyl-hexyl, 2; 5-dimethyl-hexyl, 2; 2-dimethyl-hexyl, 3,3-dimethyl-hexyl, 4,4-dimethyl-hexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethyl pentyl group, 2-methyl-3-ethyl pentyl group, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2; 2-diethylammonium amyl group, positive decyl, 3; 3-diethylhexyl, 2, the 2-diethylhexyl, and various branched chain isomers etc.The low alkyl group that more preferably contains 1 to 6 carbon atom, non-limiting example comprise methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec.-butyl, n-pentyl, 1,1-dimethyl propyl, 1; 2-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl propyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl-propyl, 1,1; 2-trimethylammonium propyl group, 1; 1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1; 3-dimethylbutyl, 2-ethyl-butyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2,3-dimethylbutyl etc.Alkyl can be substituted or unsubstituted; When being substituted; Substituting group can be substituted on any spendable tie point; Be preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyanic acid, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio, oxo ,-OR 6,-S (O) mR 6,-C (O) R 6,-C (O) OR 6,-NR 6R 7,-C (O) NR 6R 7,-NR 6C (O) R 7,-NR 6S (O) mR 7Or-SO 2NR 6R 7
" naphthenic base " refers to saturated or the unsaturated monocycle of part or encircle the cyclic hydrocarbon substituting group more, and it comprises 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, and more preferably cycloalkyl ring comprises 3 to 10 carbon atoms.The non-limiting example of monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, suberyl, cycloheptatriene base, ring octyl group etc.The polycyclic naphthene base comprises volution, condensed ring and endocyclic naphthenic base.
" spiro cycloalkyl group " refers to 5 to 20 yuan, many cyclic groups of a shared carbon atom (title spiro atom) between the monocycle, and these can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to shared spiro atom between ring and the ring is divided into single spiro cycloalkyl group, two spiro cycloalkyl group base or many spiro cycloalkyl group with spiro cycloalkyl group, is preferably single spiro cycloalkyl group and two spiro cycloalkyl group.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl group.The non-limiting example of spiro cycloalkyl group comprises
" condensed ring alkyl " refers to 5 to 20 yuan; Each ring in the system and other rings in the system are shared the many cyclic groups of full carbon of a pair of carbon atom that adjoins; Wherein one or more rings can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or polycyclic fused ring alkyl, is preferably dicyclo or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 yuan bicyclic alkyls.The non-limiting example of condensed ring alkyl comprises
Figure BSA00000223622300091
" bridge ring alkyl " refers to 5 to 20 yuan, shared two the many cyclic groups of full carbon of direct-connected carbon atom not of any two rings, and these can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or encircle bridge ring alkyl more, is preferably dicyclo, three ring or Fourth Rings, more elects dicyclo or three rings as.The non-limiting example of bridge ring alkyl comprises
Figure BSA00000223622300092
Said cycloalkyl ring can condense on aryl, heteroaryl or heterocycloalkyl ring, and the ring that wherein links together with precursor structure is a naphthenic base, and non-limiting example comprises indanyl, tetralyl, benzocyclohepta alkyl etc.Naphthenic base can be optional substituted or unsubstituted; When being substituted; Substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyanic acid, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio, oxo ,-OR 6,-S (O) mR 6,-C (O) R 6,-C (O) OR 6,-NR 6R 7,-C (O) NR 6R 7,-NR 6C (O) R 7,-NR 6S (O) mR 7Or-SO 2NR 6R 7
" thiazolinyl " refers to the alkyl as defined above be made up of at least two carbon atoms and at least one carbon-to-carbon double bond.For example vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-crotonyl etc.Thiazolinyl can be substituted or unsubstituted; When being substituted; Substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyanic acid, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-OR 6,-S (O) mR 6,-C (O) R 6,-C (O) OR 6,-NR 6R 7,-C (O) NR 6R 7,-NR 6C (O) R 7,-NR 6S (O) mR 7Or-SO 2NR 6R 7
" alkynyl " refers to the as above defined alkyl that at least two carbon atoms and at least one carbon-to-carbon triple bond are formed.For example ethynyl, 1-proyl, 2-propynyl, 1-, 2-or 3-butynyl etc.Alkynyl can be substituted or unsubstituted; When being substituted; Substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyanic acid, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-OR 6,-S (O) mR 6,-C (O) R 6,-C (O) OR 6,-NR 6R 7,-C (O) NR 6R 7,-NR 6C (O) R 7,-NR 6S (O) mR 7Or-SO 2NR 6R 7
" heterocyclic radical " refers to saturated or the unsaturated monocycle of part or encircle the cyclic hydrocarbon substituting group more, and it comprises 3 to 20 annular atomses, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) mThe heteroatoms of (wherein m is an integer 0 to 2), but do not comprise-O-O-,-O-S-or-loop section of S-S-, all the other annular atomses are carbon.Preferably include 3 to 12 annular atomses, wherein 1～4 is heteroatoms, and more preferably cycloalkyl ring comprises 3 to 10 annular atomses.The non-limiting example of monocyclic cycloalkyl comprises pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, high piperazinyl etc.The polycyclic naphthene base comprises volution, condensed ring and endocyclic heterocyclic radical." spiro heterocyclic radical " refers to 5 to 20 yuan, many rings heterocyclic group of a shared atom (title spiro atom) between the monocycle, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) pThe heteroatoms of (wherein p is an integer 0 to 2), all the other annular atomses are carbon.These can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number based on shared spiro-atom between ring and the ring is divided into single spiro heterocyclic radical, two spiro heterocyclic radical or many spiro heterocyclic radicals with spiro cycloalkyl group, is preferably single spiro cycloalkyl group and two spiro cycloalkyl group.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl group.The non-limiting example of spiro cycloalkyl group comprises
Figure BSA00000223622300101
" fused heterocycle base " refers to 5 to 20 yuan; Each ring in the system and other rings in the system are shared many rings heterocyclic group of a pair of atom that adjoins; One or more rings can contain one or more pairs of keys; But the none ring has the πDian Zi system of total conjugated, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) pThe heteroatoms of (wherein p is an integer 0 to 2), all the other annular atomses are carbon.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or encircle the fused heterocycle alkyl more, is preferably dicyclo or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 yuan fused bicyclic heterocycle bases.The non-limiting example of fused heterocycle base comprises
Figure BSA00000223622300102
" bridge heterocyclic radical " refers to 5 to 14 yuan; Shared two the many rings heterocyclic groups of direct-connected atom not of any two rings; These can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) mThe heteroatoms of (wherein m is an integer 0 to 2), all the other annular atomses are carbon.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or encircle bridge ring alkyl more, is preferably dicyclo, three ring or Fourth Rings, more elects dicyclo or three rings as.The non-limiting example of bridge ring alkyl comprises:
Figure BSA00000223622300111
Said heterocyclic ring can condense on aryl, heteroaryl or cycloalkyl ring, and the ring that wherein links together with precursor structure is a heterocyclic radical, and non-limiting example comprises:
Figure BSA00000223622300112
Deng.Heterocyclic radical can be optional substituted or unsubstituted; When being substituted; Substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyanic acid, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio, oxo ,-OR 6,-S (O) mR 6,-C (O) R 6,-C (O) OR 6,-NR 6R 7,-C (O) NR 6R 7,-NR 6C (O) R 7,-NR 6S (O) mR 7Or-SO 2NR 6R 7
" aryl " refers to 6 to 14 yuan of full carbon monocycles or fused polycycle (just share and adjoin the right ring of carbon atom) group, and many rings (being its ring that the has phase adjacency pair carbon atom) group with conjugated πDian Zi system is preferably 6 to 10 yuan, for example phenyl and naphthyl.Said aryl rings can condense on heteroaryl, heterocyclic radical or cycloalkyl ring, and the ring that wherein links together with precursor structure is an aryl rings, and non-limiting example comprises:
Aryl can be substituted or unsubstituted; When being substituted; Substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyanic acid, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-OR 6,-S (O) mR 6,-C (O) R 6,-C (O) OR 6,-NR 6R 7,-C (O) NR 6R 7,-NR 6C (O) R 7,-NR 6S (O) mR 7Or-SO 2NR 6R 7
" heteroaryl " refers to comprise 1 to 4 heteroatoms, the heteroaromatic system of 5 to 14 annular atomses, and wherein heteroatoms comprises oxygen, sulphur and nitrogen.Be preferably 5 to 10 yuan.It is 5 yuan or 6 yuan that heteroaryl is preferably, for example furyl, thienyl, pyridyl, pyrryl, N-alkyl pyrryl, pyrimidyl, pyrazinyl, imidazolyl, tetrazyl etc.Said heteroaryl ring can condense on aryl, heterocyclic radical or cycloalkyl ring, and the ring that wherein links together with precursor structure is a heteroaryl ring, and non-limiting example comprises:
Figure BSA00000223622300121
Heteroaryl can be optional substituted or unsubstituted; When being substituted; Substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyanic acid, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-C (O) OR 5,-OC (O) R 5,-O (CH 2) nC (O) OR 5,-C (O) R 5,-NHC (O) R 5,-NR 6R 7,-OC (O) NR 6R 7Or-C (O) NR 6R 7
" alkoxyl group " refer to-O-(alkyl) and-O-(unsubstituted naphthenic base), wherein the definition of alkyl is as stated.Non-limiting example comprises methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.Alkoxyl group can be optional substituted or unsubstituted; When being substituted; Substituting group is preferably one or more following groups, be independently selected from into alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyanic acid, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-OR 6,-S (O) mR 6,-C (O) R 6,-C (O) OR 6,-NR 6R 7,-C (O) NR 6R 7,-NR 6C (O) R 7,-NR 6S (O) mR 7Or-SO 2NR 6R 7
" haloalkyl " refers to that alkyl is replaced by one or more halogens.
" hydroxyl " refers to-the OH group.
" halogen " refers to fluorine, chlorine, bromine or iodine.
" amino " refers to-NH 2
" cyanic acid " refers to-CN.
" nitro " refers to-NO 2
" benzyl " refers to-CH 2-phenyl.
" oxo " refers to=O.
" carboxylic acid " refers to-C (O) OH.
" carboxylicesters " refers to-C (O) O (alkyl) or (naphthenic base).
" choose wantonly " or " randomly " mean describe subsequently ground incident or environment can but needn't take place, this explanation comprises that this incident or environment take place or spot occasion not.For example, " optional by the substituted heterocyclic group of alkyl " mean alkyl can but must not exist, this explanation comprise heterocyclic group by the substituted situation of alkyl and heterocyclic group not by the substituted situation of alkyl.
" substituted " refers to the one or more Wasserstoffatomss in the group, is preferably maximum 5, and more preferably 1～3 Wasserstoffatoms is replaced by the substituting group of respective number independently of one another.Self-evident, substituting group only is in their possible chemical position, and those skilled in the art can confirm (through experiment or theoretical) possibility or impossible replacement under the situation of not paying too much effort.For example, amino or the hydroxyl that has a free hydrogen possibly be unsettled when combining with the carbon atom with unsaturated (like olefinic) key.
" pharmaceutical composition " expression contains on one or more compounds described herein or its physiology/mixture of pharmaceutically useful salt or prodrug and other chemical compositions, and other components physiology/pharmaceutically useful carrier and vehicle for example.The purpose of pharmaceutical composition is the administration that promotes organism, is beneficial to the absorption and then the performance biological activity of activeconstituents.
M, n and R 6～R 7Definition such as general formula (I) compound described in.
The compound method of The compounds of this invention
In order to accomplish the object of the invention, the present invention adopts following technical scheme:
The preparation method of the described compound or its salt of general formula of the present invention (I) may further comprise the steps:
Figure BSA00000223622300131
On the other hand, the preparation method of the described compound or its salt of general formula of the present invention (IA) may further comprise the steps:
Figure BSA00000223622300132
General formula (ID) compound through reduction reaction, is obtained general formula (IE) compound; General formula (IE) compound deaminize protection base, the general formula that obtains (IF) compound is converted into general formula (IG) compound; General formula (IG) compound is oxidized to carboxylic acid general formula (IH) compound; General formula (IH) compound changes into acid amides general formula (IJ) compound; General formula (IJ) compound further is converted into general formula (IB) compound; General formula (IB) compound and the reaction of general formula (IC) compound obtain general formula (IA) compound.
Wherein: R is selected from hydroxyl, alkoxy or halogen;
PG is amino protection base;
X is selected from halogen, and D is selected from carbon atom, and E is selected from nitrogen-atoms, and G is selected from the S atom;
L and R 1～R 5Definition such as general formula (IA) described in.
Embodiment
Be used to further describe the present invention below in conjunction with embodiment, but these embodiment and unrestricted scope of the present invention.
Embodiment
The structure of compound through nucleus magnetic resonance (NMR) or/and mass spectrum (MS) come to confirm.NMR displacement (δ) is with 10 -6(ppm) unit provides.The mensuration of NMR is with Bruker AVANCE-400 nuclear magnetic resonance spectrometer, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d 6), deuterochloroform (CDCl 3), deuterated methanol (CD 3OD), be designated as TMS (TMS) in.
The mensuration of MS is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Thermo, model: FinniganLCQ advantage MAX).
The mensuration of HPLC is used Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 * 4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 * 4.6mm chromatographic column).
The tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate, and the specification that the silica-gel plate that tlc (TLC) is used adopts is 0.15mm～0.2mm, and the specification that thin-layer chromatography separation and purification product adopts is 0.4mm～0.5mm.
Column chromatography generally uses Huanghai Sea silica gel 200～300 order silica gel in Yantai to be carrier.
Known starting raw material of the present invention can adopt or synthesize according to methods known in the art; Maybe can buy from ABCR GmbH&Co.KG; Acros Organics, Aldrich Chemical Company, reaches company such as auspicious chemical at splendid chemistry science and technology far away (Accela ChemBio Inc).
Argon atmospher or nitrogen atmosphere are meant that reaction flask connects an about 1L volumetrical argon gas or nitrogen balloon.
Nitrogen atmosphere is meant that reaction flask connects an about 1L volumetrical hydrogen balloon.
Parr 3916EKX type hydrogenation appearance and clear blue QL-500 type steam iron generator or HC2-SS type hydrogenation appearance are used in the pressure hydration reaction.
Hydrogenation vacuumizes usually, charges into hydrogen, repeatable operation 3 times.
Microwave reaction uses CEM Discover-S 908860 type microwave reactors.
Do not have specified otherwise among the embodiment, be reflected under nitrogen atmosphere or the argon atmospher and carry out.
Do not have specified otherwise among the embodiment, solution is meant the aqueous solution.
Do not have specified otherwise among the embodiment, the temperature of reaction is a room temperature.
Room temperature is optimum temperature of reaction, is 20 ℃～30 ℃.
Tlc (TLC) is adopted in the monitoring of the reaction process among the embodiment, and the system of reacting employed developping agent has: methylene dichloride and methanol system, and normal hexane and ethyl acetate system, the volume ratio of solvent is according to different adjusting of polarity of compound.
The system of the eluent of the column chromatography that purifying compounds adopts and the developping agent system of tlc comprise: A: methylene dichloride and methanol system; B: normal hexane and ethyl acetate system; The volume ratio of solvent is regulated according to the polarity of compound is different, also can add alkalescence such as a spot of triethylamine and acetic acid or acid reagent and regulate.
Lawesson ' s reagent among the embodiment is meant
Figure BSA00000223622300151
Embodiment 1
(1R, 5S)-[4-[(4-methylsulfonyl phenoxy) methylthiazol-2-yl]-3-azabicyclo is [3.1.0] hexane-3-formic acid also for 6- The tert-butyl ester
Figure BSA00000223622300152
The first step
5-benzyl-4,6-dicarbapentaborane-3a, 6a-dihydro-1H-pyrrolo-[3,4-c] pyrazoles-3-ethyl formate
With 1-benzyl-pyrrole-2, (5.0g 26.7mmol) is dissolved in the 30mL toluene 5-diketone 1a, and (2.9mL 28mmol), reacted 5 hours down in 100 ℃ to add ethyl diazoacetate.The concentrating under reduced pressure reaction solution with eluent system B purifying gained resistates, obtains title product 5-benzyl-4 with silica gel column chromatography; 6-dicarbapentaborane-3a, 6a-dihydro-1H-pyrrolo-[3,4-c] pyrazoles-3-ethyl formate 1b (6.7g; White solid), productive rate: 91.9%.
MS?m/z(ESI)：302.1[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.36-7.28(m，5H)，7.14(s，1H)，4.90-4.87(m，1H)，4.64(s，2H)，4.57-4.54(m，1H)，4.33(q，2H)，1.36(t，3H).
Second step
(1R, 5S)-3-benzyl 2,4-dicarbapentaborane-3-azabicyclo is [3.1.0] hexane-6-ethyl formate also
With 5-benzyl-4,6-dicarbapentaborane-3a, (2.1g 7mmol) places reaction flask to 6a-dihydro-1H-pyrrolo-[3,4-c] pyrazoles-3-ethyl formate 1b, under 190 ℃, is heated to fusion, and add 1b (18.9g 63mmol), reacted 1 hour down in 190 ℃ in batches.Be chilled to room temperature; Add 200mL acetic acid ethyl dissolution resistates, with eluent system B purifying gained resistates, obtain title product (1R with silica gel column chromatography; 5S)-3-benzyl 2; 4-dicarbapentaborane-3-azabicyclo is [3.1.0] hexane-6-ethyl formate 1c (11.0g, white solid) also, productive rate: 57.9%.
MS?m/z(ESI)：274.1[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.33-7.28(m，5H)，4.52(s，2H)，4.19(q，2H)，2.88-2.87(m，2H)，2.29-2.27(m，1H)，1.28(t，3H).
The 3rd step
[(1R, 5S)-3-benzyl-3-azabicyclo [3.1.0] hexane-6-yl also] methyl alcohol
(3.0g 81mmol) is dissolved in the 200mL THF, slowly adds 50mL (1R with Lithium Aluminium Hydride; 5S)-3-benzyl 2; 4-dicarbapentaborane-3-azabicyclo also [3.1.0] hexane-6-ethyl formate 1c (5.4g, tetrahydrofuran solution 20mmol) finishes; Back flow reaction 5 hours was reacted 16 hours down in 50 ℃.Be chilled to room temperature, slowly splash into the 6mL saturated ammonium chloride solution under the ice-water bath, filter; Collect filtrating, anhydrous magnesium sulfate drying filters; Concentrating under reduced pressure filtrating, obtain title product [(1R, 5S)-3-benzyl-3-azabicyclo [3.1.0] hexane-6-yl also] methyl alcohol 1d (3.7g; Brown oil), productive rate: 91.1%.
MS?m/z(ESI)：204.1[M+1]
The 4th step
[(1R, 5S)-3-azabicyclo [3.1.0] hexane-6-yl also] methyl alcohol
Will [(1R, 5S)-3-benzyl-3-azabicyclo [3.1.0] hexane-6-yl also] methyl alcohol 1d (3.7g 18.3mmol) is dissolved in the 150mL methyl alcohol, add successively palladium/carbon (200mg, 10%) and ammonium formiate (6.9g, 109.8mmol), back flow reaction 1 hour.Be chilled to room temperature, filter, concentrating under reduced pressure filtrating, obtain the bullion title product [(1R, 5S)-3-azabicyclo [3.1.0] hexane-6-yl also] methyl alcohol 1e (2.3g, colorless oil), directly be used for next step reaction without separation.
MS?m/z(ESI)：114.1[M+1]
The 5th step
(1R, 5S)-6-(methylol)-3-azabicyclo [3.1.0] hexane-3-t-butyl formate also
With bullion [(1R, 5S)-3-azabicyclo [3.1.0] hexane-6-yl also] (2.1g 18.3mmol) is dissolved in the 80mL methylene dichloride methyl alcohol 1e; (5.98g 0.75mmol), reacted 3 hours to add tert-Butyl dicarbonate; (2.52g 18.3mmol), reacted 30 minutes to add 5mL methyl alcohol and salt of wormwood.The concentrating under reduced pressure reaction solution, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product (1R, 5S)-6-(methylol)-3-azabicyclo [3.1.0] hexane-3-t-butyl formate 1f (3.1g, colorless oil) also, productive rate: 79.5%.
The 6th step
(1R, 5S)-uncle's 3-fourth supports also [3.1.0] hexane-6-formic acid of basic carbonyl-3-azabicyclo
Will (1R, 5S)-6-(methylol)-3-azabicyclo also [3.1.0] hexane-3-t-butyl formate 1f (2.0g 9.4mmol) is dissolved in 30mL N, and in the dinethylformamide, (14.1g 37.6mmol), reacted 16 hours to add the dichromic acid pyridinium.Add 80mL water, with ethyl acetate extraction (50mL * 3), organic phase is used water washing (100mL) successively, saturated nacl aqueous solution washing (100mL); Merge organic phase, anhydrous magnesium sulfate drying filters; Concentrating under reduced pressure filtrating with eluent system A purifying gained resistates, obtains title product (1R with silica gel column chromatography; 5S)-uncle's 3-fourth supports also [3.1.0] hexane-6-formic acid 1g (1.6g, brown oil) of basic carbonyl-3-azabicyclo, productive rate: 75.1%.
MS?m/z(ESI)：226.1[M-1]
The 7th step
(1R, 5S)-6-carbamyl-3-azabicyclo [3.1.0] hexane-3-t-butyl formate also
Will (1R, 5S)-uncle's 3-fourth support basic carbonyl-3-azabicyclo also [3.1.0] hexane-6-formic acid 1g (1.6g 7.0mmol) is dissolved in the mL methylene dichloride; Add two (2-oxo-3-oxazolidinyl) inferior phosphoryl chloride (3.6g successively; 14mmol), and triethylamine (3.9mL, 28mmol) and volatile salt (1.35g; 14.0mmol), reacted 16 hours.The concentrating under reduced pressure reaction solution adds 30mL water in resistates, with ethyl acetate extraction (30mL * 2), organic phase is with saturated common salt water washing (30mL); Merge organic phase, anhydrous magnesium sulfate drying filters; Concentrating under reduced pressure filtrating with eluent system B purifying gained resistates, obtains title product (1R with silica gel column chromatography; 5S)-and 6-carbamyl-3-azabicyclo [3.1.0] hexane-3-t-butyl formate 1h (1.4g, yellow solid) also, productive rate: 88.1%.
MS?m/z(ESI)：249.1[M+23]
The 8th step
(1R, 5S)-6-thiocarbamyl-3-azabicyclo [3.1.0] hexane-3-t-butyl formate also
Will (1R, 5S)-6-carbamyl-3-azabicyclo also [3.1.0] hexane-3-t-butyl formate 1h (1.4g 6.2mmol) is dissolved in the 30mL THF, and (1.5g 3.7mmol), reacted 16 hours to add Lawesson ' s reagent.The concentrating under reduced pressure reaction solution; With silica gel column chromatography with eluent system B purifying gained resistates, obtain title product (1R, 5S)-6-thiocarbamyl-3-azabicyclo [3.1.0] hexane-3-t-butyl formate 1i (740mg also; Colorless oil), productive rate: 49.3%.
MS?m/z(ESI)：243.1[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.66(s，1H)，7.37(s，1H)，3.67-3.56(m，2H)，3.48-3.45(m，2H)，2.35(s，2H)，1.79-1.77(m，1H)，1.45(s，9H).
The 9th step
1,3-dibromopropane-2-ketone
With ETHYLE ACETATE (17mL, 0.17mol) and acetone (2.5mL 33.6mmol) mixes, and (3.45mL 66.7mmol), dripped Bi Fanying 5 minutes to slow dropping liquid bromine under the ice-water bath, in reaction solution, blasted nitrogen 30 minutes.Add 150mL water,, merge organic phase, anhydrous magnesium sulfate drying with ethyl acetate extraction (80mL * 2); Filter, concentrating under reduced pressure filtrating obtains bullion title product 1; 3-dibromopropane-2-ketone 1j (7.5g, brown oil) directly is used for next step reaction without separating.
1H?NMR(400MHz，CDCl 3)：δ4.13(s，4H).
The tenth step
(1R, 5S)-6-[4-(brooethyl) thiazol-2-yl]-3-azabicyclo [3.1.0] hexane-3-t-butyl formate also
Will (1R, 5S)-6-thiocarbamyl-3-azabicyclo also [3.1.0] hexane-3-t-butyl formate 1i (730mg 3.0mmol) is dissolved in the 20mL methylene dichloride, adds 1, and (970mg 4.5mmol), reacted 16 hours 3-dibromopropane-2-ketone 1j.The concentrating under reduced pressure reaction solution; With silica gel column chromatography with eluent system B purifying gained resistates, obtain title product (1R, 5S)-6-[4-(brooethyl) thiazol-2-yl]-3-azabicyclo [3.1.0] hexane-3-t-butyl formate 1k (460mg also; Light yellow oil), productive rate: 43.0%.
MS?m/z(ESI)：359.0[M]
1H?NMR(400MHz，CD 3OD)：δ7.35(s，1H)，4.55(s，2H)，3.74-3.66(m，2H)，3.51-3.48(m，2H)，2.20-2.17(m，2H)，2.15-2.13(m，1H)，1.45(s，9H).
The 11 step
(1R, 5S)-[4-[(4-methylsulfonyl phenoxy) methylthiazol-2-yl]-3-azabicyclo is [3.1.0] hexane-3-t-butyl formate also for 6-
With (1R; 5S)-6-[4-(brooethyl) thiazol-2-yl]-3-azabicyclo also [3.1.0] hexane-3-t-butyl formate 1k (46mg 0.13mmol) is dissolved in 5mL N, in the dinethylformamide; Add 4-sulfonyloxy methyl phenol (33mg successively; 0.19mmol) and cesium carbonate (123.5mg 0.38mmol), reacted 16 hours.Add 20mL water, with ethyl acetate extraction (20mL * 3), organic phase is with water washing (20mL * 2); Merge organic phase, anhydrous magnesium sulfate drying filters; Concentrating under reduced pressure filtrating with eluent system B purifying gained resistates, obtains title product (1R with silica gel column chromatography; 5S)-[4-[(4-methylsulfonyl phenoxy) methylthiazol-2-yl]-3-azabicyclo is [3.1.0] hexane-3-t-butyl formate 1 (30mg, white solid) also, productive rate: 52.6% for 6-.
MS?m/z(ESI)：451.1[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.89-7.81(m，2H)，7.13-6.98(m，3H)，5.22(s，2H)，3.84-3.73(m，2H)，3.51-3.48(m，2H)，3.04(s，3H)，2.22-2.19(m，2H)，2.18-2.17(m，1H)，1.47(s，9H).
Test case:
Biological assessment
Following method is used for measuring the agonist activity of The compounds of this invention to GPR119.Experimental technique is summarized as follows:
Inoculation hamster beta islet cells (HIT-T15) (purchasing in ATCC article No. CRL-1777) in 96 orifice plates, inoculating cell density is 2x10 4Cell is at 37 ℃, 5%CO 2Cultivate under the condition after 48 hours, remove nutrient solution, add 100 μ L stimulate damping fluid (Hanks, 5mM HEPES, 0.5mM IBMX, 0.1%BSA, pH7.4), and in incubated at room 15 minutes.In the hole, add the different concns medicine, hatch 30 minutes after, remove damping fluid, add the lysate of 75 μ L precoolings, and hatched 20 minutes, suitably vibration on ice.Lysate is transferred in the 1.5mL centrifuge tube centrifugal 10 minutes with the rotating speed of 13000rpm.Get 50 μ L sample supernatants, (Cell Biolabs, Inc.) standard step detects cAMP content according to cAMP ELISA test kit.
Experimental data:
Compound Relative intensity of fluorescence
Embodiment 1 86.83％
Conclusion: embodiment 1 compound has certain activity under 10 μ M.

Claims (14)

1. the compound shown in the general formula (I) or its pharmaceutically useful salt:
Figure FSA00000223622200011
Wherein:
Ar is selected from aryl or heteroaryl, wherein said aryl or heteroaryl optional further by one or more be selected from halogen, cyanic acid, nitro, alkyl, thiazolinyl, alkynyl, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-OR 6,-S (O) mR 6,-C (O) R 6,-C (O) OR 6,-NR 6R 7,-C (O) NR 6R 7,-NR 6C (O) R 7,-NR 6S (O) mR 7Or-SO 2NR 6R 7Substituting group replace, wherein said alkyl, thiazolinyl, alkynyl, naphthenic base, heterocyclic radical, aryl or heteroaryl independently optional separately further by one or more be selected from alkyl, halogen, haloalkyl, oxo, thiazolinyl, alkynyl, nitro, cyanic acid, alkoxyl group, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-OR 6,-S (O) mR 6,-C (O) R 6,-C (O) OR 6,-NR 6R 7,-C (O) NR 6R 7,-NR 6C (O) R 7,-NR 6S (O) mR 7Or-SO 2NR 6R 7Substituting group replace;
D, E and G are selected from O, N, N (R independently of one another 8), S or C (R 8), simultaneously, have at least one to be selected from O, N, N (R among D, E and the G 8) or S;
L is selected from-(CH 2) n-, wherein at least one CH 2By O, N (R 9), S, S (O) or S (O) 2Substitute all the other CH 2Choose wantonly and further replaced by one or two substituting group that is selected from halogen, alkyl or haloalkyl;
R 1Be selected from alkyl, thiazolinyl, alkynyl, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-A-C (O) R 6,-A-C (O) OR 6,-A-C (O) NR 6R 7With-SO 2R 6, wherein said alkyl, naphthenic base, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from alkyl, halogen, haloalkyl, oxo, thiazolinyl, alkynyl, nitro, cyanic acid, alkoxyl group, naphthenic base ,-OR 6,-S (O) mR 6,-C (O) R 6,-C (O) OR 6,-NR 6R 7,-C (O) NR 6R 7,-NR 6C (O) R 7,-NR 6S (O) mR 7Or-SO 2NR 6R 7Substituting group replace;
A be selected from a key ,-C (O)-,-C (O)-or-(CH 2) 1-4-, wherein-(CH 2) 1-4-optional further replaced by one or more substituting groups that are selected from halogen, alkyl or haloalkyl;
R 2, R 3, R 4And R 5Be selected from independently of one another Wasserstoffatoms, alkyl, halogen, haloalkyl, thiazolinyl, alkynyl, nitro, cyanic acid, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-OR 6,-S (O) 2R 6,-C (O) R 6,-C (O) OR 6,-NR 6R 7,-C (O) NR 6R 7,-NR 6C (O) R 7Or-SO 2NR 6R 7Perhaps R 2And R 3, R 4And R 5Form oxo together;
R 6And R 7Be selected from Wasserstoffatoms, alkyl, thiazolinyl, alkynyl, naphthenic base, heterocyclic radical, aryl or heteroaryl independently of one another, wherein said alkyl, thiazolinyl, alkynyl, naphthenic base, heterocyclic radical, aryl or heteroaryl independently optional separately further by one or more be selected from alkyl, halogen, haloalkyl, oxo, thiazolinyl, alkynyl, nitro, cyanic acid, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-OR 10,-S (O) mR 10,-C (O) R 10,-C (O) OR 10,-NR 10C (O) OR 11,-NR 10R 11,-C (O) NR 10R 11,-NR 10S (O) 2NR 10R 11,-NR 10S (O) 2R 11,-NR 10C (O) R 11Or-SO 2NR 10R 11Substituting group replace;
Simultaneously, R 6And R 7Form heterocyclic radical with the nitrogen-atoms that is connected, wherein said heterocyclic radical contains one or more N, O or S (O) mHeteroatoms, and said heterocyclic radical optional further by one or more be selected from alkyl, halogen, haloalkyl, oxo, thiazolinyl, alkynyl, nitro, cyanic acid, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-OR 10,-S (O) mR 10,-C (O) R 10,-C (O) OR 10,-NR 10C (O) OR 11,-NR 10R 11,-C (O) NR 10R 11,-NR 10S (O) 2NR 10R 11,-NR 10S (O) 2R 11,-NR 10C (O) R 11Or-SO 2NR 10R 11Substituting group replace;
R 8Be selected from Wasserstoffatoms, alkyl, halogen, haloalkyl, naphthenic base or-OR 6
R 9Be selected from-R 6,-C (O) R 6Or-S (O) 2R 6
R 10And R 11Independently be selected from Wasserstoffatoms, alkyl, haloalkyl, naphthenic base, heterocyclic radical, aryl or heteroaryl separately;
M is 0,1 or 2; And
N is 2,3 or 4.
2. the compound shown in the general formula according to claim 1 (I) or its pharmaceutically useful salt, comprising the compound shown in the general formula (II) or its pharmaceutically useful salt:
Figure FSA00000223622200021
3. the compound shown in the general formula according to claim 1 (I) or its pharmaceutically useful salt, wherein Ar is an aryl, is preferably phenyl, said aryl is optional further by one or more-S (O) mR 6Replace.
4. the compound shown in the general formula according to claim 1 (I) or its pharmaceutically useful salt, wherein L is-CH 2-O-.
5. the compound shown in the general formula according to claim 1 (I) or its pharmaceutically useful salt, wherein R 1For-C (O) OR 6
6. the compound shown in the general formula according to claim 1 (I) or its pharmaceutically useful salt, wherein R 2, R 3, R 4And R 5Be Wasserstoffatoms.
7. according to compound or its pharmaceutically useful salt shown in any one described general formula (I) of claim 1～6, wherein this compound is:
Figure FSA00000223622200031
8. method for preparing the compound or pharmaceutically acceptable salt thereof shown in the general formula according to claim 1 (I), this method comprises:
With general formula (IA) compound and Ar-OH reaction, obtain general formula (I) compound;
Wherein: X is selected from halogen;
D, E, G, L, Ar and R 1～R 5Definition such as claim 1 described in.
9. the compound shown in the general formula (IA) or its pharmaceutically useful salt, wherein:
Figure FSA00000223622200033
X is selected from halogen;
D, E and G are selected from O, N, N (R independently of one another 8), S or C (R 8), simultaneously, have at least one to be selected from O, N, N (R among D, E and the G 8) or S;
L is selected from-(CH 2) n-, wherein at least one CH 2By O, N (R 9), S, S (O) or S (O) 2Substitute all the other CH 2Choose wantonly and further replaced by one or two substituting group that is selected from halogen, alkyl or haloalkyl;
R 1Be selected from alkyl, thiazolinyl, alkynyl, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-A-C (O) R 6,-A-C (O) OR 6,-A-C (O) NR 6R 7With-SO 2R 6, wherein said alkyl, naphthenic base, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from alkyl, halogen, haloalkyl, oxo, thiazolinyl, alkynyl, nitro, cyanic acid, alkoxyl group, naphthenic base ,-OR 6,-S (O) mR 6,-C (O) R 6,-C (O) OR 6,-NR 6R 7,-C (O) NR 6R 7,-NR 6C (O) R 7,-NR 6S (O) mR 7Or-SO 2NR 6R 7Substituting group replace;
A be selected from a key ,-C (O)-,-C (O)-or-(CH 2) 1-4-, wherein-(CH 2) 1-4-optional further replaced by one or more substituting groups that are selected from halogen, alkyl or haloalkyl;
R 2, R 3, R 4And R 5Be selected from independently of one another Wasserstoffatoms, alkyl, halogen, haloalkyl, thiazolinyl, alkynyl, nitro, cyanic acid, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-OR 6,-S (O) 2R 6,-C (O) R 6,-C (O) OR 6,-NR 6R 7,-C (O) NR 6R 7,-NR 6C (O) R 7Or-SO 2NR 6R 7, perhaps R 2And R 3, R 4And R 5Form oxo together;
R 6And R 7Be selected from Wasserstoffatoms, alkyl, thiazolinyl, alkynyl, naphthenic base, heterocyclic radical, aryl or heteroaryl independently of one another, wherein said alkyl, thiazolinyl, alkynyl, naphthenic base, heterocyclic radical, aryl or heteroaryl independently optional separately further by one or more be selected from alkyl, halogen, haloalkyl, oxo, thiazolinyl, alkynyl, nitro, cyanic acid, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-OR 10,-S (O) mR 10,-C (O) R 10,-C (O) OR 10,-NR 10C (O) OR 11,-NR 10R 11,-C (O) NR 10R 11,-NR 10S (O) 2NR 10R 11,-NR 10S (O) 2R 11,-NR 10C (O) R 11Or-SO 2NR 10R 11Substituting group replace;
Simultaneously, R 6And R 7Form heterocyclic radical with the nitrogen-atoms that is connected, wherein said heterocyclic radical contains one or more N, O or S (O) mHeteroatoms, and said heterocyclic radical optional further by one or more be selected from alkyl, halogen, haloalkyl, oxo, thiazolinyl, alkynyl, nitro, cyanic acid, naphthenic base, heterocyclic radical, aryl, heteroaryl ,-OR 10,-S (O) mR 10,-C (O) R 10,-C (O) OR 10,-NR 10C (O) OR 11,-NR 10R 11,-C (O) NR 10R 11,-NR 10S (O) 2NR 10R 11,-NR 10S (O) 2R 11,-NR 10C (O) R 11Or-SO 2NR 10R 11Substituting group replace;
R 8Be selected from Wasserstoffatoms, alkyl, halogen, haloalkyl, naphthenic base or-OR 6
R 9Be selected from-R 6,-C (O) R 6Or-S (O) 2R 6
R 10And R 11Independently be selected from Wasserstoffatoms, alkyl, haloalkyl, naphthenic base, heterocyclic radical, aryl or heteroaryl separately;
M is 0,1 or 2; And
N is 2,3 or 4.
10. one kind prepares the compound shown in the general formula according to claim 9 (IA) or the method for its pharmaceutically useful salt, and this method comprises:
Figure FSA00000223622200041
General formula (ID) compound through reduction reaction, is obtained general formula (IE) compound;
Figure FSA00000223622200042
General formula (IE) compound deaminize protection base, the general formula that obtains (IF) compound;
Figure FSA00000223622200051
General formula (IF) compound is converted into general formula (IG) compound;
Figure FSA00000223622200052
General formula (IG) compound is oxidized to carboxylic acid general formula (IH) compound;
Figure FSA00000223622200053
General formula (IH) compound changes into acid amides general formula (IJ) compound;
Figure FSA00000223622200054
General formula (IJ) compound further is converted into general formula (IB) compound;
Figure FSA00000223622200055
With general formula (IB) compound and the reaction of general formula (IC) compound, obtain general formula (IA) compound;
Wherein:
R is selected from hydroxyl, alkoxy or halogen;
X is a halogen, and D is a carbon atom, and E is a nitrogen-atoms, and G is the S atom;
PG is an amino protecting group, preferred benzyl;
L and R 1～R 5Definition such as claim 9 described in.
11. a pharmaceutical composition, said pharmaceutical composition contain the treatment effective dose according to the compound shown in any one described general formula (I) or its pharmaceutically useful salt and pharmaceutically useful carrier in the claim 1～7.
12. according to compound or its pharmaceutically useful salt shown in any one described general formula (I) of claim 1～7, or the purposes of pharmaceutical composition according to claim 11 in preparation GPR119 agonist.
13. according to compound or its pharmaceutically useful salt shown in any one described general formula (I) of claim 1～7, or the purposes of pharmaceutical composition according to claim 11 in the medicine of the disease of preparation treatment mellitus and metabolic syndrome.
14. a method of regulating Regular Insulin, this method comprise the compound shown in the general formula according to claim 1 (I) that gives effective dose or its pharmaceutically useful salt.
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