CN103342700A - 11[beta]-hydroxysteroid dehydrogenase type 1 inhibitor - Google Patents
11[beta]-hydroxysteroid dehydrogenase type 1 inhibitor Download PDFInfo
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- CN103342700A CN103342700A CN2012100171472A CN201210017147A CN103342700A CN 103342700 A CN103342700 A CN 103342700A CN 2012100171472 A CN2012100171472 A CN 2012100171472A CN 201210017147 A CN201210017147 A CN 201210017147A CN 103342700 A CN103342700 A CN 103342700A
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- PSCINYGCZSGCPG-UHFFFAOYSA-N N#CCC1(c2ccccc2CCC1)O Chemical compound N#CCC1(c2ccccc2CCC1)O PSCINYGCZSGCPG-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention belongs to the technical field of medicines, and concretely relates to a 11[beta]-hydroxysteroid dehydrogenase type 1 inhibitor as shown in a formula (I), pharmaceutically acceptable salts and isomers thereof, wherein X1, X2, R1, R2, R6a, R6b, A1, A2, Cy1, Cy2, Cy3, m and n are as defined in the specification. The invention further relates to a preparation method of these compounds, medicinal preparations containing these compounds, pharmaceutical compositions containing these compounds, and applications of these compounds in preparing medicaments for treating and/or preventing diseases related with diabetes, metabolism syndromes, etc.
Description
Technical field
The invention belongs to medical technical field, be specifically related to 11beta-Hydroxysteroid dehydrogenase 1 type inhibitor, its pharmacy acceptable salt or its isomer, the preparation method of these compounds, the pharmaceutical preparation that contains these compounds, the pharmaceutical composition that contains these compounds, and these compounds treat and/or prevent purposes in the medicine of the disease relevant with diabetes and metabolism syndrome etc. in preparation.
Background technology
Glucocorticosteroid such as hydrocortisone (hydrocortisone) are the steroid hormone of adjusting metabolism of fat, function and distribution, and work in carbohydrate, protein and metabolism of fat.Glucocorticosteroid can be induced insulin resistant as the important hormone antagonist of picking up of Regular Insulin, and insulin resistant is the key link of diabetes B morbidity.Excessive glucocorticosteroid can cause that hyperinsulinemia, lipid metabolism are unusual, impaired glucose tolerance, hypertension, abdominal obesity, develops into diabetes at last.
11beta-Hydroxysteroid dehydrogenase (11 β-hydroxysteroid dehydrogenase, 11 β-HSD) are the metabolic enzyme of glucocorticosteroid, the ketone group of its catalysis glucocorticosteroid C11 position and the redox reaction between the hydroxyl in human body, bioactive hydrocortisone (cortisol, hydrocortisone) and the cortisone (cortisone) of non-activity are transformed mutually.In rodent, the conversion between its catalysis Kendall compound (corticosterone) and the dehydrocorticosterone (dehydrocorticosterone).
11 β-HSD1 enzyme has the dual catalytic effect (being that existing reductase activity has dehydrogenase activity again) of oxidation and reduction, and it mainly plays the activator effect of cortisone in vivo.It makes the cortisone of non-activity be converted into the hydrocortisone with activity, thereby regulates the concentration of glucocorticosteroid in the circulation and the amount of arrival acceptor thereof.Be single-minded reductase enzyme at liver 11 β-HSD1, it can strengthen the activity of glucocorticosteroid, and glucocorticosteroid has the key enzyme of glyconeogenesis in the activation liver cell such as the effect of PCK (PEPCK) and G-6-Pase, and glyconeogenesis is accelerated; It can also directly suppress the secreting function of beta Cell of islet by the expression of downward modulation receptor protein,intracellular, thereby causes insulin resistant and infringement beta Cell of islet function.
11 β-HSD1 is a kind of NADPH dependent dehydrogenase/oxydo-reductase of low-affinity, in the endocytoplasmic reticulum, when G-6-P (G6P) is converted into the 6-phosphogluconolactone, NADP is converted into NADPH.It is distributed widely in the target organ of glucocorticosteroids such as liver, kidney, vascular system, testis, ovary, fatty tissue and central nervous system.
11beta-Hydroxysteroid dehydrogenase 1 (11 β-hydroxysteroid dehydrogenasetype1,11 β-HSD1) have tissue specificity, regulating local glucocorticosteroid concentration in vivo, is the another kind of mechanism of regulating glucocorticosteroid except hypothalmus-pituitary-adrenal axis.
Suppress the amount that 11 β-HSD1 can reduce activated glucocorticosteroid, reduce insulin resistant, the protection islet cells.11 beta-HSD 1 inhibitors suppress the activity of 11 β-HSD1 by selectivity, reduce in the liver and the hydrocortisone concentration of fatty tissue, reduce the glycogen heteroplasia, improve tissue to the susceptibility of Regular Insulin, for research and the treatment of diabetes and metabolism syndrome provides new target spot.
11 beta hsd 1 inhibitors below Boehringer Ingelheim discloses in WO2010010150:
In addition, 11 beta hsd 1 inhibitors below Boehringer Ingelheim discloses in WO2010127237:
Summary of the invention
The invention provides and have the 11beta-Hydroxysteroid dehydrogenase 1 type inhibitor that selectivity suppresses 11 β-H SD1 activity.
Technical scheme of the present invention is as follows:
The solution of the present invention 1 has provided compound, its pharmacy acceptable salt shown in the general formula (I), and isomer:
Wherein, X
1Be C (O), S (O)
wOr C (=NR
5), w is 0,1 or 2, R
5Be cyano group, hydroxyl, C
1-6Alkyl, C
3-8Cycloalkyl, C
2-6Thiazolinyl, C
5-8Cycloalkenyl group, C
2-6Alkynyl, C
1-6Alkoxyl group or C
3-8Cycloalkyloxy, described C
1-6Alkyl, C
3-8Cycloalkyl, C
2-6Thiazolinyl, C
5-8Cycloalkenyl group, C
2-6Alkynyl, C
1-6Alkoxyl group and C
3-8Cycloalkyloxy can be chosen wantonly by 1-6 and be independently selected from following substituting group replacement: halogen atom, cyano group, hydroxyl, carboxyl and amino;
X
2Be O, S, N (R
4a) or C (R
4a) (R
4b), R
4aAnd R
4bBe hydrogen atom, C independently respectively
1-6Alkyl, halo C
1-6Alkyl, C
3-8Cycloalkyl, C
2-6Thiazolinyl, C
5-8Cycloalkenyl group or C
2-6Alkynyl;
R
1Be hydrogen, C
1-6Alkyl, C
3-8Cycloalkyl, C
2-6Thiazolinyl, C
5-8Cycloalkenyl group, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkylthio, C
1-6Alkyl-carbonyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6Carbalkoxy, C
1-6Alkyl carbonyl oxy, 6-14 unit aryl, 5-14 unit's heteroaryl or 3-14 unit heterocyclic radical, described C
1-6Alkyl, C
3-8Cycloalkyl, C
2-6Thiazolinyl, C
5-8Cycloalkenyl group, C
2-6Alkynyl and C
1-6Alkoxyl group can be chosen wantonly by 1-6 and be independently selected from following substituting group replacement: halogen atom, cyano group, hydroxyl, carboxyl, amino, halo C
1-6Alkyl, oxo, R
3-, R
3O-, (R
3)
2N-, R
3O (O) C-, R
3C (O) O-, R
3S (O)
2O-, R
3S (O)
2-, R
3C (O) N (R
3)-, (R
3)
2NC (O)-, (R
3)
2NC (O) O-, (R
3)
2NC (O) N (R
3)-, R
3OC (O) N (R
3)-, (R
3)
2NC (NCN) N (R
3)-, (R
3O)
2P (O) O-, (R
3O)
2P (O) N (R
3)-, R
3OS (O)
2N (R
3)-, (R
3)
2NS (O)
2O-, (R
3)
2NS (O)
2N (R
3)-, R
3S (O)
2N (R
3)-, R
3S (O)
2N (R
3) C (O)-, R
3S (O)
2N (R
3) C (O) O-, R
3S (O)
2N (R
3) C (O) N (R
3)-, R
3OS (O)
2N (R
3) C (O)-, R
3OS (O)
2N (R
3) C (O) O-, R
3OS (O)
2N (R
3) C (O) N (R
3)-, (R
3)
2NS (O)
2N (R
3) C (O)-, (R
3)
2NS (O)
2N (R
3) C (O) O-, (R
3)
2NS (O)
2N (R
3) C (O) N (R
3)-, R
3C (O) N (R
3) S (O)
2-, R
3C (O) N (R
3) S (O)
2O-, R
3C (O) N (R
3) S (O)
2N (R
3)-, R
3OC (O) N (R
3) S (O)
2-, R
3OC (O) N (R
3) S (O)
2O-, R
3OC (O) N (R
3) S (O)
2N (R
3)-, (R
3)
2NC (O) N (R
3) S (O)
2-, (R
3)
2NC (O) N (R
3) S (O)
2O-, (R
3)
2NC (O) N (R
3) S (O)
2N (R
3The first aryl of 6-14)-,, 5-14 unit's heteroaryl or 3-14 unit heterocyclic radical;
R
2For do not exist, C
1-6Alkyl, halo C
1-6Alkyl or oxo;
R
3Be hydrogen, C
1-6Alkyl, amino C
1-6Alkyl, halo C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group or C
3-6Alkoxy C
1-6Alkyl;
A
1Be key, C
1-6Alkyl, C
1-6Alkoxyl group, C
2-6Thiazolinyl, C
2-6Alkynyl or C
1-6Alkyl-carbonyl;
A
2Be key, O, S (O)
w, N (R
3), C
1-6Alkyl or C
1-6Alkoxyl group, w are 0,1 or 2, described C
1-6Alkyl and C
1-6Alkoxyl group can be chosen wantonly by 1-4 and be independently selected from following substituting group replacement: methyl, ethyl, trifluoromethyl or oxo;
Cy
1Be 6-14 unit aryl, 5-14 unit heteroaryl, C
3-8Cycloalkyl or 3-14 unit heterocyclic radical, the first aryl of described 6-14,5-14 unit heteroaryl, C
3-8Cycloalkyl and 3-14 unit heterocyclic radical can be chosen wantonly by 1-4 substituting group that is independently selected from R ' and replace;
Cy
2Be hydrogen, 6-14 unit aryl, 5-14 unit heteroaryl, C
3-8Cycloalkyl or 3-14 unit heterocyclic radical, the first aryl of described 6-14,5-14 unit heteroaryl, C
3-8Cycloalkyl and 3-14 unit heterocyclic radical can be chosen wantonly by 1-4 substituting group that is independently selected from R ' and replace;
R ' is halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, oxo, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, hydroxyl C
3-6Cycloalkyl, halo C
3-6Cycloalkyl, C
4-8Cycloalkyl C
1-6Alkyl, halo C
4-8Cycloalkyl C
1-6Alkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl, halo C
2-6Thiazolinyl, hydroxyl C
2-6Thiazolinyl, C
5-8Cycloalkenyl group, C
2-6Alkynyl, C
3-6Cycloalkyloxy group C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-6Cycloalkylthio, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Alkyl amine group formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, C
1-6Alkylsulfonamido, two (C
1-6Alkyl) amido formyl radical, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy;
Cy
3Be 6-14 unit fractional saturation aryl, C
3-8Cycloalkyl, C
5-8Cycloalkenyl group, 3-14 unit heterocyclic radical, the first fractional saturation aryl of described 6-14, C
3-8Cycloalkyl, C
5-8Cycloalkenyl group and 3-14 unit heterocyclic radical can be chosen wantonly by 1-4 and be independently selected from R
8Substituting group replace R
8Be hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, hydroxyl C
3-6Cycloalkyl, halo C
3-6Cycloalkyl, C
4-8Cycloalkyl C
1-6Alkyl, halo C
4-8Cycloalkyl C
1-6Alkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl, halo C
2-6Thiazolinyl, hydroxyl C
2-6Thiazolinyl, C
5-8Cycloalkenyl group, C
2-6Alkynyl, C
3-6Cycloalkyloxy group C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-6Cycloalkylthio, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy;
R
6aAnd R
6bRepresent hydrogen atom, halogen atom, hydroxyl, cyano group, carboxyl, C respectively
1-6Alkyl, C
3-8Cycloalkyl, halo C
1-6Alkyl, halo C
1-6Alkoxyl group, oxo, 6-14 unit aryl, 5-14 unit heteroaryl, the heterocyclic radical of 3-14 unit, R
7aO-, R
7aOC (O)-, R
7bC (O)-, R
7bC (O) NH-, R
7cS (O)-, R
7cS (O)
2-, R
7cS (O)
2NH-, R
7d(OR
7a) CH-, R
7dS-, (R
7eR
7f) N-, (R
7eR
7f) NC (O)-, the aryl-OCH of aryl-O-, 6-14 unit of 6-14 unit
2-, the aryl-S (O) of 6-14 unit
2Aryl-the S (O) of NH-, 6-14 unit
2-,
Or R
6aAnd R
6bInterconnect the Cy that is connected with them
3On atom form 3-14 unit cyclic group, this cyclic group and Cy together
3With and ring, volution, bridged ring form condense, described 3-14 unit cyclic group contains 0-4 and is selected from C (O), N, O, S, SO and/or SO
2Atom, and can further be independently selected from R by 1-4
9Substituting group replace R
9Be hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, hydroxyl C
3-6Cycloalkyl, halo C
3-6Cycloalkyl, C
4-8Cycloalkyl C
1-6Alkyl, halo C
4-8Cycloalkyl C
1-6Alkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl, halo C
2-6Thiazolinyl, hydroxyl C
2-6Thiazolinyl, C
5-8Cycloalkenyl group, C
2-6Alkynyl, C
3-6Cycloalkyloxy group C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-6Cycloalkylthio, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy;
R
7a, R
7b, R
7c, R
7d, R
7e, R
7fBe respectively hydrogen atom, C
1-6Alkyl, C
3-8Cycloalkyl, or R
7eAnd R
7fThe N that connects with them forms and contains 1-4 and be selected from C (O), N, O, S, SO and/or SO
23-14 unit heterocyclic radical;
M is 0,1 or 2;
N is 0,1,2,3 or 4.
The preferred version of scheme 1 is:
Wherein, X
1, X
2, R
1, R
2, A
1, A
2, Cy
1, Cy
2, Cy
3, m, n be as described in the scheme 1;
R
6aAnd R
6bInterconnect the Cy that is connected with them
3On atom form 3-14 unit cyclic group, this cyclic group and Cy together
3Condense with the volution form, the first cyclic group of described 3-14 contains 0-4 and is selected from C (O), N, O, S, SO and/or SO
2Atom, and can further be independently selected from R by 1-4
9Substituting group replace R
9Be hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, hydroxyl C
3-6Cycloalkyl, halo C
3-6Cycloalkyl, C
4-8Cycloalkyl C
1-6Alkyl, halo C
4-8Cycloalkyl C
1-6Alkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl, halo C
2-6Thiazolinyl, hydroxyl C
2-6Thiazolinyl, C
5-8Cycloalkenyl group, C
2-6Alkynyl, C
3-6Cycloalkyloxy group C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-6Cycloalkylthio, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy.
The preferred version of scheme 1 is:
Wherein, X
1, X
2, R
1, R
2, A
1, A
2, Cy
1, Cy
2, Cy
3, m, n be as described in the scheme 1;
R
6aAnd R
6bInterconnect the Cy that is connected with them
3On atom form 3-14 unit cyclic group, this cyclic group and Cy together
3Condense with the bridged ring form, the first cyclic group of described 3-14 contains 0-4 and is selected from C (O), N, O, S, SO and/or SO
2Atom, and can further be independently selected from R by 1-4
9Substituting group replace R
9Be hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, hydroxyl C
3-6Cycloalkyl, halo C
3-6Cycloalkyl, C
4-8Cycloalkyl C
1-6Alkyl, halo C
4-8Cycloalkyl C
1-6Alkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl, halo C
2-6Thiazolinyl, hydroxyl C
2-6Thiazolinyl, C
5-8Cycloalkenyl group, C
2-6Alkynyl, C
3-6Cycloalkyloxy group C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-6Cycloalkylthio, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy.
The preferred version of scheme 1 is:
Wherein, X
1, X
2, R
1, R
2, A
1, A
2, Cy
1, Cy
2, Cy
3, m, n be as described in the scheme 1;
R
6aAnd R
6bInterconnect the Cy that is connected with them
3On atom form 3-14 unit cyclic group, this cyclic group and Cy together
3With and loop type condense, described 3-14 unit cyclic group contains 0-4 and is selected from C (O), N, O, S, SO and/or SO
2Atom, and can further be independently selected from R by 1-4
9Substituting group replace R
9Be hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, hydroxyl C
3-6Cycloalkyl, halo C
3-6Cycloalkyl, C
4-8Cycloalkyl C
1-6Alkyl, halo C
4-8Cycloalkyl C
1-6Alkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl, halo C
2-6Thiazolinyl, hydroxyl C
2-6Thiazolinyl, C
5-8Cycloalkenyl group, C
2-6Alkynyl, C
3-6Cycloalkyloxy group C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-6Cycloalkylthio, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy.
The solution of the present invention 2 has provided compound, its pharmacy acceptable salt shown in the general formula (II), and isomer:
Wherein, X
1, X
2, R
1, R
2, A
1, A
2, Cy
1, Cy
2, Cy
3, R
8, R
9, m, n be as described in the scheme 1;
Cy
4Represent 6-14 unit aryl, 5-14 unit heteroaryl, C
3-8The heterocyclic radical of cycloalkyl or 3-14 unit is with Cy
3With and loop type condense R
9Be halogen atom, hydroxyl, C
1-6Alkyl or C
1-6Alkoxyl group;
R is 0,1,2,3 or 4;
Q is 0,1,2,3 or 4.
The solution of the present invention 3 has provided compound, its pharmacy acceptable salt shown in the general formula (III), and isomer:
Wherein, X
1, X
2, R
1, R
2, Cy
1, Cy
2, R
8, R
9, m, n be as described in the scheme 1;
X
3Be O, S (O)
w, N (R
4a) or C (R
4a) (R
4b), w is 0,1 or 2, R
4aAnd R
4bBe hydrogen atom, C independently respectively
1-6Alkyl, halo C
1-6Alkyl, C
3-8Cycloalkyl, C
2-6Thiazolinyl, C
5-8Cycloalkenyl group or C
2-6Alkynyl;
X
4, X
5, X
6, X
7Be respectively CH or N;
R is 0,1,2,3 or 4;
P is 0,1 or 2.
Q is 0,1,2 or 3.
The preferred version of scheme 3 is
X
1Be C (O), S (O)
wOr C (=NR
5), w is 0,1 or 2, R
5Be cyano group, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, described C
1-6Alkyl, C
1-6Alkoxyl group can be chosen wantonly by 1-4 and be independently selected from following substituting group replacement: halogen atom, cyano group, hydroxyl, carboxyl and amino;
X
2Be O, S or N (R
4a), R
4aBe hydrogen atom, C
1-6Alkyl, halo C
1-6Alkyl;
X
3Be O, S (O)
w, N (R
4a) or C (R
4a) (R
4b), w is 0,1 or 2, R
4aAnd R
4bBe hydrogen atom, C independently respectively
1-6Alkyl, halo C
1-6Alkyl;
X
4, X
5, X
6, X
7Be respectively CH or N;
R
1Be hydrogen, C
1-6Alkyl, C
3-8Cycloalkyl, C
2-6Thiazolinyl, C
5-8Cycloalkenyl group, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Carbalkoxy, C
1-6Alkyl carbonyl oxy or phenyl;
R
2For do not exist, C
1-4Alkyl, halo C
1-4Alkyl or oxo;
Cy
1Be 6-10 unit aryl, the single heterocyclic radical of the 5-8 single heteroaryl of unit or 3-8 unit, the first aryl of described 6-10, the single heterocyclic radical of the 5-8 single heteroaryl of unit and 3-8 unit can be chosen wantonly by 1-4 substituting group that is independently selected from R ' and replace;
Cy
2Be 6-10 unit aryl, the single heterocyclic radical of the 5-8 single heteroaryl of unit or 3-8 unit, the first aryl of described 6-10, the single heterocyclic radical of the 5-8 single heteroaryl of unit and 3-8 unit can be chosen wantonly by 1-4 substituting group that is independently selected from R ' and replace;
R ' is halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, oxo, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, halo C
3-6Cycloalkyl, C
4-8Cycloalkyl C
1-6Alkyl, halo C
4-8Cycloalkyl C
1-6Alkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, halo C
1-6Alkoxyl group, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy;
R
8Be hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, hydroxyl C
3-6Cycloalkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, halo C
1-6Alkoxyl group, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy;
R
9Be hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, hydroxyl C
3-6Cycloalkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, halo C
1-6Alkoxyl group, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy;
M is 0,1 or 2; N is 0,1,2,3 or 4;
R is 0,1 or 2; P is 0,1,2,3 or 4; Q is 0,1,2 or 3.
The preferred version of scheme 3 is
X
1Be C (O), S (O)
wOr C (=NR
5), w is 0,1 or 2, R
5Be cyano group, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group;
X
2Be O, S or N (R
4a), R
4aBe hydrogen atom or C
1-6Alkyl;
X
3Be O, S, N (R
4a) or C (R
4a) (R
4b), R
4aAnd R
4bBe hydrogen atom or C independently respectively
1-4Alkyl;
X
4, X
5, X
6, X
7Be respectively CH or N;
R
1Be hydrogen or C
1-4Alkyl;
R
2For not existing or C
1-4Alkyl;
Cy
1Be 6-10 unit aryl, the first aryl of described 6-10 can be chosen wantonly by 1-4 substituting group that is independently selected from R ' and replace;
Cy
2Be the single heterocyclic radical of 3-8 unit, the single heterocyclic radical of described 3-8 unit can be chosen wantonly by 1-4 substituting group that is independently selected from R ' and replace;
R ' is halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, oxo, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, halo C
1-6Alkyl, C
2-6Thiazolinyl, halo C
1-6Alkoxyl group, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy;
R
8Be hydrogen or C
1-4Alkyl;
R
9Be hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, halo C
1-6Alkyl, halo C
1-6Alkoxyl group, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy;
M is 0,1 or 2; N is 0,1 or 2;
R is 0,1 or 2; P is 0,1 or 2; Q is 0,1 or 2.
The preferred version of scheme 3 is
X
1Be C (O) or S (O)
2
X
2Be O;
X
3Be O, S, N (R
4a) or C (R
4a) (R
4b), R
4aAnd R
4bBe hydrogen atom or C independently respectively
1-4Alkyl;
X
4, X
5, X
6, X
7Be respectively CH or N;
R
1Be hydrogen or C
1-4Alkyl;
R
2For not existing;
Cy
1Be phenyl, described phenyl can be chosen wantonly by 1-4 substituting group that is independently selected from R ' and replace;
Cy
2Be the single heterocyclic radical of 5-7 unit, the single heterocyclic radical of described 5-7 unit can be chosen wantonly by 1-4 substituting group that is independently selected from R ' and replace;
R ' is halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, oxo, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkyl, halo C
1-6Alkoxyl group, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Carbalkoxy or C
1-9Alkyl carbonyl oxy;
R
8Be hydrogen or C
1-4Alkyl;
R
9Be hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, halo C
1-6Alkyl, halo C
1-6Alkoxyl group, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy;
N is 0 or 1;
R is 0,1 or 2; P is 0,1 or 2; Q is 0,1 or 2.
The preferred version of scheme 3 is
X
1Be C (O);
X
2Be O;
X
3Be O or CH
2
X
4, X
5, X
6, X
7Be CH;
R
1Be C
1-4Alkyl;
R
2For not existing;
Cy
1Be phenyl, described phenyl can be chosen wantonly by 1 or 2 substituting group that is independently selected from R ' and replace;
Cy
2For containing the single heterocyclic radical of 5-6 unit of a N atom at least, the described single heterocyclic radical of 5-6 unit that contains a N atom at least can be chosen wantonly by 1 or 2 substituting group that is independently selected from R ' and replace;
R ' is halogen atom, hydroxyl, amino, oxo, C
1-4Alkyl, C
1-4Alkoxyl group or halo C
1-4Alkyl;
R
8Be hydrogen or C
1-4Alkyl;
R
9Be hydrogen, halogen atom or C
1-6Alkyl;
N is 0 or 1;
R is 0,1 or 2; P is 0,1 or 2; Q is 0,1 or 2.
" C of the present invention
1-6Alkyl " expression straight or branched the alkyl that contains 1-6 carbon atom; specific examples includes but not limited to methyl; ethyl; n-propyl; sec.-propyl; normal-butyl, the 2-methyl-propyl, the 1-methyl-propyl, 1, the 1-dimethyl ethyl, n-pentyl, the 3-methyl butyl, the 2-methyl butyl, the 1-methyl butyl, the 1-ethyl propyl, n-hexyl, the 4-methyl amyl, the 3-methyl amyl, the 2-methyl amyl, the 1-methyl amyl, 3, the 3-dimethylbutyl, 2, the 2-dimethylbutyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 3-dimethylbutyl, the 2-ethyl-butyl, 1,2-dimethyl propyl etc." C of the present invention
1-4Alkyl " refer to contain in the above-mentioned example specific examples of 1-4 carbon atom.
" C of the present invention
3-8Cycloalkyl " be the alkyl that contains the ring-type of 3-8 carbon atom, specific examples includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group etc." C of the present invention
3-6Cycloalkyl " refer to contain in the above-mentioned example specific examples of 3-6 carbon atom." C of the present invention
4-8Cycloalkyl " refer to contain in the above-mentioned example specific examples of 4-8 carbon atom.
" C of the present invention
2-6Thiazolinyl " be the thiazolinyl of the straight or branched of 2-6 carbon atom containing two keys; include but not limited to vinyl, 1-propenyl, 2-propenyl, 1-butylene base, crotyl, 1; 3-divinyl, 1-pentenyl, pentenyl, 3-pentenyl, 1; 3-pentadiene, 1; 4-pentadiene, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,4-hexadiene etc." C of the present invention
2-4Thiazolinyl " refer to contain in the above-mentioned example specific examples of 2-4 carbon atom.
" C of the present invention
2-6Alkynyl " for the alkynyl of straight or branched of 2-6 carbon atom containing three key, include but not limited to ethynyl, proyl, ethyl acetylene base, 2-butyne base, 3-methyl isophthalic acid-butynyl, 1-pentynyl, valerylene base, 3-pentynyl, 3-methyl-1-pentene alkynyl, 4-methyl-1-pentene alkynyl, 4-methyl-valerylene base, 1-hexin base, 2-hexin base, 3-hexin base etc." C of the present invention
2-4Alkynyl " refer to contain in the above-mentioned example specific examples of 2-4 carbon atom." C of the present invention
3-6Alkynyl " refer to contain in the above-mentioned example specific examples of 3-6 carbon atom.
" C of the present invention
5-8Cycloalkenyl group " for containing the cyclic group that 5-8 carbon atom and ring contain one or more pairs of keys, include but not limited to
Deng.
" C of the present invention
1-6Alkoxyl group " refer to " C
1-6Alkyl " be connected formed group, i.e. C with Sauerstoffatom
1-6Alkyl-O-, specific examples include but are not limited to methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, pentyloxy, neopentyl oxygen, hexyloxy etc." C of the present invention
1-4Alkoxyl group " refer to " C
1-4Alkyl-O-" mode connects formed group, " C
1-4Alkyl " civilian described as defined above.
" C of the present invention
1-6Alkylthio " refer to C
1-6Alkyl is connected formed group, i.e. C with sulphur atom
1-6Alkyl S-, described " C
1-6Alkyl " as mentioned before.
" C of the present invention
1-6Alkyl amine group " refer to a C
1-6The formed group of hydrogen atom, i.e. a C in the alkyl-substituted amino
1-6Alkyl NH-, described " C
1-6Alkyl " as mentioned before.
" two (C of the present invention
1-6Alkyl) amido " refer to two identical or different C
1-6Two the formed groups of hydrogen atom, i.e. (C in the alkyl difference substituted-amino
1-6Alkyl) 2N-, described " C
1-6Alkyl " as mentioned before.
" C of the present invention
1-6Alkyl-carbonyl " refer to C
1-6Alkyl is connected formed group, i.e. C with carbonyl
1-6Alkyl C (O)-, described " C
1-6Alkyl " as mentioned before." C of the present invention
1-4Alkyl-carbonyl " refer to contain in the above-mentioned example specific examples of 1-4 carbon atom.
" C of the present invention
1-6Alkyl carbonyl oxy " refer to C
1-6Alkyl is connected formed group, i.e. C with carbonyl oxygen base
1-6Alkyl-C (O) O-, described " C
1-6Alkyl " as mentioned before.
" C of the present invention
1-6Carbalkoxy " refer to C
1-6Alkoxyl group is connected formed group, i.e. (C with carbonyl
1-6Alkyl) OC (O)-, described " C
1-6Alkoxyl group " as mentioned before.
" C of the present invention
1-6The alkyl amine group formyl radical " refer to C
1-6Alkyl is connected formed group, i.e. C with the amido formyl radical
1-6Alkyl-NHC (O)-, described " C
1-6Alkyl " as mentioned before.
" two (C of the present invention
1-6Alkyl) amido formyl radical " refer to two identical or different C
1-6Formed group, i.e. (C behind two hydrogen atoms in the alkyl difference substituted-amino formyl radical on the amido
1-6Alkyl)
2NC (O)-, described " C
1-6Alkyl " as mentioned before.
" C of the present invention
1-6Alkylamidoalkyl " refer to C
1-6Alkyl is connected formed group, i.e. (C with formamido-
1-6Alkyl) C (O) NH-, described " C
1-6Alkyl " as mentioned before.
" C of the present invention
1-6Alkyl sulphonyl " refer to C
1-6Alkyl is connected formed group, i.e. C with alkylsulfonyl
1-6Alkyl-S (O)
2-, described " C
1-6Alkyl " as mentioned before.
" C of the present invention
1-6The alkyl amine group alkylsulfonyl " refer to C
1-6Alkyl is connected formed group, i.e. C with amino-sulfonyl
1-6Alkyl-NHS (O)
2-, described " C
1-6Alkyl " as mentioned before.
" two (C of the present invention
1-6Alkyl) amido alkylsulfonyl " refer to two identical or different C
1-6Formed group, i.e. (C behind two hydrogen atoms in the alkyl difference substituted-amino alkylsulfonyl on the amido
1-6Alkyl)
2NS (O)
2-, described " C
1-6Alkyl " as mentioned before.
" C of the present invention
1-6Alkylsulfonamido " refer to C
1-6Alkyl is connected formed group, i.e. C with sulfoamido
1-6Alkyl-S (O)
2NH-, described " C
1-6Alkyl " as mentioned before.
" hydroxyl C of the present invention
1-6Alkyl " refer to that one or more hydroxyl replaces C
1-6The formed group of hydrogen atom in the alkyl, comprise methyl alcohol, ethanol, ethylene glycol, n-propyl alcohol, Virahol, glycerol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, 2-methyl isophthalic acid, 2-two propyl alcohol, amylalcohol, 1,2-pentanediol, 2-methyl-2-butanols, hexanol etc., described " C
1-6Alkyl " as mentioned before.
" hydroxyl C of the present invention
2-6Thiazolinyl " refer to that one or more hydroxyl replaces C
2-6The formed group of hydrogen atom in the thiazolinyl, described " C
2-6Thiazolinyl " as mentioned before.
" hydroxyl C of the present invention
3-6Cycloalkyl " refer to that one or more hydroxyl replaces C
3-6The formed group of cycloalkyl, described " C
3-6Cycloalkyl " as mentioned before.
" C of the present invention
4-8Cycloalkyl C
1-6Alkyl " refer to C
4-8Cycloalkyl substituted C
1-6The formed group of hydrogen atom in the alkyl, described " C
4-8Cycloalkyl ", " C
1-6Alkyl " as mentioned before.
" C of the present invention
3-6Cycloalkyloxy group C
1-6Alkoxyl group " refer to " C
3-6Cycloalkyl-O-C
1-6Alkoxyl group-" form connects formed group, described " C
3-6Cycloalkyl ", " C
1-6Alkoxyl group " as mentioned before.
" C of the present invention
3-6Cycloalkylthio " refer to C
3-6Cycloalkyl is connected formed group, i.e. C with sulphur atom
1-6Cycloalkyl S-, described " C
3-6Cycloalkyl " as mentioned before.
" halo " of the present invention refers to that one or more halogen atom replaces the formed group of one or more hydrogen atom on some group, and " halogen atom " is selected from fluorine atom, chlorine atom, bromine atoms, iodine atom." halo C
1-6Alkyl ", " halo C
1-6Alkoxyl group ", " halo C
3-6Cycloalkyl ", " halo C
4-8Cycloalkyl C
1-6Alkyl ", " halo C
2-6Thiazolinyl " refer to that one or more halogen atom replaces previously described C
1-6Alkyl, C
1-6Alkoxyl group, C
3-6Cycloalkyl, C
4-8Cycloalkyl C
1-6Alkyl, halo C
2-6The formed base of one or more hydrogen atom in the thiazolinyl.
" oxo " of the present invention refers to the group that one or more carbon atom quilt-C (O)-replacement forms.
" 6-14 unit aryl " of the present invention refers to that annular atoms all is the ring-type aromatic group of carbon atom, comprises 6-8 unit's monocyclic aryl and 8-14 unit fused ring aryl.6-8 unit monocyclic aryl refers to whole undersaturated aryl, for example phenyl, cyclooctatetraene base etc.8-14 unit fused ring aryl refers to share the formed condensed ring group that to have a ring at least be undersaturated aromatic nucleus of two adjacent carbon atoms each other by two or more ring texturees, comprise the unsaturated fused ring aryl of 8-14 unit, for example naphthalene, phenanthrene etc., also comprise 8-14 unit fractional saturation fused ring aryl, for example benzo C
3-8Cycloalkyl, benzo C
4-8Cycloalkenyl group, specific examples be as 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, 1,4-dihydro naphthyl etc." 6-10 unit aryl " refers to that annular atoms all be the first ring-type aromatic group of 6-10 of carbon atom, comprises monocyclic aryl, also comprises fused ring aryl, and fused ring aryl can be undersaturated, also can be fractional saturation.
" 5-14 unit heteroaryl " of the present invention, refer to contain 5-14 the annular atoms undersaturated cyclic group with aromaticity of (wherein containing a heteroatoms at least), comprise the single heteroaryl of 5-8 unit, the thick heteroaryl of 6-14 unit, described heteroatoms is selected from C (O), N, O, S, SO, SO
2Deng.
The single heteroaryl of 5-8 unit refers to the cyclic group of heteroatomic 5-8 of containing of an aromaticity annular atoms, specific examples includes but are not limited to furyl, thienyl, pyrryl, thiazolyl, isothiazolyl, thiadiazolyl group oxazolyl isoxazolyl oxadiazole base, imidazolyl, pyrazolyl, 1,2, the 3-triazolyl, 1,2, the 4-triazolyl, 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,2,5-oxadiazole base, 1,3,4-oxadiazole base, pyridyl, the 2-pyridone, the 4-pyridone, pyrimidyl, 1,4-Dioxin base, 2H-1, the 2-oxazinyl, 4H-1, the 2-oxazinyl, 6H-1, the 2-oxazinyl, 4H-1, the 3-oxazinyl, 6H-1, the 3-oxazinyl, 4H-1, the 4-oxazinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,2, the 4-triazinyl, 1,3,5-triazinyl, 1,3, the 4-triazinyl, 1,2,4,5-tetrazine base, the oxepin base, thia cycloheptatriene base, nitrogen heterocyclic heptantriene base, 1,3-diazacyclo heptantriene base, nitrogen heterocyclic octatetraene base, 1,4-dihydro-1,4-diazacyclo sarohornene, 1,4-dioxane sarohornene etc.Be preferably " the single heteroaryl of 5-6 unit ", refer to the cyclic group of heteroatomic 5-6 of containing of an aromaticity annular atoms.
The thick heteroaryl of 6-14 unit, refer to contain 6-14 annular atoms (wherein containing a heteroatoms at least) and share two adjacent atoms each other by two or more ring texturees and couple together the undersaturated condensed ring structure with aromaticity that forms, specific examples includes but not limited to: benzofuryl, the benzisoxa furyl, benzothienyl, indyl, isoindole benzoxazolyl, benzimidazolyl-, indazolyl, the benzotriazole base, quinolyl, the 2-quinolinone, the 4-quinolinone, the 1-isoquinolines, isoquinolyl, acridyl, phenanthridinyl, the benzo pyridazinyl, phthalazinyl, quinazolyl, quinoxalinyl, phenol piperazine base, pteridine radicals, purine radicals, naphthyridinyl, azophenlyene, thiodiphenylamine, Deng.Be preferably " the thick heteroaryl of 9-10 unit ", refer to the cyclic group of heteroatomic 9-10 of containing of an aromaticity annular atoms.
" 3-14 unit heterocyclic radical " of the present invention refers to contain the cyclic group of saturated, the fractional saturation of 3-14 annular atoms (wherein containing a heteroatoms at least), comprises the first fused heterocycle base of the 3-8 single heterocyclic radical of unit and 6-14.Described heteroatoms is selected from C (O), N, O, S, SO, SO
2Deng.
Described " the single heterocyclic radical of 3-8 unit ", its single heterocycle can be saturated, fractional saturation, its specific examples includes but are not limited to: the ethylenimine base, 2H-ethylenimine base, the diazacyclo propyl, 3H-diazacyclo propenyl, azetidinyl, 1,2-diazetidine base, the azete base, 1,2-dioxetanes alkyl, 1,2-diazetine base, the dioxirane base, oxetanyl, the oxaza propyl, 1,4-dioxane base, 1,3-dioxane base, the thiirane base, the Thietane base, 1,3-dithian base, 1,2-dithia cyclobutene base, 1,3-dioxolane base, 1,3-dithiolane base, 1,4-Dioxin base, 1,4-dithia cyclohexadienyl, 1,4-oxathiin base, tetrahydrofuran base, the pyrrolin base, pyrrolidyl, imidazolidyl, 4,5-glyoxalidine base, pyrazolidyl, 4,5-pyrazoline base, 2,5-dihydro-thiophene base, tetrahydro-thienyl, 4, the 5-dihydro-thiazolyl, piperidyl, piperazinyl, the morpholinyl base, 4,5-dihydro-oxazole base, 4,5-dihydro-isoxazole base, 2,3-dihydro-isoxazole base, 2H-1, the 2-oxazinyl, 4H-1, the 2-oxazinyl, 6H-1, the 2-oxazinyl, 2H-1, the 3-oxazinyl, 4H-1, the 3-oxazinyl, 5,6-dihydro-4H-1, the 3-oxazinyl, 6H-1, the 3-oxazinyl, 2H-1, the 4-oxazinyl, 4H-1, the 4-oxazinyl, 2H-1, the 3-thiazinyl, 4H-1, the 3-thiazinyl, 5,6-dihydro-4H-1, the 3-thiazinyl, 6H-1, the 3-thiazinyl, 2H-1, the 4-thiazinyl, 4H-1, the 4-thiazinyl, the 2H-pyranyl, 2H-pyran-2-one base, 3,4-dihydro-2H-pyranyl, the 4H-pyranyl, THP trtrahydropyranyl, 4H-pyrans-4-ketone group etc.Be preferably " the single heterocyclic radical of 5-7 unit ", more preferably " the single heterocyclic radical of 5-6 unit " its ring can be saturated, fractional saturation.
Described " 6-14 unit fused heterocycle base ", its fused heterocycle can be saturated, fractional saturation, example has imidazolidine also [4,5-c] pyridyl, 3,4-dihydroquinazoline base, 1,2-dihydro-quinoxaline base, benzo [d] [1,3] dioxa cyclopentenyl, 1,3-dihydroisobenzofuran base, 2H-chromogen thiazolinyl, 2H-chromogen alkene-2-ketone group, the 4H-chromenyl, 4H-chromene-4-ketone group, chromanyl, 4H-1, the 3-benzoxazinyl, 4,6-dihydro-1H-furo [3,4-d] imidazolyl, 3a, 4,6,6a-tetrahydrochysene-1H-furo [3,4-d] imidazolyl, 4,6-dihydro-1H-thieno-[3,4-d] imidazolyl, 4,6-dihydro-1H-pyrrolo-[3,4-d] imidazolyl, 4,5,6,7-tetrahydrochysene-1H-benzo [d] imidazolyl etc.Be preferably " 9-10 unit fused heterocycle base ", its ring can be saturated, fractional saturation.
" R of the present invention
6aAnd R
6bInterconnect the Cy that is connected with them
3On atom form 3-14 unit cyclic group together " in 3-14 unit cyclic group, refer to contain monocycle and many cyclic groups of 3-12 annular atoms, can further contain one or more and be selected from C (O), N, O, S, SO, SO
2Heteroatoms.This monocycle and many cyclic groups can be undersaturated, and for example aryl, heteroaryl also can be fractional saturations, and for example the heterocyclic radical of the aryl of fractional saturation, fractional saturation can also be saturated, for example cycloalkyl, cycloalkenyl group, saturated heterocyclic radical etc.For many cyclic groups, ring wherein can be with and the form of ring, volution, bridged ring condense mutually.
Described " and ring " refer to a class by two or more ring texturees share each other two adjacent atoms couple together form contain carbon atom or heteroatomic condensed ring structure, described heteroatoms is selected from C (O), N, O, S, SO, SO
2Be preferably the also cyclic group of 6-10 annular atoms, for example 5,6-glyoxalidine [1.2-a] pyrazine-7 (8H)-Ji, 5,6-dihydro-1,7-naphthyridines-7 (8H)-Ji, 5H-pyrroles [3.4-b] pyridine-6 (7H)-Ji, 7,8-dihydropyridine [4.3-d] pyrimidine-6 (5H)-Ji, 2,3,6,7-tetrahydrochysene-1H-pyrazoles [4.3-c] pyridine-5 (4H)-Ji, 6,7-thiazoline [5.4-c] pyridine-5 (4H)-Ji, 3-methyl-6,7-dihydro-3H-pyrazoles [4.5-c] pyridine-5 (4H)-Ji, 2-methyl six hydrogen cyclopentano [c] pyrroles-5-bases etc.
Described " volution " refers to that a class has that two rings share that atoms form at least contains carbon atom or heteroatomic condensed ring structure, and described heteroatoms is selected from C (O), N, O, S, SO, SO
2Be preferably the volution group of 7-10 annular atoms, for example 6-nitrogen spiral shell [2.5] octane-6-base, 7-nitrogen spiral shell [3.5] nonane-7-base, 8-nitrogen spiral shell [4.5] decane-8-base, 1-methyl isophthalic acid, 7-phenodiazine spiral shell [4.4] nonane-7-base, 2-methyl-2,6-phenodiazine spiral shell [3.4] octane-6-base, 6-nitrogen spiral shell [3.4] octane-6-base, 2-oxa--7-nitrogen spiral shell [4.5] certain herbaceous plants with big flowers alkane-7-base, 2-oxa--8-nitrogen spiral shell [4.5] certain herbaceous plants with big flowers alkane-8-base, 2-methyl-2,7-phenodiazine spiral shell [4.5] decane etc.
Described " bridged ring " refers to that any two rings share that the atom that neither directly links to each other forms contains carbon atom or heteroatomic condensed ring structure, and described heteroatoms is selected from C (O), N, O, S, SO, SO
2Be preferably the bridged ring group of 7-10 annular atoms, for example (1S, 4S)-2-methyl-2-nitrogen dicyclo [2.2.1] hexane, 2-nitrogen dicyclo [2.2.1] heptane, 8-methyl bicycle [3.2.1] octane, 3-oxa--8 nitrogen dicyclo [3.2.1] octane, 2-nitrogen dicyclo [2.2.2] octane, 7-nitrogen dicyclo [2.2.1] heptane, 3-nitrogen dicyclo [3.2.1] octane, 3-nitrogen dicyclo [3.3.2] decane, 7-oxabicyclo [2.2.1] heptane, 8-oxabicyclo [3.2.1] octane etc.
Preferred compound of the present invention:
The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention comprises an alkali metal salt, as sodium salt, sylvite, lithium salts etc.; Alkaline earth salt is as calcium salt, magnesium salts etc.; Other metal-salts are as aluminium salt, molysite, zinc salt, mantoquita, nickel salt, cobalt salt etc.; Inorganic base salts is as ammonium salt; Organic alkali salt, as uncle's octyl group amine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycocoll alkyl ester salt, ethylenediamine salt, N-methylglucosamine salt, guanidinesalt, diethyl amine salt, triethylamine salt, dicyclohexyl amine salt, N, N '-dibenzyl ethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-styroyl amine salt, piperazine salt, tetramethyl-amine salt, three (methylol) amido methane salt; When compound of the present invention is alkalescence, can prepare salt by the pharmaceutically acceptable non-toxic acid that comprises mineral acid and organic acid, this type of acid comprises: halogen acid salt, as hydrofluoride, hydrochloride, hydrobromate, hydriodate etc.; Inorganic acid salt is as nitrate, perchlorate, vitriol, phosphoric acid salt etc.; Lower alkyl sulfonate is as mesylate, fluoroform sulphonate, esilate etc.; Arylsulphonate is as benzene sulfonate, P-TOLUENE SULFO ACID 99's salt etc.; Organic acid salt is as acetate, malate, fumarate, succinate, Citrate trianion, tartrate, oxalate, maleate etc.; Amino acid salts is as glycinate, Trimethyl glycine salt, arginic acid salt, ornithine salt, glutaminate, aspartate etc.For fear of query, one, two or three salt-forming cations may be arranged, but this depends on quantity and the described cationic valence mumber of carboxyl functional group.It is evident that for those skilled in the art the pharmacy acceptable salt of The compounds of this invention can make by ordinary method in the formation such as free carboxy place of this compound.
The isomer of formula of the present invention (I) compound, refer to have other unsymmetrical carbons when formula (I) compound, during carbon-carbon double bond etc., all enantiomers of its generation, diastereomer, racemization isomer, cis-trans-isomer, tautomer, geometrical isomer, epimer and composition thereof, described isomer can be by standard isolation technique and the abundant purity isomer of the synthetic acquisition of stereochemistry control.
The present invention also provides the preparation method of above-claimed cpd, but is not limited only to following method, and reaction equation is as follows:
Raw material 1 intermediate 1 intermediate 2
Intermediate 3 intermediates 4
Intermediate 5 formulas (III) compound
Reactions steps is as follows:
(1) preparation of intermediate 1
Under the low temperature the 1.1 THF solution when content of starting materials 2 slowly are added drop-wise in the 1.1 equivalent butyllithiums, after reaction for some time the 1 THF solution when content of starting materials 1 slowly are added drop-wise in the system stirring reaction.Reaction finishes the back and adds saturated NH
4The cancellation of Cl solution, ethyl acetate extraction merges organic phase, washing, the saturated common salt washing, anhydrous sodium sulfate drying, concentrate intermediate 1.
(2) preparation of intermediate 2
Under the low temperature, with the BH of 2-4 equivalent
3.Me
2S solution slowly is added drop-wise in the THF solution of 1 equivalent intermediate 1, and room temperature or back flow reaction a few hours, cooling adds the methyl alcohol cancellation, and ethyl acetate extraction merges organic phase, washing, the saturated common salt washing, anhydrous sodium sulfate drying, concentrate intermediate 2.
(3) preparation of intermediate 3
Under the low temperature, about 1 monomer when content of starting materials 3,1.5-4 are worked as quantity tertiary amine such as Et
3N joins the CH of 1 equivalent intermediate 2
2Cl
2Perhaps in the toluene solution, continue reaction then, after the cooling, add water cancellation, extraction merges organic phase, washing, and the saturated common salt washing, anhydrous sodium sulfate drying concentrates, and column chromatography gets intermediate 3.
(4) preparation of intermediate 4
Under the low temperature, 1 equivalent intermediate 3 is dissolved among polar solvent such as the DMF, adds 1.5 equivalent mineral alkali such as Cs
2CO
3, K
2CO
3With 1.2 when content of starting materials 4, monitoring reaction carries out, question response is poured in the frozen water after finishing, and separates out solid, filters, dry intermediate 4.
(5) preparation of intermediate 5
At appropriate solvent such as 1; in 4-dioxane or the toluene; add the palladium catalyst of 1 equivalent intermediate 4,2 equivalent duplex tetramethyl ethylene ketone boric acid esters, 2 equivalent alkali such as Potassium ethanoate and catalytic amount successively as [1; 1 '-two (diphenylphosphine) ferrocene] palladium chloride methylene dichloride complex compound; be reflected under the nitrogen protection heated and stirred a few hours; cool off intermediate 5, not treatedly be directly used in next step.
(6) preparation of formula (III) compound
In cooled step reaction solution (being intermediate 5), add 1 when content of starting materials 5, the palladium catalyst of catalytic amount and an amount of alkali such as 2N sodium carbonate solution.System reacting by heating a few hours under nitrogen protection, cool to room temperature filters, are dissolved in the methylene dichloride behind the organic layer concentrating under reduced pressure, and washing successively, saturated common salt washing, anhydrous sodium sulfate drying concentrates, and silica gel column chromatography obtains the formula III compound.
X in the above reaction equation
1, X
2, X
3, X
4, X
5, X
6, X
7, R
1, R
2, Cy
1, Cy
2, R
8, R
9, m, n, p, q and r be as described in arbitrary scheme of scheme 3 and preferred version thereof.
The pharmaceutical preparation that the present invention also provides formula (I) compound, its pharmacy acceptable salt or its isomer and one or more pharmaceutical carriers to make, this pharmaceutical preparation can be made clinically the conventional formulation that uses, can be oral or mode such as administered parenterally be applied to the patient who needs this treatment.As tablet, particle, capsule, powder, injection, inhalation, sublingual administration preparation, syrup, gel, ointment, suppository, lotion, nasal cavity drop, sprays, preparation capable of permeating skin etc.These preparations can pass through ordinary method, add pharmaceutical carrier such as vehicle, tamanori, moistening agent, disintegrating agent, thickening material etc. and are prepared from.
The present invention also provides formula (I) compound, its pharmacy acceptable salt or its isomer treat and/or prevent diabetes in preparation, fat, glucose does not tolerate, hyperglycemia, hypertension, hyperlipidemia, cognitive loss, dull-witted, glaucoma, cardiovascular disorder, osteoporosis, atherosclerosis, peripheral vascular disease, hyperlipemia, hyperlipoproteinemia, diabetes hyperlipemia, mixed dyslipidemia, hypercholesteremia, hypertriglyceridemia, insulin resistance, inflammation male sex hormone excess (hirsutism, menoxenia, hyperandrogenism), application in the medicine of polycystic ovary syndrome or metabolism syndrome.
The present invention also provides formula (I) compound, the pharmaceutical composition that its pharmacy acceptable salt or its isomer and one or more therapeutic active substance are made, described therapeutic active substance is selected from Regular Insulin and insulin analog, sulfonylurea, meals glucose conditioning agent, the PPAR gamma agonist, aldose reductase inhibitor, the Tyrosine O-phosphate phosphatase inhibitors, glucose 6-phosphatase inhibitors, the glucagon acceptor is picked up anti-dose, glucokinase activators, glycogen phosphorylase inhibitors, fructose 1,6 biphosphonate enzyme inhibitors, L-glutamic acid: fructose-6-phosphate esteramides transferase inhibitor, the HMG-CoA reductase inhibitor, the PPAR alfa agonists, bile acid chelating agent, cholesterol absorption inhibitor, the ileal bile acid absorption inhibitor, cholestery ester transfer protein inhibitors, nicotinic acid and analogue thereof, beta-blocker, ACE inhibitor, calcium is picked up anti-dose, angiotensin receptor is picked up anti-dose, α picks up anti-dose, aldosterone receptor is picked up anti-dose, diuretic(s), the agent of antithrombotic stroke, the fibrinolysis activator, anti-platelet agents, zymoplasm is picked up anti-dose, the Xa factor inhibitor, the VIIa factor inhibitors, dispersion stabilizer or antiphlogiston.
Below further set forth the beneficial effect of The compounds of this invention by the external pharmacologically active of part The compounds of this invention, cited part The compounds of this invention has identical beneficial effect in other compound of the present invention and the test, but this should be interpreted as that The compounds of this invention only has following beneficial effect.
Experimental example 1 The compounds of this invention is to the restraining effect of 11 β 3-HSD1 enzymes
Trial-product: The compounds of this invention 1-4, chemical name and structural formula are seen embodiment;
Experimental technique: Cortisol Kit
1. prepare the tris assay buffer solution of 333 μ M NADPH and 266nM Cortisone, every hole adds 6 μ l.
2. prepare certain density compound solution with DMSO, 10 gradients of four times of gradient dilutions, after one by one with 20 times of tris assay buffer dilutions, obtain the gradient soup of ultimate density, add 2 μ l in every hole.
3. the microsomal enzyme solution of preparation 1mg/ml adds 2 μ l in every hole.
4.37 ℃ hatched 2 hours.
5. add 5 μ l cortisol-d2 and 5 μ l anti-cortisol-cryptate in every hole.
6. incubated at room is 2 hours.
7. microplate reader 665nm/620nm reads plate.
8. adopt GraphPad Prism5 processing data, measure IC
50
Experimental result and conclusion:
The antibacterial activity in vitro of table 1 The compounds of this invention
By table 1 as seen, The compounds of this invention 1-4 has very high inhibition activity for 11 β-HSD1 enzyme.
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.
Embodiment 13 '-(1-(4-(1-methyl-2-oxo-1,2-dihydropyridine-4-yl) phenyl) ethyl)-3,4-dihydro-2H-spiral shell [naphthalene-1,6 '-[1,3] oxazines]-2 '-preparation (compound 1) of ketone
(1) preparation of 2-(1-hydroxyl-1,2,3,4-naphthane-1-yl) acetonitrile
Under-78 ℃, with the acetonitrile of drying (5.14g, 20mLTHF solution 125mmol) slowly be added drop-wise to the 2.5M butyllithium (50mL, 125mmol) with the 30mL tetrahydrofuran (THF) in, stir 0.5h in this temperature, be raised to-20 ℃ and stir 0.5h, be as cold as-78 ℃ again, with 3,4-dihydronaphthalene-1 (2H)-ketone (14.6g, 30mL THF solution 100mmol) slowly is added drop-wise in the system, muddiness occurs, is raised to-20 ℃ behind the stirring 15min and stirs 0.5h.Add saturated NH
4The cancellation of Cl solution, ethyl acetate extraction merges organic phase, washing, the saturated common salt washing, anhydrous sodium sulfate drying, silica gel column chromatography get yellow solid 11.4g, yield 60.9%.
(2) 1-(2-amino-ethyl)-1,2,3, the preparation of 4-naphthane-1-alcohol
Under 0 ℃, (62mL 124mmol) slowly is added drop-wise to 2-(1-hydroxyl-1 with 2.0M BH3.Me2S, 2,3,4-naphthane-1-yl) acetonitrile (7.82g, 41.8mmol) 30mL THF solution in, back flow reaction is 4 hours then, the cooling, add the methyl alcohol cancellation, ethyl acetate extraction merges organic phase, washing, the saturated common salt washing, anhydrous sodium sulfate drying is directly cast in the single step reaction.
(3) 3,4-dihydro-2H-spiral shell [naphthalene-1,6 '-[1,3] oxazines]-2 '-preparation of ketone
Under 0 ℃, with triphosgene (two (trichloromethyl) carbonic ether) (4.124g, 13.9mmol) and Et
3(11.8mL 85mmol) joins the 1-(2-amino-ethyl)-1,2,3 that the step obtains, the 50mL CH of 4-naphthane-1-alcohol to N
2Cl
2In the solution, continue reaction 2 hours then, add water cancellation, CH
2Cl
2Extraction merges organic phase, washing, and the saturated common salt washing, anhydrous sodium sulfate drying concentrates, and column chromatography gets product 3.2g, two step yields 35.2%.
(4) preparation of 1-bromo-4-(1-bromotrifluoromethane) benzene
In the dry reaction flask, take by weighing 1-(4-bromophenyl) ethanol (16g, 79.6mmol), add anhydrous diethyl ether 30mL, drip phosphorus tribromide (25.99g, diethyl ether solution 96mmol), room temperature reaction spends the night, concentrate frozen water cancellation, ethyl acetate extraction, concentrate, silica gel column chromatography gets yellow oil 10g, yield 47.6%.
(5) 3 '-(1-(4-bromophenyl) ethyl)-3,4-dihydro-2H-spiral shell [naphthalene-1,6 '-[1,3] oxazines]-2 '-preparation of ketone
With 3,4-dihydro-2H-spiral shell [naphthalene-1,6 '-[1,3] oxazines]-2 '-(2g 9.2mmol) is dissolved in 40mL DMF to ketone, adds Cs
2CO
3(6g, 18.4mmol), (3g 11.4mmol), reacted 48 hours 1-bromo-4-(1-bromotrifluoromethane) benzene, pour in the frozen water, ethyl acetate extraction, organic phase is through the saturated common salt water washing, anhydrous sodium sulfate drying, silica gel column chromatography get white solid 1.083g, yield 29.5%.
(6) preparation of 1-methyl-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) pyridine-2 (1H)-ketone
In the dry reaction flask; 1,4-dioxane (4mL) add successively 4-bromo-1-picoline-2 (1H)-ketone (226mg, 1.20mmol); duplex pinacol boric acid ester (457mg; 1.8mmol), (294mg is 3.0mmol) with [1 for Potassium ethanoate; 1 '-two (diphenylphosphine) ferrocene] palladium chloride methylene dichloride complex compound 16mg; under the nitrogen protection, 90 ℃ are stirred down and spend the night, and not treatedly after the cooling are directly used in next step.
(7) 3 '-(1-(4-(1-methyl-2-oxo-1,2-dihydropyridine-4-yl) phenyl) ethyl)-3,4-dihydro-2H-spiral shell [naphthalene-1,6 '-[1,3] oxazines]-2 '-preparation of ketone
In the previous step reaction solution of cooling, adding 3 '-(1-(4-bromophenyl) ethyl)-3,4-dihydro-2H-spiral shell [naphthalene-1,6 '-[1,3] oxazines]-2 '-ketone (320mg, 0.80mmol), four (triphenyl phosphorus) palladium 10mg, 2N aqueous sodium carbonate 1.8mL.System in 90 ℃ of reaction 6h, is cooled to room temperature under nitrogen protection, filter, and is dissolved in the methylene dichloride behind the organic layer concentrating under reduced pressure; water, saturated common salt water washing successively, anhydrous sodium sulfate drying concentrates; silica gel column chromatography gets white solid 302mg, yield 88.1%.
Molecular formula: C
27H
28N
2O
3Molecular weight: 428.52 mass spectrums (M+H): 429.2
1H-NMR(CDCl
3，400MHz)：δ7.62-7.57(2H，m)，7.55-7.40(3H，m)，7.36(1H，dd)，7.25-7.17(2H，m)，7.12-7.06(1H，m)，6.82(1H，t)，6.45(1H，dt)，5.99-5.90(1H，m)，3.59(3H，s)，3.40-3.31(1H，m)，2.96-2.70(3H，m)，2.30-1.89(5H，m)，1.85-1.70(1H，m)，1.65(3H，d).
Embodiment 23 '-(1-(4-(1-methyl-2-oxo-1,2-dihydropyridine-4-yl) phenyl) ethyl)-2,3-dihydro [indenes-1,6 '-[1,3] oxazines]-2 '-preparation (compound 2) of ketone
(1) preparation of 2-(1-hydroxyl-2,3-dihydro-1H-indenes-1-yl) acetonitrile
Under-78 ℃, in the dry there-necked flask, add the THF 50mL that heavily steams, N
2Protection, and the butyllithium of adding 2.5M (50mL, 125mmo1); stir 5min; (5.137g, THF solution 125mmol) keep-78 ℃ slowly to drip acetonitrile in the system; reaction 30min; be warming up to-20 ℃ and continue reaction 30min, be cooled to-78 ℃ subsequently, slowly drip 2; 3-dihydro-1H-1-Indanone (13.22g; THF solution 100mmol) keeps this thermotonus 15min, slowly rises to continue to stir 30min after the room temperature; the aqueous ammonium chloride solution cancellation; ethyl acetate extraction, organic phase is through saturated common salt water washing, anhydrous sodium sulfate drying; silica gel column chromatography gets yellow solid 12g, yield 69.3%.
(2) 1-(2-amino-ethyl)-2, the preparation of 3-dihydro-1H-indenes-1-alcohol
Under the ice-water bath, in the dry reaction flask, take by weighing 2-(1-hydroxyl-2,3-dihydro-1H-indenes-1-yl) (12g 69.3mmol), adds THF 50mL to acetonitrile, add the borine dimethyl sulphide tetrahydrofuran solution 69mL (138mmol) of 2M, room temperature reaction spends the night, the methyl alcohol cancellation, concentrate, add salt solution, ethyl acetate extraction, organic phase is through the saturated aqueous common salt water washing, anhydrous sodium sulfate drying is directly cast in the single step reaction.
(3) 2,3-dihydro spiral shells [indenes-1,6 '-[1,3] oxazines]-2 '-preparation of ketone
Under the ice-water bath, in the dry reaction flask, the 1-(2-amino-ethyl)-2 that the step obtains in the adding, 3-dihydro-1H-indenes-1-alcohol adds the dissolving of 100mL methylene dichloride, adds triphosgene (20.56g, 69.3mmol), drip under the equality of temperature triethylamine (29mL, 208mmol), dropwise the back and continue reaction 2h, filter, add water, dichloromethane extraction, organic phase is through saturated common salt water washing, anhydrous sodium sulfate drying, silica gel column chromatography gets white solid 9.3g, two step yields 66.1%.
(4) 3 '-(1-(4-bromophenyl) ethyl)-2,3-dihydro spiral shell [indenes-1,6 '-[1,3] oxazines]-2 '-preparation of ketone
In the dry reaction flask, take by weighing 2,3-dihydro spiral shell [indenes-1,6 '-[1,3] oxazines]-2 '-ketone (1.3g, 6.4mmol), add DMF30mL, (6.2g 19mmol), stirs 15min under the room temperature to cesium carbonate, go into 1-bromo-4-(1-bromotrifluoromethane) benzene (2.53g, 9.58mmol), reacted four days, filter, add water, ethyl acetate extraction, organic phase is through saturated common salt water washing, anhydrous sodium sulfate drying, silica gel column chromatography gets two diastereomers, the white solid 860mg that polarity is little, the white solid 852mg that polarity is big, two yields 69.2% that isomer is total.
(5) 3 '-(1-(4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl) ethyl)-2,3-dihydro spiral shell [indenes-1,6 '-[1,3] oxazines]-2 '-preparation of ketone
In the dry reaction flask; add successively 15mL dioxane, 3 '-(1-(4-bromophenyl) ethyl)-2; 3-dihydro spiral shell [indenes-1; 6 '-[1; 3] oxazines]-2 '-isomer (583mg that ketone polarity is little; 1.51mmol); duplex pinacol boric acid ester (571mg; 2.25mmol), (367mg is 3.74mmol) with [1 for Potassium ethanoate; 1 '-two (diphenylphosphine) ferrocene] palladium chloride methylene dichloride complex compound 20mg; under the nitrogen protection, 90 ℃ are stirred down and spend the night, and not treatedly after the cooling are directly used in next step.
For 3 '-(1-(4-bromophenyl) ethyl)-2,3-dihydro spiral shell [indenes-1,6 '-[1,3] oxazines]-2 '-isomer that ketone polarity is big handles with same working method.
(6) 3 '-(1-(4-(1-methyl-2-oxo-1,2-dihydropyridine-4-yl) phenyl) ethyl)-2,3-dihydro [indenes-1,6 '-[1,3] oxazines]-2 '-preparation of ketone
In the previous step reaction solution of cooling (corresponding to 3 '-(1-(4-bromophenyl) ethyl)-2,3-dihydro spiral shell [indenes-1,6 '-[1,3] oxazines]-2 '-isomer that ketone polarity is little), add 4-bromo-1-picoline-2 (1H)-ketone (423mg, 2.25mmol), tetrakis triphenylphosphine palladium 20mg, 2N aqueous sodium carbonate 3mL.System in 90 ℃ of reaction 6h, is cooled to room temperature under nitrogen protection, filter, and is dissolved in the methylene dichloride behind the organic layer concentrating under reduced pressure; water, saturated common salt water washing successively, anhydrous sodium sulfate drying concentrates; silica gel column chromatography gets white solid 450mg, two-step reaction yield 71.9%.
Molecular formula: C
26H
26N
2O
3Molecular weight: 414.50 mass spectrums (M+H): 415.2
The isomer of little polarity
1H-NMR (d
6-DMSO, 400MHz): δ 7.79-7.72 (3H, m), 7.46 (2H, d), 7.40-7.25 (4H, m), 6.69 (1H, d), 6.59 (1H, dd), 5.58 (1H, q), 3.44 (3H, s), 3.03-2.92 (1H, m), 2.92-2.78 (2H, m), 2.35-2.25 (1H, m), 2.15 (2H, t), 2.03-1.93 (2H, m), 1.58 (3H, d).
The isomer of big polarity
1H-NMR (d
6-DMSO, 400MHz): δ 7.79-7.72 (3H, m), 7.47 (2H, d), 7.33-7.28 (3H, m), 7.25-7.18 (1H, m), 6.69 (1H, d), 6.59 (1H, dd), 5.57 (1H, q), 3.50-3.40 (1H, m), 3.44 (3H, s), 3.06-2.94 (2H, m), and 2.92-2.81 (1H, m), 2.33-2.21 (3H, m), 2.00 (1H, dt), 1.59 (3H, d).
The preparation (compound 3) of embodiment 33 '-(1-(4-(1-methyl-2-oxo-1,2-dihydropyridine-4-yl) phenyl) ethyl) spiral shell [chroman-4,6 '-[1,3] oxazines]-2 '-ketone
(1) preparation of 2-(4-hydroxychroman-4-yl) acetonitrile
Under-78 ℃, in the dry there-necked flask, add the THF 20mL that heavily steams, N
2Protection; (19.2mL 48mmol), stirs 5min to the butyllithium of adding 2.5M; slowly drip acetonitrile (1.97g; THF solution 48mmol) keeps-78 ℃, reaction 30min; be warming up to-20 ℃ and continue reaction 30min; be cooled to-78 ℃ subsequently, slowly drip chroman-4-on-(5.92g, THF solution 40mmol); keep this thermotonus 15min; continue to stir 30min, aqueous ammonium chloride solution cancellation, ethyl acetate extraction after slowly rising to room temperature; organic phase is through the saturated common salt water washing; anhydrous sodium sulfate drying, silica gel column chromatography get yellow solid 3.4g, yield 45.1%.
(2) preparation of 4-(2-amino-ethyl) chroman-4-alcohol
Under the ice-water bath, in the dry reaction flask, take by weighing 2-(4-hydroxychroman-4-yl) acetonitrile (3.4g, 18mmol), add THF20mL, add the borine dimethyl sulphide tetrahydrofuran solution (27mL of 2M, 54mmol), room temperature reaction spends the night, the methyl alcohol cancellation, concentrate, add salt solution, ethyl acetate extraction, organic phase is through the saturated aqueous common salt water washing, anhydrous sodium sulfate drying is directly cast in the single step reaction.
(3) spiral shell [chroman-4,6 '-[1,3] oxazines]-2 '-preparation of ketone
Under the ice-water bath, in the dry reaction flask, add 4-(2-amino-ethyl) chroman-4-alcohol crude product, add the dissolving of 20mL methylene dichloride, and the adding triphosgene (1.78g, 6.0mmol), (5.0mL 36mmol), dropwises the back and continues reaction 2h to drip triethylamine under the equality of temperature, filter, add water dichloromethane extraction, organic phase is through the saturated common salt water washing, anhydrous sodium sulfate drying, silica gel column chromatography get white solid 1.6g, two step yields 40.6%.
(4) 3 '-(1-(4-bromophenyl) ethyl) spiral shell [chroman-4,6 '-[1,3] oxazines]-2 '-preparation of ketone
In the dry reaction flask, take by weighing spiral shell [chroman-4,6 '-[1,3] oxazines]-2 '-ketone (1.38g, 6.3mmol), add DMF 30mL, cesium carbonate (5.13g, 15.7mmol), stir 15min under the room temperature, and adding 1-bromo-4-(1-bromotrifluoromethane) benzene (2.98g, 11.3mmol), reaction 48h, filter, add water ethyl acetate extraction, organic phase is through the saturated common salt water washing, anhydrous sodium sulfate drying, silica gel column chromatography get two chiral isomers, the white solid 800mg that polarity is little, the white solid 880mg that polarity is big, two yields 66.3% that isomer is total.
(5) 3 '-(1-(4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl) ethyl) spiral shell [chroman-4,6 '-[1,3] oxazines]-2 '-preparation of ketone
In the dry reaction flask, add 3 successively '-(1-(4-bromophenyl) ethyl) spiral shell [chroman-4,6 '-[1; 3] oxazines]-2 '-isomer (428mg that ketone polarity is little; 1.06mmol), duplex pinacol boric acid ester (381mg, 1.5mmol); Potassium ethanoate (245mg; 2.5mmol) and [1,1 '-two (diphenylphosphine) ferrocene] palladium chloride complex compound 20mg, under the nitrogen protection; 90 ℃ are stirred down and spend the night, and not treatedly after the cooling are directly used in next step.
For 3 '-(1-(4-bromophenyl) ethyl) spiral shell [chroman-4,6 '-[1,3] oxazines]-2 '-isomer that ketone polarity is big handles with same working method.
(6) 3 '-(1-(4-(1-methyl-2-oxo-1,2-dihydropyridine-4-yl) phenyl) ethyl) spiral shell [chroman-4,6 '-[1,3] oxazines]-2 '-preparation of ketone
In the previous step reaction solution of cooling, and adding 4-bromo-1-picoline-2 (1H)-ketone (470mg, 2.5mmol), four (triphenyl phosphorus) palladium 20mg, 2N aqueous sodium carbonate 3mL.System in 90 ℃ of reaction 6h, is cooled to room temperature under nitrogen protection, filter, and is dissolved in the methylene dichloride behind the organic layer concentrating under reduced pressure; water, saturated common salt water washing successively, anhydrous sodium sulfate drying concentrates; silica gel column chromatography gets white solid 312mg, two-step reaction yield 68.4%.
Molecular formula: C
26H
26N
2O
4Molecular weight: 430.50 mass spectrums (M+H): 431.2
The isomer of little polarity
1H-NMR (CDCl
3, 400MHz): δ 7.60 (2H, d), 7.47 (2H, d), 7.39 (1H, dd), 7.36 (1H, d), 7.23 (1H, td), 6.97 (1H, td), 6.84 (1H, dd), 6.81 (1H, d), 6.44 (1H, m), 5.91 (1H, q), 4.38-4.29 (1H, m), 4.23-4.15 (1H, m), 3.60 (3H, s), 3.21 (1H, ddd), 2.92-2.82 (1H, m), 2.47 (1H, ddd), 2.27 (1H, ddd), 2.06-1.91 (2H, m), 1.67 (3H, d).
The isomer of big polarity
1H-NMR (CDCl
3, 400MHz): δ 7.60 (2H, d), 7.51 (2H, d), 7.38-7.34 (2H, m), 7.22 (1H, td), 6.93 (1H, td), 6.85 (1H, dd), 6.82 (1H, d), 6.45 (1H, m), 5.95 (1H, q), and 4.42-4.33 (1H, m), 4.29-4.20 (1H, m), 3.60 (3H, s), 3.43-3.34 (1H, m), 3.00 (1H, ddd), 2.44-2.33 (2H, m), 2.15 (1H, ddd), 1.97 (1H, ddd) 1.65 (3H, d).
Embodiment 42,2-dimethyl-3 '-(1-(4-(1-methyl-2-oxo-1,2-dihydropyridine-4-yl) phenyl) ethyl) spiral shell [chroman-4,6 '-[1,3] oxazines]-2 '-preparation (compound 4) of ketone
(1) preparation of 2-(4-hydroxyl-2,2-dimethylchroman-4-yl) acetonitrile
Under-78 ℃, in the dry there-necked flask, add the THF 20mL that heavily steams, N
2Protection, and the butyllithium of adding 2.5M (23mL, 57.5mmol); stir 5min; (2.36g, THF solution 57.5mmol) keep-78 ℃ slowly to drip acetonitrile; reaction 30min; be warming up to-20 ℃ and continue reaction 30min, be cooled to-78 ℃ subsequently, slowly drip 2; 2-dimethylchroman-4-ketone (8g; 45.4mmol) THF solution, keep this thermotonus 15min, slowly rise to and continue to stir 30min after the room temperature; the aqueous ammonium chloride solution cancellation; ethyl acetate extraction, organic phase is through saturated common salt water washing, anhydrous sodium sulfate drying; silica gel column chromatography gets yellow solid 5.86g, yield 59.4%.
(2) 4-(2-amino-ethyl)-2, the preparation of 2-dimethylchroman-4-alcohol
Under the ice-water bath, in the dry reaction flask, take by weighing 2-(4-hydroxyl-2,2-dimethylchroman-4-yl) (5.86g 27mmol), adds THF 20mL to acetonitrile, the borine dimethyl sulphide tetrahydrofuran solution of adding 2M (33mL, 66mmol), room temperature reaction spends the night, the methyl alcohol cancellation concentrates, and adds salt solution, ethyl acetate extraction, organic phase is through the saturated aqueous common salt water washing, and anhydrous sodium sulfate drying is directly cast in the single step reaction.
(3) 2,2-dimethyl spiral shells [chroman-4,6 '-[1,3] oxazines]-2 '-preparation of ketone
Under the ice-water bath, in the dry reaction flask, add 4-(2-amino-ethyl)-2,2-dimethylchroman-4-alcohol crude product adds the dissolving of 20mL methylene dichloride, adds triphosgene (2.67g, 9.0mmol), drip under the equality of temperature triethylamine (11.3mL, 81mmol), dropwise the back and continue reaction 2h, filter, add water, dichloromethane extraction, organic phase is through saturated common salt water washing, anhydrous sodium sulfate drying, silica gel column chromatography gets white solid 4.21g, two step yields 63.0%.
(4) 3 '-(1-(4-bromophenyl) ethyl)-2,2-dimethyl spiral shell [chroman-4,6 '-[1,3] oxazines]-2 '-preparation of ketone
In the dry reaction flask, take by weighing 2,2-dimethyl spiral shell [chroman-4,6 '-[1,3] oxazines]-2 '-(1.7g 6.87mmol), adds DMF 20mL, cesium carbonate (6.72g to ketone, 20.65mmol), stir 15min under the room temperature, add 1-bromo-4-(1-bromotrifluoromethane) benzene (3.63g, 13.75mmol), reaction 48h filters, add water, ethyl acetate extraction, organic phase is through the saturated common salt water washing, anhydrous sodium sulfate drying, silica gel column chromatography get white solid 1.5g, yield 50.7%.
(5) 2,2-dimethyl-3 '-(1-(4-(4,4,5,5-tetramethyl--1,3,2-dioxo bora pentamethylene-2-yl) phenyl) ethyl) spiral shell [chroman-4,6 '-[1,3] oxazines]-2 '-preparation of ketone
In the dry reaction flask; the 30mL dioxane is solvent; add 3 successively '-(1-(4-bromophenyl) ethyl)-2; 2-dimethyl spiral shell [chroman-4; 6 '-[1; 3] oxazines]-2 '-ketone (740mg, 1.72mmol), duplex pinacol boric acid ester (655mg; 2.58mmol); Potassium ethanoate (421mg, 4.29mmol) and [1,1 '-two (diphenylphosphine) ferrocene] palladium chloride methylene dichloride complex compound (20mg; 0.02mmol); under the nitrogen protection, 90 ℃ are stirred down and spend the night, and not treatedly after the cooling are directly used in next step.
(6) 2,2-dimethyl-3 '-(1-(4-(1-methyl-2-oxo-1,2-dihydropyridine-4-yl) phenyl) ethyl) spiral shell [chroman-4,6 '-[1,3] oxazines]-2 '-preparation of ketone
In the previous step reaction solution of cooling, and adding 4-bromo-1-picoline-2 (1H)-ketone (485mg, 2.58mmol), four (triphenyl phosphorus) palladium (20mg, 0.2mmol), 2N aqueous sodium carbonate 3mL.System in 90 ℃ of reaction 6h, is cooled to room temperature under nitrogen protection, filter, and is dissolved in the methylene dichloride behind the organic layer concentrating under reduced pressure; water, saturated common salt water washing successively, anhydrous sodium sulfate drying concentrates; silica gel column chromatography gets white solid 513mg, two-step reaction yield 61.4.0%.
Molecular formula: C
28H
30N
2O
4Molecular weight: 458.55 mass spectrums (M+H): 459.3
1H-NMR(CDCl
3，400MHz)：7.80-7.71(3H，m)，7.56-7.43(3H，m)，7.23(1H，t)，6.98-6.92(1H，m)，6.79(1H，td)，6.69(1H，dd)，6.61-6.56(1H，m)，5.56(1H，q)，3.44(3H，s)，3.28-3.18(1H，m)，2.99，2.79(1H，two?m)，2.40(1H，ddd)，2.30，2.13(1H，two?d)，2.03-1.80(2H，m)，1.60，1.57(3H，two?d)，1.34-1.25(6H，m)。
Claims (14)
1. the compound shown in the general formula (I), its pharmacy acceptable salt, and isomer,
Wherein, X
1Be C (O), S (O)
wOr C (=NR
5), w is 0,1 or 2, R
5Be cyano group, hydroxyl, C
1-6Alkyl, C
3-8Cycloalkyl, C
2-6Thiazolinyl, C
5-8Cycloalkenyl group, C
2-6Alkynyl, C
1-6Alkoxyl group or C
3-8Cycloalkyloxy, described C
1-6Alkyl, C
3-8Cycloalkyl, C
2-6Thiazolinyl, C
5-8Cycloalkenyl group, C
2-6Alkynyl, C
1-6Alkoxyl group and C
3-8Cycloalkyloxy can be chosen wantonly by 1-6 and be independently selected from following substituting group replacement: halogen atom, cyano group, hydroxyl, carboxyl and amino;
X
2Be O, S, N (R
4a) or C (R
4a) (R
4b), R
4aAnd R
4bBe hydrogen atom, C independently respectively
1-6Alkyl, halo C
1-6Alkyl, C
3-8Cycloalkyl, C
2-6Thiazolinyl, C
5-8Cycloalkenyl group or C
2-6Alkynyl;
R
1Be hydrogen, C
1-6Alkyl, C
3-8Cycloalkyl, C
2-6Thiazolinyl, C
5-8Cycloalkenyl group, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkylthio, C
1-6Alkyl-carbonyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6Carbalkoxy, C
1-6Alkyl carbonyl oxy, 6-14 unit aryl, 5-14 unit's heteroaryl or 3-14 unit heterocyclic radical, described C
1-6Alkyl, C
3-8Cycloalkyl, C
2-6Thiazolinyl, C
5-8Cycloalkenyl group, C
2-6Alkynyl and C
1-6Alkoxyl group can be chosen wantonly by 1-6 and be independently selected from following substituting group replacement: halogen atom, cyano group, hydroxyl, carboxyl, amino, halo C
1-6Alkyl, oxo, R
3-, R
3O-, (R
3)
2N-, R
3O (O) C-, R
3C (O) O-, R
3S (O)
2O-, R
3S (O)
2-, R
3C (O) N (R
3)-, (R
3)
2NC (O)-, (R
3)
2NC (O) O-, (R
3)
2NC (O) N (R
3)-, R
3OC (O) N (R
3)-, (R
3)
2NC (NCN) N (R
3)-, (R
3O)
2P (O) O-, (R
3O)
2P (O) N (R
3)-, R
3OS (O)
2N (R
3)-, (R
3)
2NS (O)
2O-, (R
3)
2NS (O)
2N (R
3)-, R
3S (O)
2N (R
3)-, R
3S (O)
2N (R
3) C (O)-, R
3S (O)
2N (R
3) C (O) O-, R
3S (O)
2N (R
3) C (O) N (R
3)-, R
3OS (O)
2N (R
3) C (O)-, R
3OS (O)
2N (R
3) C (O) O-, R
3OS (O)
2N (R
3) C (O) N (R
3)-, (R
3)
2NS (O)
2N (R
3) C (O)-, (R
3)
2NS (O)
2N (R
3) C (O) O-, (R
3)
2NS (O)
2N (R
3) C (O) N (R
3)-, R
3C (O) N (R
3) S (O)
2-, R
3C (O) N (R
3) S (O)
2O-, R
3C (O) N (R
3) S (O)
2N (R
3)-, R
3OC (O) N (R
3) S (O)
2-, R
3OC (O) N (R
3) S (O)
2O-, R
3OC (O) N (R
3) S (O)
2N (R
3)-, (R
3)
2NC (O) N (R
3) S (O)
2-, (R
3)
2NC (O) N (R
3) S (O)
2O-, (R
3)
2NC (O) N (R
3) S (O)
2N (R
3The first aryl of 6-14)-,, 5-14 unit's heteroaryl or 3-14 unit heterocyclic radical;
R
2For do not exist, C
1-6Alkyl, halo C
1-6Alkyl or oxo;
R
3Be hydrogen, C
1-6Alkyl, amino C
1-6Alkyl, halo C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group or C
3-6Alkoxy C
1-6Alkyl;
A
1Be key, C
1-6Alkyl, C
1-6Alkoxyl group, C
2-6Thiazolinyl, C
2-6Alkynyl or C
1-6Alkyl-carbonyl;
A
2Be key, O, S (O)
w, N (R
3), C
1-6Alkyl or C
1-6Alkoxyl group, w are 0,1 or 2, described C
1-6Alkyl and C
1-6Alkoxyl group can be chosen wantonly by 1-4 and be independently selected from following substituting group replacement: methyl, ethyl, trifluoromethyl or oxo;
Cy
1Be 6-14 unit aryl, 5-14 unit heteroaryl, C
3-8Cycloalkyl or 3-14 unit heterocyclic radical, the first aryl of described 6-14,5-14 unit heteroaryl, C
3-8Cycloalkyl and 3-14 unit heterocyclic radical can be chosen wantonly by 1-4 substituting group that is independently selected from R ' and replace;
Cy
2Be hydrogen, 6-14 unit aryl, 5-14 unit heteroaryl, C
3-8Cycloalkyl or 3-14 unit heterocyclic radical, the first aryl of described 6-14,5-14 unit heteroaryl, C
3-8Cycloalkyl and 3-14 unit heterocyclic radical can be chosen wantonly by 1-4 substituting group that is independently selected from R ' and replace;
R ' is halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, oxo, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, hydroxyl C
3-6Cycloalkyl, halo C
3-6Cycloalkyl, C
4-8Cycloalkyl C
1-6Alkyl, halo C
4-8Cycloalkyl C
1-6Alkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl, halo C
2-6Thiazolinyl, hydroxyl C
2-6Thiazolinyl, C
5-8Cycloalkenyl group, C
2-6Alkynyl, C
3-6Cycloalkyloxy group C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-6Cycloalkylthio, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Alkyl amine group formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, C
1-6Alkylsulfonamido, two (C
1-6Alkyl) amido formyl radical, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy;
Cy
3Be 6-14 unit fractional saturation aryl, C
3-8Cycloalkyl, C
5-8Cycloalkenyl group, 3-14 unit heterocyclic radical, the first fractional saturation aryl of described 6-14, C
3-8Cycloalkyl, C
5-8Cycloalkenyl group and 3-14 unit heterocyclic radical can be chosen wantonly by 1-4 and be independently selected from R
8Substituting group replace R
8Be hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, hydroxyl C
3-6Cycloalkyl, halo C
3-6Cycloalkyl, C
4-8Cycloalkyl C
1-6Alkyl, halo C
4-8Cycloalkyl C
1-6Alkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl, halo C
2-6Thiazolinyl, hydroxyl C
2-6Thiazolinyl, C
5-8Cycloalkenyl group, C
2-6Alkynyl, C
3-6Cycloalkyloxy group C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-6Cycloalkylthio, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy;
R
6aAnd R
6bRepresent hydrogen atom, halogen atom, hydroxyl, cyano group, carboxyl, C respectively
1-6Alkyl, C
3-8Cycloalkyl, halo C
1-6Alkyl, halo C
1-6Alkoxyl group, oxo, 6-14 unit aryl, 5-14 unit heteroaryl, the heterocyclic radical of 3-14 unit, R
7aO-, R
7aOC (O)-, R
7bC (O)-, R
7bC (O) NH-, R
7cS (O)-, R
7cS (O)
2-, R
7cS (O)
2NH-, R
7d(OR
7a) CH-, R
7dS-, (R
7eR
7f) N-, (R
7eR
7f) NC (O)-, the aryl-OCH of aryl-O-, 6-14 unit of 6-14 unit
2-, the aryl-S (O) of 6-14 unit
2Aryl-the S (O) of NH-, 6-14 unit
2-,
Or R
6aAnd R
6bInterconnect the Cy that is connected with them
3On atom form 3-14 unit cyclic group, this cyclic group and Cy together
3With and ring, volution, bridged ring form condense, described 3-14 unit cyclic group contains 0-4 and is selected from C (O), N, O, S, SO and/or SO
2Atom, and can further be independently selected from R by 1-4
9Substituting group replace R
9Be hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, hydroxyl C
3-6Cycloalkyl, halo C
3-6Cycloalkyl, C
4-8Cycloalkyl C
1-6Alkyl, halo C
4-8Cycloalkyl C
1-6Alkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl, halo C
2-6Thiazolinyl, hydroxyl C
2-6Thiazolinyl, C
5-8Cycloalkenyl group, C
2-6Alkynyl, C
3-6Cycloalkyloxy group C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-6Cycloalkylthio, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy;
R
7a, R
7b, R
7c, R
7d, R
7e, R
7fBe respectively hydrogen atom, C
1-6Alkyl, C
3-8Cycloalkyl, or R
7eAnd R
7fThe N that connects with them forms and contains 1-4 and be selected from C (O), N, O, S, SO and/or SO
23-14 unit heterocyclic radical;
M is 0,1 or 2;
N is 0,1,2,3 or 4.
2. the described compound of claim 1, its pharmacy acceptable salt, and isomer,
Wherein, X
1, X
2, R
1, R
2, A
1, A
2, Cy
1, Cy
2, Cy
3, m, n according to claim 1;
R
6aAnd R
6bInterconnect the Cy that is connected with them
3On atom form 3-14 unit cyclic group, this cyclic group and Cy together
3Condense with the volution form, the first cyclic group of described 3-14 contains 0-4 and is selected from C (O), N, O, S, SO and/or SO
2Atom, and can further be independently selected from R by 1-4
9Substituting group replace R
9Be hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, hydroxyl C
3-6Cycloalkyl, halo C
3-6Cycloalkyl, C
4-8Cycloalkyl C
1-6Alkyl, halo C
4-8Cycloalkyl C
1-6Alkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl, halo C
2-6Thiazolinyl, hydroxyl C
2-6Thiazolinyl, C
5-8Cycloalkenyl group, C
2-6Alkynyl, C
3-6Cycloalkyloxy group C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-6Cycloalkylthio, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy.
3. the described compound of claim 1, its pharmacy acceptable salt, and isomer,
Wherein, X
1, X
2, R
1, R
2, A
1, A
2, Cy
1, Cy
2, Cy
3, m, n according to claim 1;
R
6aAnd R
6bInterconnect the Cy that is connected with them
3On atom form 3-14 unit cyclic group, this cyclic group and Cy together
3Condense with the bridged ring form, the first cyclic group of described 3-14 contains 0-4 and is selected from C (O), N, O, S, SO and/or SO
2Atom, and can further be independently selected from R by 1-4
9Substituting group replace R
9Be hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, hydroxyl C
3-6Cycloalkyl, halo C
3-6Cycloalkyl, C
4-8Cycloalkyl C
1-6Alkyl, halo C
4-8Cycloalkyl C
1-6Alkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl, halo C
2-6Thiazolinyl, hydroxyl C
2-6Thiazolinyl, C
5-8Cycloalkenyl group, C
2-6Alkynyl, C
3-6Cycloalkyloxy group C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-6Cycloalkylthio, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy.
4. the described compound of claim 1, its pharmacy acceptable salt, and isomer,
Wherein, X
1, X
2, R
1, R
2, A
1, A
2, Cy
1, Cy
2, Cy
3, m, n according to claim 1;
R
6aAnd R
6bInterconnect the Cy that is connected with them
3On atom form 3-14 unit cyclic group, this cyclic group and Cy together
3With and loop type condense, described 3-14 unit cyclic group contains 0-4 and is selected from C (O), N, O, S, SO and/or SO
2Atom, and can further be independently selected from R by 1-4
9Substituting group replace R
9Be hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, hydroxyl C
3-6Cycloalkyl, halo C
3-6Cycloalkyl, C
4-8Cycloalkyl C
1-6Alkyl, halo C
4-8Cycloalkyl C
1-6Alkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl, halo C
2-6Thiazolinyl, hydroxyl C
2-6Thiazolinyl, C
5-8Cycloalkenyl group, C
2-6Alkynyl, C
3-6Cycloalkyloxy group C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-6Cycloalkylthio, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy.
5. the compound shown in the general formula (II), its pharmacy acceptable salt, and isomer,
Wherein, X
1, X
2, R
1, R
2, A
1, A
2, Cy
1, Cy
2, Cy
3, R
8, R
9, m, n according to claim 1;
Cy
4Represent 6-14 unit aryl, 5-14 unit heteroaryl, C
3-8The heterocyclic radical of cycloalkyl or 3-14 unit is with Cy
3With and loop type condense R
9Be halogen atom, hydroxyl, C
1-6Alkyl or C
1-6Alkoxyl group;
R is 0,1,2,3 or 4;
Q is 0,1,2,3 or 4.
6. the compound shown in the general formula (III), its pharmacy acceptable salt, and isomer,
Wherein, X
1, X
2, R
1, R
2, Cy
1, Cy
2, R
8, R
9, m, n according to claim 1;
X
3Be O, S (O)
w, N (R
4a) or C (R
4a) (R
4b), w is 0,1 or 2, R
4aAnd R
4bBe hydrogen atom, C independently respectively
1-6Alkyl, halo C
1-6Alkyl, C
3-8Cycloalkyl, C
2-6Thiazolinyl, C
5-8Cycloalkenyl group or C
2-6Alkynyl;
X
4, X
5, X
6, X
7Be respectively CH or N;
R is 0,1,2,3 or 4;
P is 0,1 or 2.
Q is 0,1,2 or 3.
7. compound as claimed in claim 6, its pharmacy acceptable salt, and isomer,
X
1Be C (O), S (O)
wOr C (=NR
5), w is 0,1 or 2, R
5Be cyano group, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, described C
1-6Alkyl, C
1-6Alkoxyl group can be chosen wantonly by 1-4 and be independently selected from following substituting group replacement: halogen atom, cyano group, hydroxyl, carboxyl and amino;
X
2Be O, S or N (R
4a), R
4aBe hydrogen atom, C
1-6Alkyl, halo C
1-6Alkyl;
X
3Be O, S (O)
w, N (R
4a) or C (R
4a) (R
4b), w is 0,1 or 2, R
4aAnd R
4bBe hydrogen atom, C independently respectively
1-6Alkyl, halo C
1-6Alkyl;
X
4, X
5, X
6, X
7Be respectively CH or N;
R
1Be hydrogen, C
1-6Alkyl, C
3-8Cycloalkyl, C
2-6Thiazolinyl, C
5-8Cycloalkenyl group, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Carbalkoxy, C
1-6Alkyl carbonyl oxy or phenyl;
R
2For do not exist, C
1-4Alkyl, halo C
1-4Alkyl or oxo;
Cy
1Be 6-10 unit aryl, the single heterocyclic radical of the 5-8 single heteroaryl of unit or 3-8 unit, the first aryl of described 6-10, the single heterocyclic radical of the 5-8 single heteroaryl of unit and 3-8 unit can be chosen wantonly by 1-4 substituting group that is independently selected from R ' and replace;
Cy
2Be 6-10 unit aryl, the single heterocyclic radical of the 5-8 single heteroaryl of unit or 3-8 unit, the first aryl of described 6-10, the single heterocyclic radical of the 5-8 single heteroaryl of unit and 3-8 unit can be chosen wantonly by 1-4 substituting group that is independently selected from R ' and replace;
R ' is halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, oxo, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, halo C
3-6Cycloalkyl, C
4-8Cycloalkyl C
1-6Alkyl, halo C
4-8Cycloalkyl C
1-6Alkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, halo C
1-6Alkoxyl group, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy;
R
8Be hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, hydroxyl C
3-6Cycloalkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, halo C
1-6Alkoxyl group, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy;
R
9Be hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, hydroxyl C
3-6Cycloalkyl, halo C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, halo C
1-6Alkoxyl group, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy;
M is 0,1 or 2; N is 0,1,2,3 or 4;
R is 0,1 or 2; P is 0,1,2,3 or 4; Q is 0,1,2 or 3.
8. compound as claimed in claim 7, its pharmacy acceptable salt, and isomer,
X
1Be C (O), S (O)
wOr C (=NR
5), w is 0,1 or 2, R
5Be cyano group, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group;
X
2Be O, S or N (R
4a), R
4aBe hydrogen atom or C
1-6Alkyl;
X
3Be O, S, N (R
4a) or C (R
4a) (R
4b), R
4aAnd R
4bBe hydrogen atom or C independently respectively
1-4Alkyl;
X
4, X
5, X
6, X
7Be respectively CH or N;
R
1Be hydrogen, C
1-4Alkyl or C
3-6Cycloalkyl;
R
2For not existing or C
1-4Alkyl;
Cy
1Be 6-10 unit aryl, the first aryl of described 6-10 can be chosen wantonly by 1-4 substituting group that is independently selected from R ' and replace;
Cy
2Be the single heterocyclic radical of 3-8 unit, the single heterocyclic radical of described 3-8 unit can be chosen wantonly by 1-4 substituting group that is independently selected from R ' and replace;
R ' is halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, oxo, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, halo C
1-6Alkyl, C
2-6Thiazolinyl, halo C
1-6Alkoxyl group, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy;
R
8Be hydrogen or C
1-4Alkyl;
R
9Be hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, halo C
1-6Alkyl, halo C
1-6Alkoxyl group, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Alkyl amine group formyl radical, two (C
1-6Alkyl) amido formyl radical, C
1-6Alkylamidoalkyl, C
1-6Alkyl sulphonyl, C
1-6Alkyl amine group alkylsulfonyl, two (C
1-6Alkyl) amido alkylsulfonyl, C
1-6Alkylsulfonamido, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy;
M is 0,1 or 2; N is 0,1 or 2;
R is 0,1 or 2; P is 0,1 or 2; Q is 0,1 or 2.
9. compound as claimed in claim 8, its pharmacy acceptable salt, and isomer,
X
1Be C (O) or S (O)
2
X
2Be O;
X
3Be O, S, N (R
4a) or C (R
4a) (R
4b), R
4aAnd R
4bBe hydrogen atom or C independently respectively
1-4Alkyl;
X
4, X
5, X
6, X
7Be respectively CH or N;
R
1Be hydrogen, C
1-4Alkyl or C
3-6Cycloalkyl;
R
2For not existing;
Cy
1Be phenyl, described phenyl can be chosen wantonly by 1-4 substituting group that is independently selected from R ' and replace;
Cy
2Be the single heterocyclic radical of 5-7 unit, the single heterocyclic radical of described 5-7 unit can be chosen wantonly by 1-4 substituting group that is independently selected from R ' and replace;
R ' is halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, oxo, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkyl, halo C
1-6Alkoxyl group, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy;
R
8Be hydrogen or C
1-4Alkyl;
R
9Be hydrogen, halogen atom, cyano group, nitro, hydroxyl, carboxyl, amino, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
3-6Cycloalkyl, C
1-6Alkoxyl group, halo C
1-6Alkyl, halo C
1-6Alkoxyl group, C
1-6Alkyl amine group, two (C
1-6Alkyl) amido, C
1-6Alkyl-carbonyl, formamyl, amino-sulfonyl, C
1-6Carbalkoxy or C
1-6Alkyl carbonyl oxy;
N is 0 or 1;
R is 0,1 or 2; P is 0,1 or 2; Q is 0,1 or 2.
10. compound as claimed in claim 9, its pharmacy acceptable salt, and isomer,
X
1Be C (O);
X
2Be O;
X
3Be O or CH
2
X
4, X
5, X
6, X
7Be CH;
R
1Be hydrogen, C
1-4Alkyl or C
3-6Cycloalkyl;
R
2For not existing;
Cy
1Be phenyl, described phenyl can be chosen wantonly by 1 or 2 substituting group that is independently selected from R ' and replace;
Cy
2For containing the single heterocyclic radical of 5-6 unit of a N atom at least, the described single heterocyclic radical of 5-6 unit that contains a N atom at least can be chosen wantonly by 1 or 2 substituting group that is independently selected from R ' and replace;
R ' is halogen atom, hydroxyl, amino, oxo, C
1-4Alkyl, C
1-4Alkoxyl group or halo C
1-4Alkyl;
R
8Be hydrogen or C
1-4Alkyl;
R
9Be hydrogen, halogen atom or C
1-6Alkyl;
N is 0 or 1;
R is 0,1 or 2; P is 0,1 or 2; Q is 0,1 or 2.
11. compound as claimed in claim 10, its pharmacy acceptable salt, and isomer,
12. contain the pharmaceutical preparation of each described compound of claim 1-11, its pharmacy acceptable salt or its isomer, it is characterized in that comprising one or more pharmaceutical carriers.
13. each described compound of claim 1-11, its pharmacy acceptable salt or its isomer treat and/or prevent diabetes in preparation, fat, glucose does not tolerate, hyperglycemia, hypertension, hyperlipidemia, cognitive loss, dull-witted, glaucoma, cardiovascular disorder, osteoporosis, atherosclerosis, peripheral vascular disease, hyperlipemia, hyperlipoproteinemia, diabetes hyperlipemia, mixed dyslipidemia, hypercholesteremia, hypertriglyceridemia, insulin resistance, application in the medicine of inflammation male sex hormone excess polycystic ovary syndrome or metabolism syndrome.
14. pharmaceutical composition, it is characterized in that comprising each described compound of claim 1-11, its pharmacy acceptable salt or its isomer and one or more therapeutic active substance, described therapeutic active substance is selected from Regular Insulin and insulin analog, sulfonylurea, meals glucose conditioning agent, the PPAR gamma agonist, aldose reductase inhibitor, the Tyrosine O-phosphate phosphatase inhibitors, glucose 6-phosphatase inhibitors, the glucagon acceptor is picked up anti-dose, glucokinase activators, glycogen phosphorylase inhibitors, fructose 1,6 biphosphonate enzyme inhibitors, L-glutamic acid: fructose-6-phosphate esteramides transferase inhibitor, the HMG-CoA reductase inhibitor, the PPAR alfa agonists, bile acid chelating agent, cholesterol absorption inhibitor, the ileal bile acid absorption inhibitor, cholestery ester transfer protein inhibitors, nicotinic acid and analogue thereof, beta-blocker, ACE inhibitor, calcium is picked up anti-dose, angiotensin receptor is picked up anti-dose, α picks up anti-dose, aldosterone receptor is picked up anti-dose, diuretic(s), the agent of antithrombotic stroke, the fibrinolysis activator, anti-platelet agents, zymoplasm is picked up anti-dose, the Xa factor inhibitor, the VIIa factor inhibitors, dispersion stabilizer or antiphlogiston.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001045704A1 (en) * | 1999-12-21 | 2001-06-28 | Merck & Co., Inc. | Inhibitors of prenyl-protein transferase |
| WO2008007210A2 (en) * | 2006-07-11 | 2008-01-17 | Universita' Di Pisa | Nitrogenous n-substituted 4-spiro-heterocyclic 2, 2 -dimethylchromane derivatives |
| WO2009134400A1 (en) * | 2008-05-01 | 2009-11-05 | Vitae Pharmaceuticals, Inc. | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
| WO2010010157A2 (en) * | 2008-07-25 | 2010-01-28 | Boehringer Ingelheim International Gmbh | INHIBITORS OF 11beta-HYDROXYSTEROID DEHYDROGENASE 1 |
| CN102105454A (en) * | 2008-07-25 | 2011-06-22 | 贝林格尔.英格海姆国际有限公司 | Synthesis of inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 |
| CN102421773A (en) * | 2008-07-25 | 2012-04-18 | 贝林格尔·英格海姆国际有限公司 | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
-
2012
- 2012-01-19 CN CN201210017147.2A patent/CN103342700B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001045704A1 (en) * | 1999-12-21 | 2001-06-28 | Merck & Co., Inc. | Inhibitors of prenyl-protein transferase |
| WO2008007210A2 (en) * | 2006-07-11 | 2008-01-17 | Universita' Di Pisa | Nitrogenous n-substituted 4-spiro-heterocyclic 2, 2 -dimethylchromane derivatives |
| WO2009134400A1 (en) * | 2008-05-01 | 2009-11-05 | Vitae Pharmaceuticals, Inc. | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
| WO2010010157A2 (en) * | 2008-07-25 | 2010-01-28 | Boehringer Ingelheim International Gmbh | INHIBITORS OF 11beta-HYDROXYSTEROID DEHYDROGENASE 1 |
| CN102105454A (en) * | 2008-07-25 | 2011-06-22 | 贝林格尔.英格海姆国际有限公司 | Synthesis of inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 |
| CN102421773A (en) * | 2008-07-25 | 2012-04-18 | 贝林格尔·英格海姆国际有限公司 | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
Non-Patent Citations (2)
| Title |
|---|
| GONZALEZ TRIGO, G. 等: "Heterocyclic spirane derivatives. VII. Some aminomethyl derivatives (Mannich bases) of cyclopentane-, indane-2- and fluorene-9-spiro-5"-oxazolidinediones", 《ANALES DE QUIMICA》 * |
| RAPPOSELLI, SIMONA 等: "Synthesis and biological evaluation of 5-membered spiro heterocycle-benzopyran derivatives against myocardial ischemia", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
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