CN101115742B - Heterocycle derivatives as histone deacetylase (hdac) inhibitors - Google Patents
Heterocycle derivatives as histone deacetylase (hdac) inhibitors Download PDFInfo
- Publication number
- CN101115742B CN101115742B CN2005800476341A CN200580047634A CN101115742B CN 101115742 B CN101115742 B CN 101115742B CN 2005800476341 A CN2005800476341 A CN 2005800476341A CN 200580047634 A CN200580047634 A CN 200580047634A CN 101115742 B CN101115742 B CN 101115742B
- Authority
- CN
- China
- Prior art keywords
- amino
- oxo
- alkyl
- imidazoles
- base
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 0 C=C1*CCC1 Chemical compound C=C1*CCC1 0.000 description 12
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to compounds of formula (I), or pharmaceutically acceptable salts or tautomers thereof, which are inhibitors of histone deacetylase (HDAC). The compounds of the present invention are useful for treating cellular proliferative diseases, including cancer. Further, the compounds of the present invention are useful for treating neurodegenerative diseases, schizophrenia and stroke among other diseases.
Description
The present invention relates to Hete rocyclic derivatives for histone deacetylase (HDAC) inhibitor.The compounds of this invention can be used for the treatment of cell breeding disease, comprises cancer.In addition, The compounds of this invention can be used for the treatment of neurodegenerative disease, schizophrenia and apoplexy and other disease.
DNA in the nucleus exists for fine and close chromatin Structure level.Chromatinic basic repeating unit is a karyosome.Karyosome is made up of the protein octameric histone in the nucleus, and the DNA around it is capped twice.The generegulation function aspects that is packaged in order of DNA plays an important role in the nucleus.The covalent modified of histone changing chromatin higher structure and function and finally carrying out playing keying action in the genetic expression.Histone covalent modified such as acetylize, undertaken by enzyme mediation method.
By suppress genetic expression that cell ribozyme histone deacetylase (HDAC) carries out regulate be several can influence that chromatin is active in may regulation mechanism a kind of.The homeostasis of histone nucleus acetylizing can be by regulating the activity of antienzyme histone acetyltransferase (HAT) and histone deacetylase (HDAC).The chromatinic karyosome that is characterised in that of Transcriptional Silencing with low-level acetylated histones.Acetylizing has reduced the positive charge of histone, thereby has expanded karyosome structure and the interaction that has promoted transcription factor and DNA.Remove deacetylate and will recover positive charge, retract kernel structure.Acetylation of histone can activated dna be transcribed, reinforcing gene expression.Histone deacetylase can reverse said process and can be used for suppressor gene again and express.Referring to, for example, Grunstein, Nature389,349-352 (1997); People such as Pazin, Cell 89,325-328 (1997); People such as Wade, Trends Biochem.ScL 22,128-132 (1997); And Wolffe, Science272,371-372 (1996).
The WO 04/072047 that is disclosed on August 26th, 2004 discloses indoles, benzoglyoxaline and the naphtho-imidazoles as hdac inhibitor, and the structure of these compounds is different from The compounds of this invention.
WO 99/64401 and WO 02/10140 disclose the imidazolyl derivatives as the structurally associated of somatostatin receptor stimulant and antagonist.
The compounds of this invention can be used for the inhibition of histone deacetylase.The invention provides formula (I) compound:
P is 0,1,2,3,4 or 5;
Q is 1,2,3 or 4;
T is 0 or 1;
D represents not exist, (CH
2)
bPerhaps (CH=CH)
c
B is 1,2 or 3;
C is 1,2 or 3;
X is C or S=O;
Het contains 1,2,3 or 4 heteroatomic 5 membered unsaturated heterocycle that are independently selected from N, O and S, but wherein at the most a heteroatoms be O or S; Perhaps contain 1,2,3 or 4 heteroatomic 6 membered unsaturated heterocycle that are independently selected from N and O; It is chosen wantonly by one or more and is independently selected from following group replacement: cyano group, halogen, hydroxyl, oxo, nitro, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
3-10Cycloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl and C
6-10Aryl;
R
1Be hydrogen, hydroxyl, halogen, C
1-6Alkyl-carbonyl, C
1-6Alkoxy carbonyl, C
1-6Alkyl, halo C
1-6Alkyl, N (R
h)
2, R wherein
hBe independently selected from hydrogen, C
1-6Alkyl, C
6-10Aryl and C
6-10Aryl C
1-6Alkyl; C
3-10Cycloalkyl, C
6-10Aryl, contain 1,2 or 3 heteroatomic 5 yuan or 6 yuan of saturated or fractional saturation heterocycle that are independently selected from N, O and S, contain 1,2,3 or 4 heteroatoms that is independently selected from O, N and S but wherein at the most one be 5 membered unsaturated heterocycles of O or S, 6 membered unsaturated heterocycles that contain 1,2 or 3 nitrogen-atoms perhaps contain the unsaturated or fractional saturation heterocycle of heteroatomic 8-13 unit that is independently selected from O, N and S; Any above-mentioned ring is all chosen wantonly by one or more and is independently selected from following group replacement: cyano group, halogen, nitro, oxo, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkyl-carbonyl, C
1-6Alkoxy carbonyl, carboxyl, C
6-10Aryl, C
6-10Aryloxy, C
6-10Aryl carbonyl, N (R
a)
2, R wherein
aBe independently selected from hydrogen, C
1-6Alkyl, C
6-10Aryl, C
1-6Alkyl-carbonyl and C
6-10Aryl carbonyl; C
1-6Alkyl N (R
a)
2(CO)
dR
k, wherein d is 0 or 1, and R
kThe following definition;
R
2Be hydrogen, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, C
3-10Cycloalkyl, hydroxyl C
1-6Alkyl, N (R
b)
2,-(C=O)-N (R
c)
2, R wherein
cBe independently selected from hydrogen and C
1-6Alkyl; C
1-6Alkyl S (O)
wR
g, R wherein
gFollowing define and w is 0,1 or 2; Contain 1,2,3 or 4 heteroatoms that is independently selected from N, O and S but wherein at the most one be 5 membered unsaturated heterocycles of O or S, perhaps contain 1,2 or 3 heteroatomic 6 membered unsaturated heterocycle that are independently selected from N and O; Any described ring is optional to be independently selected from following group replacement by one or more: cyano group, halogen, hydroxyl, oxo, nitro, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
3-10Cycloalkyl, C
2-6Thiazolinyl, C
2- 6Alkynyl and C
6-10Aryl;
R
3Be hydrogen, halogen, hydroxyl, cyano group, C
1-6Alkyl, halo C
1-6Alkyl, hydroxyl C
1- 6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
3-10Cycloalkyl, halo C
3-10Cycloalkyl, C
2-10Thiazolinyl, C
2-10Alkynyl, nitro, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, C
6-10Aryl, C
6-10Aryl C
1-6Alkyl, C
6-10Aryl C
1-6Alkoxyl group; 6-13 unit fractional saturation hydrocarbon ring; Contain 1,2 or 3 heteroatomic 4,5 or 6 yuan of saturated or fractional saturation heterocycle that are independently selected from N, O and S, its optional C that passes through
1-4Alkyl carries out bridge joint; Contain 1,2,3 or 4 heteroatoms that is independently selected from N, O and S but wherein at the most one be 5 membered unsaturated heterocycles of O or S; 6 membered unsaturated heterocycles that contain 1,2 or 3 nitrogen-atoms; Contain perhaps that the heteroatomic 7-15 unit that is independently selected from N, O or S is saturated, fractional saturation or unsaturated heterocycle; Any above-mentioned ring is optional to be selected from (CH by one or more
2)
m(CO)
nR
dGroup replace;
M is 0,1,2 or 3;
N is 0,1 or 2;
R
4And R
5Be independently selected from hydrogen and C
1-6Alkyl;
R
6And R
8Be hydrogen, C independently
1-6Alkyl, contain the saturated or fractional saturation heterocycle of 1,2 or 3 heteroatomic 5 yuan or 6 yuan that are independently selected from N, O and S or contain 6 membered unsaturated heterocycles of 1,2 or 3 nitrogen-atoms; Any above-mentioned ring is optional to be independently selected from following group replacement by one or more: halogen, nitro, amino, cyano group, oxo, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
3-10Cycloalkyl, C
2-6Thiazolinyl and C
2-6Alkynyl; Perhaps
R
6And R
8Represent oxo group altogether;
R
bBe hydrogen, C independently of one another
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkyl S (O)
wR
g, R wherein
gFollowing define and w is 0,1 or 2; SO
2R
g, R wherein
gBe C
1-6Alkyl, halo C
1-6Alkyl, amino, C
1-6Alkylamino or two (C
1-6Alkyl) amino; Perhaps be C
6-10Aryl, C
6-10Aryl C
1-6Alkyl or contain 1,2,3 or 4 heteroatoms that is independently selected from N, O and S but wherein at the most one be the ring of 5 membered unsaturated heterocycles of O or S, above-mentioned ring is optional to be independently selected from following group by one or more and to replace: amino, hydroxyl, nitro, cyano group, halogen, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group and halo C
1-6Alkoxyl group;
Each R
dBe halogen, hydroxyl, cyano group, C
1-6Alkyl, halo C
1-6Alkyl, halo C
1-6Alkyl-carbonyl, halo C
1-6Alkyl carbonyl oxy, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, carboxyl, C
1-6Alkyl-carbonyl, C
1-6Alkoxy carbonyl, nitro, oxo, SO
2N (R
e)
2, N (R
e)
2, R wherein
eBe independently selected from hydrogen, C
1-6Alkyl, C
1-6Alkyl-carbonyl, carboxyl and C
1-6Alkoxy carbonyl; C
1-6Alkyl N (R
e)
2, C
6-10Aryl; C
6-10Aryl C
1-6Alkoxyl group; Contain 1,2 or 3 heteroatomic 5 yuan or 6 yuan of saturated or fractional saturation heterocycle that are independently selected from N, O and S, its optional C that passes through
1-4Alkyl carries out bridge joint; Contain 1,2,3 or 4 heteroatoms that is independently selected from N, O and S but wherein at the most one be 5 membered unsaturated heterocycles of O or S; Contain 0,1 or 2 heteroatomic 5 yuan or 6 yuan of volution that are independently selected from N, O or S, perhaps contain 6 membered unsaturated heterocycles of 1,2 or 3 nitrogen-atoms; Any above-mentioned ring is optional to be independently selected from following group replacement by one or more: halogen, hydroxyl, amino, cyano group, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group and halo C
1-6Alkoxyl group;
R
kBe NHSO
2R
gContain 1,2 or 3 heteroatomic 5 yuan or 6 yuan of saturated or fractional saturation heterocycle that are independently selected from N, O and S, perhaps contain 1,2,3 or 4 heteroatoms that is independently selected from N, O and S, but wherein at the most one be 5 membered unsaturated heterocycles of O or S; Any above-mentioned ring is optional to be independently selected from halogen and C by one or more
1-6The group of alkyl replaces;
Perhaps its pharmacy acceptable salt or tautomer.
In one embodiment:
D does not exist;
P is 0,1,2 or 3;
Q is 1,2,3 or 4;
T is 0 or 1;
X is C or S=O;
But Het contains 1,2,3 or 4 heteroatoms that is independently selected from N, O and S 5 membered unsaturated heterocycles that heteroatoms is O or S at the most wherein; Perhaps contain 1,2,3 or 4 heteroatomic 6 membered unsaturated heterocycle that are independently selected from N and O; It is chosen wantonly by one or more and is independently selected from following group replacement: cyano group, halogen, hydroxyl, oxo, nitro, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
3-10Cycloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl and C
6-10Aryl;
R
1Be hydrogen, C
1-6Alkyl, halo C
1-6Alkyl, C
6-10Aryl, contain 1,2,3 or 4 heteroatoms that is independently selected from O, N and S but wherein at the most heteroatoms 5 membered unsaturated heterocycles that are O or S, contain 6 membered unsaturated heterocycles of 1,2 or 3 nitrogen-atoms or contain the unsaturated or fractional saturation heterocycle of heteroatomic 8-10 unit that is independently selected from O, N and S; Any above-mentioned ring is optional to be independently selected from following group replacement by one or more: cyano group, halogen, nitro, oxo, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkyl-carbonyl, C
6-10Aryl, C
6-10Aryloxy, C
6-10Aryl carbonyl and N (R
a)
2, R wherein
aBe independently selected from hydrogen, C
1-6Alkyl, C
6-10Aryl, C
1-6Alkyl-carbonyl and C
6-10Aryl carbonyl;
R
2Be hydrogen, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, hydroxyl C
1-6Alkyl, N (R
b)
2,-(C=O)-N (R
c)
2, R wherein
cBe independently selected from hydrogen and C
1-6Alkyl; Contain 1,2,3 or 4 heteroatoms that is independently selected from N, O and S but 5 membered unsaturated heterocycles that heteroatoms is O or S at the most wherein, perhaps contain 1,2 or 3 heteroatomic 6 membered unsaturated heterocycle that are independently selected from N and O; Any above-mentioned ring is optional to be independently selected from following group replacement by one or more: cyano group, halogen, hydroxyl, oxo, nitro, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
3-10Cycloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl and C
6-10Aryl;
R
3Be hydrogen, halogen, hydroxyl, cyano group, C
1-6Alkyl, halo C
1-6Alkyl, hydroxyl C
1- 6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
3-10Cycloalkyl, halo C
3-10Cycloalkyl, C
2-10Thiazolinyl, C
2-10Alkynyl, nitro, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, C
6-10Aryl, C
6-10Aryl C
1-6Alkyl, C
6-10Aryl C
1-6Alkoxyl group; Contain 1,2 or 3 heteroatomic 4 yuan, 5 yuan or 6 yuan of saturated or fractional saturation heterocycle that are independently selected from N, O and S, its optional C that passes through
1-4Alkyl carries out bridge joint; Contain 1,2,3 or 4 heteroatoms that is independently selected from N, O and S but 5 membered unsaturated heterocycles that heteroatoms is O or S at the most wherein; 6 membered unsaturated heterocycles that contain 1,2 or 3 nitrogen-atoms; Contain perhaps that the heteroatomic 7-13 unit that is independently selected from N, O or S is saturated, fractional saturation or unsaturated heterocycle; Any above-mentioned ring is optional to be independently selected from R by one or more
dGroup replace;
R
4And R
5Be independently selected from hydrogen and C
1-6Alkyl;
R
6And R
8Be hydrogen, C independently
1-6Alkyl, contain the saturated or fractional saturation heterocycle of 1,2 or 3 heteroatomic 5 yuan or 6 yuan that are independently selected from N, O and S or contain 6 membered unsaturated heterocycles of 1,2 or 3 nitrogen-atoms; Any above-mentioned ring is optional to be independently selected from following group replacement by one or more: halogen, nitro, amino, cyano group, oxo, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
3-10Cycloalkyl, C
2-6Thiazolinyl and C
2-6Alkynyl; Perhaps
R
6And R
8Represent oxo group together;
R
bBe hydrogen, C independently of one another
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, SO
2R
g, R wherein
gBe C
1-6Alkyl or halo C
1-6Alkyl; Perhaps be C
6-10Aryl, C
6-10Aryl C
1-6But alkyl or contain 1,2,3 or 4 heteroatoms that is independently selected from N, O and S ring that heteroatoms is 5 membered unsaturated heterocycles of O or S at the most wherein, above-mentioned ring is optional to be independently selected from following group by one or more and to replace: amino, hydroxyl, nitro, cyano group, halogen, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group and halo C
1-6Alkoxyl group;
R
dBe halogen, hydroxyl, cyano group, C
1-6Alkyl, halo C
1-6Alkyl, halo C
1-6Alkyl-carbonyl, halo C
1-6Alkyl carbonyl oxy, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, carboxyl, C
1-6Alkyl-carbonyl, C
1-6Alkoxy carbonyl, nitro, oxo, SO
2N (R
e)
2, N (R
e)
2, R wherein
eBe independently selected from hydrogen, C
1-6Alkyl, C
1-6Alkyl-carbonyl, carboxyl and C
1-6The alkyl oxy carbonyl; Perhaps C
6-10Aryl; Contain 1,2 or 3 heteroatomic 5 yuan or 6 yuan of saturated or fractional saturation heterocycle that are independently selected from N, O or S, its optional C that passes through
1-4Alkyl carries out bridge joint; Contain 1,2,3 or 4 heteroatoms that is independently selected from N, O and S but wherein at the most one be 5 membered unsaturated heterocycles of O or S; 6 membered unsaturated heterocycles that perhaps contain 1,2 or 3 nitrogen-atoms; Any above-mentioned ring can be chosen wantonly by one or more and be independently selected from following group replacement: halogen, hydroxyl, amino, cyano group, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group and halo C
1-6Alkoxyl group;
Perhaps its pharmacy acceptable salt.
Formerly in a kind of embodiment of embodiment:
R
1Be hydrogen, C
1-6Alkyl, halo C
1-6Alkyl, C
6-10Aryl, contain 1,2,3 or 4 heteroatoms that is independently selected from O, N and S but wherein at the most heteroatoms 5 membered unsaturated heterocycles that are O or S, contain 6 membered unsaturated heterocycles of 1,2 or 3 nitrogen-atoms or contain the heteroatomic 8-10 membered unsaturated heterocycle that is independently selected from O, N and S; Any above-mentioned ring is optional to be independently selected from following group replacement by one or more: cyano group, halogen, nitro, oxo, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkyl-carbonyl, C
6-10Aryl, C
6-10Aryloxy, C
6-10Aryl carbonyl and N (R
a)
2, R wherein
aBe independently selected from hydrogen, C
1-6Alkyl, C
6-10Aryl, C
1-6Alkyl-carbonyl and C
6-10Aryl carbonyl;
R
2Be hydrogen, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, hydroxyl C
1-6Alkyl or N (R
b)
2, R wherein
bBe independently selected from hydrogen, C
1-6Alkyl, hydroxyl and optional by amino, hydroxyl, nitro, cyano group, halogen or C
1-6The phenyl that alkyl replaces;-(C=O)-N (R
c)
2, R wherein
cBe independently selected from hydrogen and C
1-6Alkyl; Contain 1,2,3 or 4 heteroatoms that is independently selected from N, O and S but 5 membered unsaturated heterocycles that heteroatoms is O or S at the most wherein; Perhaps contain 1,2 or 3 heteroatomic 6 membered unsaturated heterocycle that are independently selected from N and O; Any above-mentioned ring is optional to be independently selected from following group replacement by one or more: cyano group, halogen, hydroxyl, oxo, nitro, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
3-10Cycloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl and C
6-10Aryl;
R
3Be hydrogen, halogen, hydroxyl, cyano group, C
1-6Alkyl, halo C
1-6Alkyl; Hydroxyl C
1- 6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
3-10Cycloalkyl, halo C
3-10Cycloalkyl, C
2-10Thiazolinyl, C
2-10Alkynyl, nitro, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino; C
6-10Aryl; Contain 1,2 or 3 heteroatomic 4 yuan, 5 yuan or 6 yuan of saturated or fractional saturation heterocycle that are independently selected from N, O and S, its optional C that passes through
1-4Alkyl carries out bridge joint; Contain 1,2,3 or 4 heteroatoms that is independently selected from N, O and S but wherein at the most one be 5 membered unsaturated heterocycles of O or S; 6 membered unsaturated heterocycles that contain 1,2 or 3 nitrogen-atoms; Contain perhaps that the heteroatomic 7-10 unit that is independently selected from N, O or S is saturated, fractional saturation or unsaturated heterocycle; Any above-mentioned ring is optional to be independently selected from R by one or more
dGroup replace;
R
4And R
5Be independently selected from hydrogen and C
1-6Alkyl;
R
6Be hydrogen, C
1-6Alkyl, contain the saturated or fractional saturation heterocycle of 1,2 or 3 heteroatomic 5 yuan or 6 yuan that are independently selected from N, O and S or contain 6 membered unsaturated heterocycles of 1,2 or 3 nitrogen-atoms; Any above-mentioned ring is optional to be independently selected from following group replacement by one or more: halogen, nitro, amino, cyano group, oxo, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
3-10Cycloalkyl, C
2-6Thiazolinyl and C
2-6Alkynyl;
R
8Be hydrogen;
R
dBe halogen, hydroxyl, cyano group, C
1-6Alkyl, halo C
1-6Alkyl, halo C
1-6Alkyl-carbonyl, halo C
1-6Alkyl carbonyl oxy, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, carboxyl, C
1-6Alkyl-carbonyl, C
1-6Alkoxy carbonyl, nitro, SO
2N (R
e)
2, N (R
e)
2, R wherein
eBe independently selected from hydrogen, C
1-6Alkyl, C
1-6Alkyl-carbonyl, carboxyl and C
1-6Alkoxy carbonyl; Perhaps C
6-10Aryl; Contain 1,2 or 3 heteroatomic 5 yuan or 6 yuan of saturated or fractional saturation heterocycle that are independently selected from N, O or S, its optional C that passes through
1-6Alkyl carries out bridge joint; Contain 1,2,3 or 4 heteroatoms that is independently selected from N, O and S but wherein at the most one be 5 membered unsaturated heterocycles of O or S; 6 membered unsaturated heterocycles that perhaps contain 1,2 or 3 nitrogen-atoms; Any above-mentioned ring is optional to be independently selected from following group replacement by one or more: halogen, hydroxyl, amino, cyano group, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group and halo C
1-6Alkoxyl group;
With p, q, t, X and Het as defined above;
Perhaps its pharmacy acceptable salt.
B is preferably 1 or 2.
C is preferably 1.
Preferred D represents not exist, CH
2, CH
2CH
2Perhaps CH=CH.
In one embodiment, D does not exist.
P is preferably 0,1,2,3 or 4.P is preferably 0,1 or 2.
In one embodiment, p is 0.
Q is preferably 2,3 or 4, and particularly 3 or 4, and the most particularly 3.
In one embodiment, t is 0.
In another embodiment, t is 1, and R
5Be hydrogen or methyl, preferable methyl.
In one embodiment of the present invention, X is C.
In another embodiment, X is S=O.
Preferred Het for optional replace contain 1,2 or 3 heteroatoms that is independently selected from N, O and S but 5 membered unsaturated heterocycles or optional 6 membered unsaturated heterocycles that contain 1,2 or 3 nitrogen-atoms that replace that heteroatoms is O or S at the most wherein.
In one embodiment, Het for optional replace contain 1,2,3 or 4 heteroatoms that is independently selected from N, O and S but 5 membered unsaturated heterocycles that heteroatoms is O or S at the most wherein.
More especially, Het is optional imidazolyl, oxazolyl, triazolyl or the thienyl that replaces.Other concrete Het group comprises optional furyl, oxadiazole base, thiazolyl, pyrazolyl and the pyridyl that replaces.
Preferred Het is not substituted or is replaced by one, two or three groups.More especially Het is not substituted or the coverlet replacement.The preferred optional substituting group comprises C
1-4Alkyl and C
6-10Aryl, particularly methyl and phenyl.
In one embodiment, Het is not substituted.
For fear of suspection, R
1Can be as any optional substituting group on the Het, but be connected on any the position of substitution of Het.
Thus, concrete preferred Het group comprises imidazolyl, methylimidazolyl, phenylimidazole base, Ben Ji oxazolyl, triazolyl and thienyl.Further preferred Het group comprises furyl, oxadiazole base, thiazolyl, oxazolyl, pyrazolyl and pyridyl.
Concrete Het group is imidazoles-2-base, 4-methylimidazole-2-base, 4-phenylimidazole-2-base, 4-Ben Ji oxazole-2-base, 1,2,4-triazole-3-base, 1-Methylimidazole-2-base and 2-thienyl.Other concrete Het group is a 2-furyl, 1,3,4-oxadiazole-2-base, 1,3-thiazoles-2-base, 1,2,4-oxadiazole-5-base, 1,3-thiazoles-5-base, 1,2,4-oxadiazole-3-base, 1,3-oxazole-2-base, imidazol-4 yl, pyrazoles-5-base and pyridine-2-base.
Preferred R
1Be hydrogen, hydroxyl, halogen, C
1-6Alkyl-carbonyl, C
1-6Alkoxy carbonyl, two (C
1-6Alkyl) amino, (C
6-10Aryl C
1-6Alkyl) (C
1-6Alkyl) amino or optional replace be selected from following ring: C
3-7Cycloalkyl, C
6-10The heterocycle of the saturated or fractional saturation of aryl, 5 yuan or 6 yuan, contain 1,2 or 3 heteroatoms that is independently selected from N, O and S but wherein at the most heteroatoms 5 membered unsaturated heterocycles that are O or S, contain 6 membered unsaturated heterocycles of 1,2 or 3 nitrogen-atoms or contain 1,2,3 or 4 heteroatomic 8,9,10,11,12 or 13 yuan of unsaturated or fractional saturation heterocycle that are independently selected from O, N and S.
Preferred R
1Be the ring that is selected from following optional replacement: C
6-10Aryl, contain 1,2 or 3 heteroatoms that is independently selected from N, O and S but wherein at the most heteroatoms 5 membered unsaturated heterocycles that are O or S, contain 6 membered unsaturated heterocycles of 1,2 or 3 nitrogen-atoms or contain 1,2,3 or 4 heteroatomic 8,9 or 10 yuan of unsaturated or fractional saturation heterocycle that are independently selected from O, N and S.
More especially, R
1Be optional phenyl, naphthyl, thienyl, isoxazolyl, pyridyl, benzothienyl or the thiazoltriazol base that replaces.The R that other is concrete
1Group comprises optional dihydrobenzo Er Evil satellite-based (benzodioxinyl), benzothiazolyl, quinolyl or the isoquinolyl that replaces.The R that other is concrete
1Group comprises hydroxyl, (benzyl) (methyl) amino, dimethylamino, methoxycarbonyl, hydrogen, ethanoyl, cyclohexyl, bromine and optional substituted quinoxaline base, morpholinyl, tetrahydro isoquinolyl, indyl, dibenzo [b, d] furyl, naphthyridinyl or dihydroquinoline base.
Preferred R
1Be not substituted or replaced by one, two or three groups.More especially, R
1Be not substituted, coverlet replaces or two replacements.In one embodiment, R
1Coverlet replaces.Favourable optional substituting group comprises cyano group, halogen, C
1-4Alkyl, halo C
1-4Alkyl, C
1-4Alkoxyl group, halo C
1-4Alkoxyl group and C
6-10Aryl.Other favourable optional substituting group comprises pyrazolyl, two (C
1-6Alkyl) amino, carboxyl, piperidino carbonyl, morpholinyl, nitro, (C
1-6Alkyl-carbonyl) amino, C
1-6Alkoxy carbonyl, amino, amino C
1-6Alkyl, tetrazyl, [(C
1-6Alkyl sulphonyl) amino] carbonyl, hydroxyl, [two (C
1-6Alkyl) amino] C
1-6Alkyl and oxo; Any above-mentioned ring is optional by one, two or three C
1-6Alkyl replaces.General optional substituent example comprises cyano group, bromine, chlorine, fluorine, methyl, trifluoromethyl, methoxyl group, difluoro-methoxy and phenyl.Substituent other example of general option comprise dimethyl pyrazole base, dimethylamino, carboxyl, piperidino carbonyl, morpholinyl, nitro, trifluoromethoxy, oxyethyl group, kharophen, methoxycarbonyl, pyrazolyl, amino, aminomethyl, tetrazyl, [(methylsulfonyl) amino] carbonyl, hydroxyl, dimethylaminomethyl and oxo.
Thus, concrete preferred R
1Group comprises phenyl, cyano-phenyl, bromophenyl, chloro-phenyl-, dichlorophenyl, fluorophenyl, difluorophenyl, trifluoromethyl, two (trifluoromethyl) phenyl, p-methoxy-phenyl, difluoro-methoxy phenyl, xenyl, naphthyl, thienyl, phenyl-isoxazole azoles base, pyridyl, (chlorine) (methyl) benzothienyl, (methyl) (trifluoromethyl) thiazoltriazol base and benzothienyl.Other preferred R
1Group is dihydrobenzo Er Evil satellite-based, benzothiazolyl, methoxy quinoline base, quinolyl and isoquinolyl.Other preferred R
1Group is a hydroxyl; quinoxalinyl; the methoxyl group naphthyl; morpholinyl; benzyl (methyl) amino; tetrahydro isoquinolyl; the toluquinoline base; indyl; (dimethyl pyrazole base) phenyl; (dimethylamino) phenyl; (fluorine) (methoxyl group) phenyl; carboxyl phenyl; dibenzo [b, d] furyl; (piperidino carbonyl) phenyl; dimethylamino; methoxycarbonyl; the dimethoxy naphthyl; the morpholinyl phenyl; nitrophenyl; Trifluoromethoxyphen-l; phenelyl; acetylamino phenyl; (methoxycarbonyl) phenyl; hydrogen; bromophenyl; the pyrazolyl phenyl; aminophenyl; Dimethoxyphenyl; (fluorine) (trifluoromethyl) phenyl; (aminomethyl) phenyl; (aminomethyl) (fluorine) phenyl; tetrazolyl phenyl; { [(methylsulfonyl) amino] carbonyl } phenyl; ethanoyl; cyclohexyl; bromine; hydroxyphenyl; (dimethylaminomethyl) phenyl; the fluoro quinolyl; naphthyridinyl and oxo-dihydro quinolyl.
Concrete R
1Group is a phenyl, the 3-cyano-phenyl, the 4-cyano-phenyl, the 4-bromophenyl, the 2-chloro-phenyl-, the 3-chloro-phenyl-, the 4-chloro-phenyl-, 3, the 4-dichlorophenyl, the 4-fluorophenyl, 3, the 4-difluorophenyl, 3-(trifluoromethyl) phenyl, 4-(trifluoromethyl) phenyl, 3,5-two (trifluoromethyl) phenyl, the 2-p-methoxy-phenyl, the 3-p-methoxy-phenyl, 4-(difluoro-methoxy) phenyl, biphenyl-4-base, the 2-naphthyl, the 3-thienyl, 3-phenyl-isoxazole azoles-5-base, the 2-pyridyl, 5-chloro-3-methyl isophthalic acid-thionaphthene-2-base, 6-methyl-2-(trifluoromethyl) [1,3] thiazole also [3,2-b] [1,2,4] triazole-5-base and 1-thionaphthene-3-base.The R that other is concrete
1Group is 3,5-dichlorophenyl, 2,3-dihydro-1,4-Ben Bing Er Evil star-6-base, 2,3-dihydro-1,4-Ben Bing Er Evil star-5-base, 1,3-benzothiazole-2-base, 1-thionaphthene-2-base, 4-methoxy quinoline-2-base, quinoline-3-base, quinoline-6-base, quinoline-2-base and isoquinoline 99.9-3-base.The R that other is concrete
1Group is quinoline-8-base; hydroxyl; quinoxaline-2-base; 3-methoxyl group-2-naphthyl; morpholine-4-base; benzyl (methyl) amino; 1; 2; 3; 4-tetrahydroisoquinoline-2-base; 2-toluquinoline-5-base; quinoline-5-base; 8-toluquinoline-5-base; 8-methoxy quinoline-5-base; 1-thionaphthene-7-base; 1H-indoles-5-base; 3-(3; 5-dimethyl-IH-pyrazol-1-yl) phenyl; 4-(dimethylamino) phenyl; 2-fluoro-4-p-methoxy-phenyl; 3-fluoro-4-p-methoxy-phenyl; the 3-carboxyl phenyl; biphenyl-2-base; dibenzo [b; d] furans-4-base; 3-(piperidines-1-base carbonyl) phenyl; quinoxalin-6-yl; dimethylamino; methoxycarbonyl; 1; 4-dimethoxy-2-naphthyl; 3; 5-dimethoxy-2-naphthyl; the 2-thienyl; the 1-naphthyl; 2-(morpholine-4-yl) phenyl; the 3-nitrophenyl; pyridin-3-yl; 3-(trifluoromethoxy) phenyl; 4-(trifluoromethoxy) phenyl; 2-(trifluoromethyl) phenyl; the 2-fluorophenyl; the 3-phenelyl; the 4-phenelyl; 4-(kharophen) phenyl; 2-(methoxycarbonyl) phenyl; hydrogen; the 3-bromophenyl; pyridin-4-yl; 4-(1H-pyrazol-1-yl) phenyl; the 2-nitrophenyl; the 3-aminophenyl; 2; the 4-Dimethoxyphenyl; 2-fluoro-5-trifluoromethyl; 3-(aminomethyl) phenyl; 2-(aminomethyl)-4-fluorophenyl; biphenyl-3-base; 3-(1H-tetrazolium-5-yl) phenyl; the 3-{[(methylsulfonyl) amino] carbonyl } phenyl; ethanoyl; cyclohexyl; bromine; the 4-carboxyl phenyl; the 3-hydroxyphenyl; the 4-[(dimethylamino) methyl] phenyl; the 2-carboxyl phenyl; 2-fluorine quinoline-3-base; quinoxalin-6-yl; 8-methoxy quinoline-5-base; 2 methoxy quinoline-3-base; 1; 8-naphthyridine-2-base; 1; 6-naphthyridine-2-base; 1; 6-naphthyridine-8-base and 2-oxo-1,2-dihydroquinoline-3-base.
In one embodiment, R
1Be hydroxyl, halogen, C
1-6Alkyl-carbonyl, N (R
h)
2, R wherein
hBe independently selected from hydrogen, C
1-6Alkyl, C
6-10Aryl and C
6-10Aryl C
1-6Alkyl; C
3-10Cycloalkyl; Contain the saturated or fractional saturation heterocycle of 1,2 or 3 heteroatomic 5 yuan or 6 yuan that are independently selected from N, O and S, contain 1,2,3 or 4 heteroatoms that is independently selected from O, N and S but wherein at the most heteroatoms 5 membered unsaturated heterocycles that are O or S, contain 6 membered unsaturated heterocycles of 1,2 or 3 nitrogen-atoms or contain the unsaturated or fractional saturation heterocycle of heteroatomic 8-13 unit that is independently selected from O, N and S; Above-mentioned any ring is optional to be selected from following group replacement by one or more: cyano group, halogen, nitro, oxo, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkyl-carbonyl, C
1-6Alkoxy carbonyl, carboxyl, C
6-10Aryl, C
6-10Aryloxy, C
6-10Aryl carbonyl, N (R
a)
2, R wherein
aBe independently selected from hydrogen, C
1-6Alkyl, C
6-10Aryl, C
1-6Alkyl-carbonyl and C
6-10Aryl carbonyl; C
1-6Alkyl N (R
a)
2(CO)
dR
k, wherein d is 0 or 1, and R
kAs defined above.
In another embodiment, R
1For contain the saturated or fractional saturation heterocycle of 1,2 or 3 heteroatomic 5 yuan or 6 yuan that are independently selected from N, O and S, contain 1,2,3 or 4 heteroatoms that is independently selected from O, N and S but wherein at the most heteroatoms 5 membered unsaturated heterocycles that are O or S, contain 6 membered unsaturated heterocycles of 1,2 or 3 nitrogen-atoms or contain the unsaturated or fractional saturation heterocycle of heteroatomic 8-13 unit that is independently selected from O, N and S; Any above-mentioned ring is all chosen wantonly by one or more and is independently selected from following group replacement: cyano group, halogen, nitro, oxo, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkyl-carbonyl, C
1-6Alkoxy carbonyl, carboxyl, C
6-10Aryl, C
6-10Aryloxy, C
6-10Aryl carbonyl, N (R
a)
2, R wherein
aBe independently selected from hydrogen, C
1-6Alkyl, C
6-10Aryl, C
1-6Alkyl-carbonyl and C
6-10Aryl carbonyl; C
1-6Alkyl N (R
a)
2(CO)
dR
k, wherein d is 0 or 1, and R
kAs defined above.
In one embodiment, R
1Be optional thienyl, isoxazolyl, pyridyl, benzothienyl, thiazoltriazol base, dihydrobenzo Er Evil satellite-based, benzothiazolyl, quinolyl, isoquinolyl, quinoxalinyl, morpholinyl, tetrahydro isoquinolyl, indyl, dibenzo [b, d] furyl, naphthyridinyl or the dihydroquinoline base that replaces.
In one embodiment, R
1Be thienyl, phenyl-isoxazole azoles base, pyridyl, (chlorine) (methyl) benzothienyl, (methyl) (trifluoromethyl) thiazoltriazol base, benzothienyl, dihydrobenzo Er Evil satellite-based, benzothiazolyl, methoxy quinoline base, quinolyl, isoquinolyl, quinoxalinyl, morpholinyl, tetrahydro isoquinolyl, toluquinoline base, indyl, dibenzo [b, d] furyl, fluoro quinolyl, naphthyridinyl or oxo-dihydro quinolyl.
In one embodiment, R
1Be the 3-thienyl, 3-phenyl-isoxazole azoles-5-base, the 2-pyridyl, 5-chloro-3-methyl isophthalic acid-thionaphthene-2-base, 6-methyl-2-(trifluoromethyl) [1,3] thiazole also [3,2-b] [1,2,4] triazole-5-base, 1-thionaphthene-3-base, 2,3-dihydro-1,4-Ben Bing Er Evil star-6-base, 2,3-dihydro-1,4-Ben Bing Er Evil star-5-base, 1,3-benzothiazole-2-base, 1-thionaphthene-2-base, 4-methoxy quinoline-2-base, quinoline-3-base, quinoline-6-base, quinoline-2-base, isoquinoline 99.9-3-base, quinoline-8-base, quinoxaline-2-base, morpholine-4-base, 1,2,3,4-tetrahydroisoquinoline-2-base, 2-toluquinoline-5-base, quinoline-5-base, 8-toluquinoline-5-base, 8-methoxy quinoline-5-base, 1-thionaphthene-7-base, 1H-indoles-5-base, dibenzo [b, d] furans-4-base, quinoxalin-6-yl, the 2-thienyl, pyridin-3-yl, pyridin-4-yl, 2-fluorine quinoline-3-base, quinoxalin-6-yl, 8-methoxy quinoline-5-base, 2 methoxy quinoline-3-base, 1,8-naphthyridine-2-base, 1,6-naphthyridine-2-base, 1,6-naphthyridine-8-base or 2-oxo-1,2-dihydroquinoline-3-base.
In one embodiment, R
1For containing the unsaturated or fractional saturation heterocycle of heteroatomic 8-13 unit that is independently selected from O, N and S; Any above-mentioned ring is optional independently to be selected from following group replacement by one or more: cyano group, halogen, nitro, oxo, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkyl-carbonyl, C
1-6Alkoxy carbonyl, carboxyl, C
6-10Aryl, C
6-10Aryloxy, C
6-10Aryl carbonyl, N (R
a)
2, R wherein
aBe independently selected from hydrogen, C
1-6Alkyl, C
6-10Aryl, C
1-6Alkyl-carbonyl and C
6-10Aryl carbonyl; C
1-6Alkyl N (R
a)
2(CO)
dR
k, wherein d is 0 or 1, and R
kAs defined above.
In one embodiment, R
11,2,3 or 4 the unsaturated or fractional saturation heterocycle of heteroatomic 8-13 unit that is independently selected from O, N and S that contains for optional replacement.
In one embodiment, R
1Be optional benzothienyl, thiazoltriazol base, dihydrobenzo two Evil satellite-baseds, benzothiazolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrahydro isoquinolyl, indyl, dibenzo [b, d] furyl, naphthyridinyl or the dihydroquinoline base of replacing.
In one embodiment, R
1Be optional quinolyl, isoquinolyl, quinoxalinyl, tetrahydro isoquinolyl, naphthyridinyl or the dihydroquinoline base that replaces.
In one embodiment, R
1Be (chlorine) (methyl) benzothienyl, (methyl) (trifluoromethyl) thiazoltriazol base, benzothienyl, dihydrobenzo Er Evil satellite-based, benzothiazolyl, methoxy quinoline base, quinolyl, isoquinolyl, quinoxalinyl, tetrahydro isoquinolyl, toluquinoline base, indyl, dibenzo [b, d] furyl, fluoro quinolyl, naphthyridinyl or oxo-dihydro quinolyl.
In one embodiment, R
1Be 5-chloro-3-methyl isophthalic acid-thionaphthene-2-base, 6-methyl-2-(trifluoromethyl) [1,3] thiazole also [3,2-b] [1,2,4] triazole-5-base, 1-thionaphthene-3-base, 2,3-dihydro-1,4-Ben Bing Er Evil star-6-base, 2,3-dihydro-1,4-Ben Bing Er Evil star-5-base, 1,3-benzothiazole-2-base, 1-thionaphthene-2-base, 4-methoxy quinoline-2-base, quinoline-3-base, quinoline-6-base, quinoline-2-base, isoquinoline 99.9-3-base, quinoline-8-base, quinoxaline-2-base, 1,2,3,4-tetrahydroisoquinoline-2-base, 2-toluquinoline-5-base, quinoline-5-base, 8-toluquinoline-5-base, 8-methoxy quinoline-5-base, 1-thionaphthene-7-base, 1H-indoles-5-base, dibenzo [b, d] furans-4-base, quinoxalin-6-yl, 2-fluorine quinoline-3-base, quinoxalin-6-yl, 8-methoxy quinoline-5-base, 2 methoxy quinoline-3-base, 1,8-naphthyridine-2-base, 1,6-naphthyridine-2-base, 1,6-naphthyridine-8-base or 2-oxo-1,2-dihydroquinoline-3-base.
In one embodiment, R
1Be 4-methoxy quinoline-2-base, quinoline-3-base, quinoline-6-base, quinoline-2-base, isoquinoline 99.9-3-base, quinoline-8-base, quinoxaline-2-base 1,2,3,4-tetrahydroisoquinoline-2-base, 2-toluquinoline-5-base, quinoline-5-base, 8-toluquinoline-5-base, 8-methoxy quinoline-5-base, quinoxalin-6-yl, 2-fluorine quinoline-3-base, quinoxalin-6-yl, 8-methoxy quinoline-5-base, 2 methoxy quinoline-3-base, 1,8-naphthyridine-2-base, 1,6-naphthyridine-2-base, 1,6-naphthyridine-8-base or 2-oxo-1,2-dihydroquinoline-3-base.
In embodiments, R
1Be quinolyl, it is chosen wantonly by one or more and is independently selected from following group replacement: cyano group, halogen, nitro, oxo, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkyl-carbonyl, C
1-6Alkoxy carbonyl, carboxyl, C
6-10Aryl, C
6-10Aryloxy, C
6-10Aryl carbonyl, N (R
a)
2, R wherein
aBe independently selected from hydrogen, C
1-6Alkyl, C
6-10Aryl, C
1-6Alkyl-carbonyl and C
6-10Aryl carbonyl; C
1-6Alkyl N (R
a)
2(CO)
dR
k, wherein d is 0 or 1, and R
kAs defined above.
In one embodiment, R
1For choosing wantonly by C
1-6Alkoxyl group, preferred methoxyl group, the quinolyl of replacement.
In one embodiment, R
1Be 2 methoxy quinoline-3-base.
Preferred R
2Be hydrogen, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, C
3-7Cycloalkyl, halo C
1-6Alkyl, hydroxyl C
1-6Alkyl, N (R
b)
2The N of ,-(C=O) (R
c)
2, C
1-6Alkyl S (O)
wR
gThe perhaps optional ring that is selected from thienyl, furyl and pyridyl that replaces.
Work as R
2Be when ring, preferably it is not substituted or is replaced by one, two or three groups.In one embodiment, R
2Ring is not substituted.
Preferred R
2Be hydrogen, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, hydroxyl C
1-6Alkyl, N (R
b)
2Perhaps-(C=O)-N (R
c)
2
Preferred R
2Be hydrogen, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, hydroxyl C
1-6Alkyl, N (R
b)
2, R wherein
bBe independently selected from hydrogen, C
1-6Alkyl, hydroxyl and optional by amino, hydroxyl, nitro, cyano group, halogen or C
1-6The phenyl that alkyl replaces ,-(C=O)-N (R
c)
2, R wherein
cBe independently selected from hydrogen and C
1-6Alkyl Huo person oxazole.
More especially, R
2Be hydrogen, hydroxyl, C
1-6Alkyl or N (R
b)
2The R that other is concrete
2Group is halo C
1-6Alkyl.The R that other is concrete
2Group is hydroxyl C
1-6Alkyl, C
1-6Alkoxyl group, C
3-5Cycloalkyl, C
1-6Alkyl S (O)
mR
gWith the optional ring that is selected from thienyl, furyl and pyridyl that replaces.
Advantageously, R
2Be C
1-4Alkyl, hydroxyl or N (R
b)
2The R that other is favourable
2Group is halo C
1-4Alkyl.
Work as R
bDuring for ring, preferably it is not substituted or is replaced by the groups of one, two or three independent selections.More especially, R
bRing is not substituted or coverlet replaces.
Preferred R
bBe hydrogen, C
1-4Alkyl, hydroxyl or optional by the amino phenyl that replaces.Other preferred R
bGroup comprises C
1-4Alkoxyl group, SO
2R
gPerhaps benzyl, thiazolyl or thiadiazolyl group, described ring is optional to be replaced by amino.Other preferred R
bGroup is C
1-6Alkyl S (O)
wR
g
Preferred R
gBe methyl, ethyl or trifluoromethyl.Other R
gGroup is amino.
Concrete R
bGroup comprises hydrogen, methyl, hydroxyl and aminophenyl.The R that other is concrete
bGroup comprises ethyl, sec.-propyl, methoxyl group, methylsulfonyl, ethylsulfonyl, trifyl, phenyl, benzyl, thiazolyl and thiadiazolyl group.The R that other is concrete
bGroup comprises oxyethyl group and methylmercaptoethyl.
Concrete R
bGroup comprises hydrogen, methyl, hydroxyl and 2-aminophenyl.The R that other is concrete
bGroup comprises ethyl, sec.-propyl, methoxyl group, methylsulfonyl, ethylsulfonyl, trifyl, phenyl, benzyl, 1,3-thiazoles-2-base and 1,3,4-thiadiazoles-2-base.The R that other is concrete
bGroup comprises oxyethyl group and 2-(methylthio group) ethyl.
Thus, concrete R
2Group is methyl, ethyl, hydroxyl, methylamino, hydroxylamino, aminophenyl amino, trifluoromethyl, amino, dimethylamino, isopropylamino, phenyl amino, benzylamino, methylsulfonyl amino, methoxymethyl amino, trifyl amino, ethylsulfonylamino, ethylamino, thiazolyl amino and thiadiazolyl group amino.The R that other is concrete
2Group comprises butyl, propyl group, (methylthio group) ethylamino, methoxyl group amino, oxyethyl group amino, (methyl) propyl group, methylol, methoxyl group, cyclopropyl, methyl sulfinyl methyl, thienyl, methylsulfonyl methyl, pyridyl, furyl and aminosulfonyl ylmethyl.
R more specifically
2Group comprises methyl, ethyl, hydroxyl, methylamino, hydroxylamino and 2-aminophenyl amino.The R that other is concrete
2Group is trifluoromethyl, amino, dimethylamino, isopropylamino, phenyl amino, benzylamino, methylsulfonyl amino, methyl methoxy base amino, trifyl amino, ethylamino, 1; 3-thiazol-2-yl amino and 1; 3,4-thiadiazoles-2-base is amino.The R that other is concrete
2Group comprises butyl, propyl group, 2-(methylthio group) ethylamino, methoxyl group amino, oxyethyl group amino, sec.-propyl, 2-methyl-propyl, methylol, methoxyl group, cyclopropyl, methyl sulfinyl methyl, 2-thienyl, methylsulfonyl methyl, pyridine-2-base, 2-furyl and aminosulfonyl ylmethyl.
In one embodiment, R
2Be C
1-6Alkyl, particularly methyl or ethyl.In another embodiment, R
2Be ethyl.
In one embodiment, R
3Be hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, C
3-10Cycloalkyl, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, C
6-10Aryl, C
6-10Aryl C
1-6Alkoxyl group, 9-10 unit fractional saturation hydrocarbon ring; Contain 1,2 or 3 heteroatomic 4,5 or 6 yuan of saturated or fractional saturation heterocycle that are independently selected from N, O and S, the optional C that passes through
1-4Alkyl carries out bridge joint; Contain 1,2,3 or 4 heteroatoms that is independently selected from N, O and S but 5 membered unsaturated heterocycles that heteroatoms is O or S at the most wherein; 6 membered unsaturated heterocycles that contain 1,2 or 3 nitrogen-atoms; Perhaps contain 1,2,3 or 4 heteroatomic 8,9,10,11,12,13 or 14 yuan of saturated, fractional saturations or unsaturated heterocycle that is independently selected from N, O and S; Any above-mentioned ring is optional independently to be selected from (CH by one or more
2)
m(CO)
nR
dGroup replace.
Preferred R
3Be hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, C
3-10Cycloalkyl, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, C
6-10Aryl, C
6-10Aryl C
1-6Alkoxyl group; Contain 1,2 or 3 heteroatomic 5 or 6 yuan of saturated or fractional saturation heterocycle that are independently selected from N, O and S, the optional C that passes through
1-4Alkyl carries out bridge joint; 6 membered unsaturated heterocycles that contain 1,2 or 3 nitrogen-atoms; Contain perhaps that 1,2,3 or 4 heteroatomic 8-13 unit that is independently selected from N, O and S is saturated, fractional saturation or unsaturated heterocycle; Any above-mentioned ring is optional to be independently selected from R by one or more
dGroup replace.
In one embodiment, R
3Be amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, C
6-10Aryl; Contain 1,2 or 3 heteroatomic 5 yuan or 6 yuan of saturated or fractional saturation heterocycle that are independently selected from N, O and S, its optional C that passes through
1-4Alkyl carries out bridge joint; Contain 1,2,3 or 4 heteroatoms that is independently selected from N, O and S but wherein at the most one be 5 membered unsaturated heterocycles of O or S; 6 membered unsaturated heterocycles that contain 1,2 or 3 nitrogen-atoms; Contain perhaps that 1,2,3 or 4 heteroatomic 8-10 unit that is independently selected from N, O or S is saturated, fractional saturation or unsaturated heterocycle; Any above-mentioned ring is optional to be independently selected from R by one or more
dGroup replace.
Concrete R
3Group comprises dimethylamino, phenyl, naphthyl, pyrrolidyl, piperidyl, azonia two ring [2.2.1] heptyl, azonia two ring [2.2.2] octyl groups, piperazinyl, morpholinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, thiadiazolyl group, pyridyl, indyl, benzothienyl, diazosulfide base, Ben Bing oxadiazole base, dihydro benzo furyl, thiazoline and pyrimidyl, isoquinolyl, dihydrobenzo Er Evil satellite-based and Er hydrogen benzoxazinyl; Any above-mentioned ring is optional to be independently selected from R by one or more
dGroup replace.The R that other is concrete
3Group is a tert.-butoxy, cyclopentyl, methyl, trifluoromethyl, methoxyl group, methylamino, amino, diethylamino, hydroxyl, benzimidazolyl-, benzofuryl, triazolopyrimidinyl, Er hydrogen benzoxazolyl, indolinyl, the dihydroquinazoline base, the dihydro phthalazinyl (phthalazinyl), indazolyl, quinolyl, the benzoisoxazole base, the benzotriazole base, the tetrahydro-b-carboline base, dihydro-iso indolyl, the Tetrahydronaphthyridderivates base, tetrazyl, benzyloxy, thio-morpholinyl and azetidinyl; Any above-mentioned ring is optional to be selected from R by one or more
dGroup replace.The R that other is concrete
3Group is the different benzopyranyl of dihydro, dihydrobenzopyrans base, dihydro indenyl, tetrahydric quinoline group, indenyl, benzothiazolyl, dihydro-benzothiazole base, tetralyl, Imidazothiazole base, naphthyridinyl, tetrahydrochysene indazole base, tetrahydro benzo thienyl, hexahydro naphthalene pyridine base, tetrahydropyridine and naphthyridinyl, tetrahydro isoquinolyl, imidazolidine and pyridyl, imidazolidine and pyrazinyl and pyrrolopyridinyl; Any above-mentioned ring is optional to be independently selected from (CH by one or more
2)
m(CO)
nR
dGroup replace.
In one embodiment, R
3Be not substituted or be independently selected from (CH by one, two, three or four
2)
m(CO)
nR
dGroup replace.
Preferred m is 0,1 or 2.In one embodiment, m is 0.
Preferred n is 0 or 1.In one embodiment, n is 0.
Preferred R
3Be not substituted or be selected from R by one, two or three
dGroup replace.
Favourable R
dGroup comprises halogen, cyano group, C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1- 6Alkoxyl group, carboxyl, C
1-6Alkoxy carbonyl, nitro, amino-sulfonyl, (C
1-6Alkyl-carbonyl) amino, morpholinyl, piperazinyl, thiazolyl, pyrazolyl, isoxazolyl and pyridyl; Any above-mentioned ring is optional to be independently selected from C by one or more
1-6Alkyl and halo C
1-6The group of alkyl replaces.The R that other is favourable
dGroup is oxo, halo C
1-6Alkyl, phenyl or pyrrolidyl, any above-mentioned ring is optional to be independently selected from C by one or more
1-6Alkyl or halo C
1-6The group of alkyl replaces.The R that other is favourable
dGroup is hydroxyl, piperidines volution, C
6-10Aryl C
1-6Alkoxyl group, two (C
1-6Alkyl) amino, C
1-6Alkyl-carbonyl and two (C
1-6Alkylamino C
1-6Alkyl.
Concrete R
dGroup comprises chlorine, fluorine, cyano group, methyl, sec.-propyl, methoxyl group, difluoro-methoxy, carboxyl, nitro, amino-sulfonyl, kharophen, methylpiperazine base, pyridyl, methylthiazol base, (methyl) (trifluoromethyl) pyrazolyl, isoxazolyl, methoxycarbonyl and morpholinyl.The R that other is concrete
dGroup is bromine, phenyl, oxo, ethyl, trifluoromethyl and pyrrolidyl.The R that other is concrete
dGroup is hydroxyl, piperidines volution, the tertiary butyl, oxyethyl group, benzyloxy, dimethylamino, ethanoyl, tertbutyloxycarbonyl and dimethylaminomethyl.
Concrete R
dGroup comprises chlorine, fluorine, cyano group, methyl, sec.-propyl, methoxyl group, difluoro-methoxy, carboxyl, nitro, amino-sulfonyl, kharophen, 1-methylpiperazine-4-base, pyridine-2-base, 2-methyl isophthalic acid, 3-thiazole-4-base, 1-methyl-3-Trifluoromethyl-1 H-pyrazoles-5-base, isoxazole-3-base, methoxycarbonyl and morpholine-4-base.The R that other is concrete
dGroup comprises bromine, phenyl, oxo, ethyl, trifluoromethyl and tetramethyleneimine-1-base.The R that other is concrete
dGroup is hydroxyl, 4 '-piperidines volution, the tertiary butyl, oxyethyl group, benzyloxy, dimethylamino, ethanoyl, tertbutyloxycarbonyl, pyridin-3-yl, tetramethyleneimine-1-base, morpholine-4-base, 1-methylpiperazine-4-base and dimethylaminomethyl.
Thus, concrete preferred R
3Group comprises dimethylamino; phenyl; chloro-phenyl-; fluorophenyl; difluorophenyl; cyano-phenyl; (chlorine) (cyano group) phenyl; (cyano group) (fluorine) phenyl; p-methoxy-phenyl; Dimethoxyphenyl; the difluoro-methoxy phenyl; carboxyl phenyl; nitrophenyl; (fluorine) (nitro) phenyl; acetylamino phenyl; (methylpiperazine) phenyl; naphthyl; the methylpyrrole alkyl; piperidyl; the methyl piperidine base; the methylpiperazine base; azonia two ring [2.2.1] heptyl; the pyridyl piperidine base; thienyl; (methylthiazol base) thienyl; [(methyl) (trifluoromethyl) pyrazolyl] thienyl isoxazolyl thienyl; the chlorothiophene base; the methoxycarbonyl thienyl; thiazolyl; the dimethylthiazole base; (kharophen) (methyl) thiazolyl; the methylimidazole base; the trimethylammonium pyrazolyl; the dimethyl isoxazole base; the methyl thiazolium di azoly; pyridyl; the morpholinyl pyridyl; (methoxyl group) (methyl) indyl; benzothienyl; diazosulfide base Ben Bing oxadiazole base; dihydro benzo furyl; thiazoline and pyrimidyl; isoquinolyl; dihydrobenzo Er Evil satellite-based; (methyl) Er hydrogen benzoxazinyl; the amino-sulfonyl phenyl; cyanopyridine-based; the sec.-propyl piperidyl; the methylmorpholine base; azonia two ring [2.2.2] octyl group and morpholinyls.Further particularly preferred R
3Group comprises indyl, the skatole base, the methoxyl group indyl, the bromo indole base, the fluoro indole base, benzimidazolyl-, methoxyl group benzo furyl, triazolopyrimidinyl, the phenyl thiazole base, the chloro thiophene base, the chloro-indole base, the oxo-dihydro benzoxazolyl, methoxyl group oxoindoline base, the ethyl benzo imidazole base, the oxo-dihydro quinazolyl, methyl oxo-dihydro phthalazinyl, dichlorophenyl, fluorine (trifluoromethyl) phenyl, the tolimidazole base, (trifluoromethyl) benzimidazolyl-, indazolyl, quinolyl, the benzoisoxazole base, the benzotriazole base, the cyanoindole base, the tetrahydro-b-carboline base, tert.-butoxy, dihydro-iso indolyl, the Tetrahydronaphthyridderivates base, the pyrrolidyl tetrazyl, cyclopentyl, benzyloxy, methyl, alkyl dimethyl pyrrole, the dioxo thio-morpholinyl, trifluoromethyl, the methyl azetidine base, the ethyl piperidine base, methoxyl group, methylamino, amino, diethylamino and hydroxyl.Further concrete preferred R
3Group comprises the oxyindole base; the different benzopyranyl of (piperidines volution) dihydro; (piperidines volution) dihydrobenzopyrans base; the chloro benzimidazole base; (oxo) Er hydrogen benzoxazolyl; (piperidines volution) dihydro indenyl; (oxo) tetrahydric quinoline group; the chlorine indazolyl; (ethyl) (methyl) indyl; methyl (nitro) indyl; (methoxyl group) (methyl) indenyl; (hydroxyl) (methyl) indyl; methoxyl group benzo imidazolyl; dimethylated indolyl; the methylbenzothiazole base; (methoxyl group) (oxo) Er hydrogen benzoxazolyl; benzothiazolyl; (fluorine) (methyl) indyl; (tertiary butyl) (methyl) indyl; (oxyethyl group) (methyl) indyl; (benzyloxy) (methyl) indyl; (oxo) dihydro-benzothiazole base; fluorobenzene and imidazolyl; tetralyl; (methyl) Tetrahydronaphthyridderivates base; the Imidazothiazole base; benzofuryl; naphthyridinyl; the tetrahydrochysene indazole base; the tetrahydro benzo thienyl; (oxo) dihydro-iso indolyl; [(dimethylamino) ethyl] (oxo) dihydro-iso indolyl; (benzyl) (oxo) hexahydro naphthalene pyridine base; tetrahydropyridine and naphthyridinyl; (ethanoyl) tetrahydro isoquinolyl; (methyl) tetrahydro isoquinolyl; tetrahydro isoquinolyl; [(tert.-butoxy) (oxo) ethyl] (methoxyl group) (methyl) indyl; (methoxyl group) (methyl) (pyridylmethyl) indyl; (methoxyl group) dimethylated indolyl; (methoxyl group) (methyl) (pyrrolidyl ethyl) indyl; (methoxyl group) (methyl) (morpholinyl ethyl) indyl; methyl benzo isoxazolyl; (dimethylamino) (methyl) indyl; isoquinolyl; (methyl) imidazolidine and pyridyl; the methyl benzothienyl; (carboxymethyl) (methoxyl group) (methyl) indyl; (methoxyl group) (methyl) [(methylpiperazine base) (oxo) ethyl] indyl; (methyl) imidazolidine and pyrazinyl; [(dimethylamino) methyl] (methyl) indyl; the tetrafluoro indyl; (fluorine) (methyl) indyl; pyrrolopyridinyl; (methoxyl group) pyrrolopyridinyl; imidazolyl; the ethanoyl piperazinyl; (dimethyl glycyl) azetidinyl; (methoxy ethyl) azetidinyl and methoxyl group azetidinyl.
Concrete R
3Group is a dimethylamino; phenyl; the 4-chloro-phenyl-; the 2-fluorophenyl; the 3-fluorophenyl; the 4-fluorophenyl; 3; the 4-difluorophenyl; the 2-cyano-phenyl; the 3-cyano-phenyl; the 4-cyano-phenyl; 2-chloro-4-cyano-phenyl; 3-cyano group-4-fluorophenyl; the 3-p-methoxy-phenyl; the 4-p-methoxy-phenyl; 2; the 5-Dimethoxyphenyl; 3; the 4-Dimethoxyphenyl; 3-difluoro-methoxy phenyl; 4-difluoro-methoxy phenyl; the 4-carboxyl phenyl; the 2-nitrophenyl; the 3-nitrophenyl; the 4-nitrophenyl; 3-fluoro-4-nitrophenyl; the 4-acetylamino phenyl; 4-(1-methylpiperazine-4-yl) phenyl; the 2-naphthyl; 1-methylpyrrolidin-3-base; piperidines-1-base; 1-methyl piperidine-2-base; 1-methyl piperidine-3-base; 1-methyl piperidine-4-base; 1-methylpiperazine-4-base; azonia two ring [2.2.1] heptan-2-base; 1-pyridine-2-phenylpiperidines-3-base; the 2-thienyl; 5-(2-methyl isophthalic acid; 3-thiazole-4-yl)-the 2-thienyl; 5-[1-methyl-3-(trifluoromethyl)-1H-pyrazoles-5-yl]-the 2-thienyl; 5-isoxazole-3-base-2-thienyl; 5-chloro-2-thienyl; 2-(methoxycarbonyl)-3-thienyl; 1; 3-thiazole-5-base; 2; 4-dimethyl-1; 3-thiazole-5-base; 2-(kharophen)-4-methyl isophthalic acid; 3-thiazole-5-base; 1; 2-dimethyl-1H-imidazol-4 yl; 1; 3; 5-trimethylammonium-1H-pyrazoles-4-base; 3; 5-dimethyl isoxazole-4-base; the 4-methyl isophthalic acid; 2; 3-thiadiazoles-5-base; pyridin-3-yl; 2-morpholine-4-yl pyridines-5-base; 5-methoxyl group-2-Methyl-1H-indole-3-base; thionaphthene-3-base; 2; 1; 3-diazosulfide-5-base; 2; 1; 3-Ben Bing oxadiazole-4-base; 2; 3-dihydro-1-cumarone-5-base; 6; 7-dihydro-5H-[1; 3] thiazole also [3; 2-a] pyrimidin-3-yl; isoquinoline 99.9-5-base; 2; 3-dihydro-1; 4-Ben Bing Er Evil star-6-base 4-methyl-3; 4-dihydro-2H-1,4-benzoxazine-7-base; pyridin-4-yl; 4-amino-sulfonyl phenyl; 2-cyanopyridine-5-base; 1-sec.-propyl piperidines-3-base; 4-methylmorpholine-2-base; azonia two ring [2.2.2] sufferings-4-base and morpholine-4-base.Further concrete R
3Group is the 1H-indol-3-yl, 2-Methyl-1H-indole-3-base, 5-methoxyl group-1H-indol-3-yl, 5-bromo-1H-indol-3-yl, 5-fluoro-1H-indol-3-yl, 1H-benzoglyoxaline-1-base, 7-methoxyl group-1-cumarone-2-base, 5-methoxyl group-1H-indoles-2-base, 5-fluoro-1H-indoles-2-base, [1,2,4] triazolo [1,5-a] pyrimidine-6-base, 4-phenyl-1, the 3-thiazol-2-yl, 5-chloro-1-thionaphthene-3-base, 4-chloro-1H-indol-3-yl, 2-oxo-1,3-benzoxazole-3 (2H)-Ji, 5-methoxyl group-2-oxo-2,3-dihydro-1H-indol-3-yl, 6-methoxyl group-2-oxo-2,3-dihydro-1H-indol-3-yl, 2-ethyl-1H-benzoglyoxaline-1-base, the 1-naphthyl, 2-oxo quinazoline-1-(2H)-Ji, 4-methyl isophthalic acid-oxo naphthyridine-2 (1H)-Ji, 2, the 4-dichlorophenyl, 2-fluoro-6-(trifluoromethyl) phenyl, 2, the 6-dichlorophenyl, 2-fluoro-3-(trifluoromethyl) phenyl, 2-methyl isophthalic acid H-benzoglyoxaline-1-base, 2-(trifluoromethyl)-1H-benzoglyoxaline-1-base, 1H-indazole-1-base, quinoline-3-base, 1,2-benzoisoxazole-3-base, 2-Methyl-1H-indole-1-base, 1H-1,2,3-benzotriazole-1-base, 5-cyano-1 H-indol--1-base, 2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-4-base, tert.-butoxy, 2,3-dihydro-1H-isoindole-2-base, 1,2,3,4-tetrahydrochysene-1,8-naphthyridine-5-base, 5-tetramethyleneimine-1-base-2H-tetrazolium-2-base, cyclopentyl, benzyloxy, methyl, 1,3-dimethyl pyrrolidine-3-base, 1,1-dioxo thiomorpholine-4-base, trifluoromethyl, 1-methyl azetidine-3-base, 1-ethyl piperidine-3-base, methoxyl group, methylamino, amino, diethylamino, 5-cyano-1 H-indol--3-base and hydroxyl.Further concrete R
3Group is 1-Methyl-1H-indole-3-base; 6-fluoro-1H-indol-3-yl; 5-chloro-1H-indol-3-yl; 1H-indoles-2-base; 5-hydroxyl-1H-indol-3-yl; 1; 4 '-piperidines volution-3; the different chromene of 4-dihydro-3-base; 2; 4-piperidines volution-3; 4-dihydrobenzopyrans-4-base; 5-chloro-1H-benzimidazolyl-2 radicals-Ji; 2-oxo-1; 3-benzoxazole-3 (2H)-Ji; 2H-indazole-2-base; 1; 4 '-piperidines volution-2; 3-dihydro indenes-3-base; 2-oxo-1; 2; 3; 4-tetrahydroquinoline-4-base; 5-chloro-1H-indazole-3-base; 2-ethyl-5-Methyl-1H-indole-3-base; 2-ethyl-6-Methyl-1H-indole-3-base; 2-methyl-5-nitro-1H-indol-3-yl; 5-methoxyl group-2-methyl isophthalic acid H-indenes-3-base; 5-hydroxy-2-methyl-1H-indol-3-yl; 5-methoxyl group-1H-benzimidazolyl-2 radicals-Ji; 2; 5-dimethyl-1H-indol-3-yl; 1H-benzimidazolyl-2 radicals-Ji; 6-methoxyl group-1H-indol-3-yl; 1H-indoles-6-base; the 2-methyl isophthalic acid; 3-benzothiazole-5-base; 5-methoxyl group-2-oxo-1; 3-benzoxazole-3 (2H)-Ji; 7-methoxyl group-1H-indol-3-yl; 1; 3-benzothiazole-2-base; 7-fluoro-2-Methyl-1H-indole-3-base; 5-ethyl-2-Methyl-1H-indole-3-base; the 5-tertiary butyl-2-Methyl-1H-indole-3-base; 5-oxyethyl group-2-Methyl-1H-indole-3-base; 5-(benzyloxy)-2-Methyl-1H-indole-3-base; 1H-indoles-1-base; 2-oxo-1; 3-benzothiazole-3 (2H)-Ji; quinoline-5-base; 6-fluoro-1H-benzimidazolyl-2 radicals-Ji; 5; 6; 7; 8-naphthane-1-base; 3-methyl-5; 6; 7; 8-tetrahydrochysene-1; 8-naphthyridine-2-base; imidazo [2; 1-b] [1,3] thiazole-6-base; 1-cumarone-5-base; 1-thionaphthene-2-base; 1,8-naphthyridine-2-base; 1; 2; 3,4-tetrahydrochysene-1,8-naphthyridine-7-base; 4; 5; 6,7-tetrahydrochysene-1H-indazole-3-base; 4,5; 6; 7-tetrahydrochysene-1-thionaphthene-3-base; 1-oxo-1,3-dihydro-2H-isoindole-2-base; 2-[2-(dimethylamino) ethyl]-3-oxo-2,3-dihydro-1H-isoindole-4-base; 6-benzyl-2-oxo-1; 2; 5,6,7; 8-six hydrogen-1; 6-naphthyridine-3-base; 6,7,8; 9-tetrahydropyridine also [2; 3-b]-1,6-naphthyridine-7-base; 2-ethanoyl-1,2; 3; 4-tetrahydroisoquinoline-1-base; the 2-methyl isophthalic acid, 2,3; 4-tetrahydroisoquinoline-3-base; 1; 2,3,4-tetrahydroisoquinoline-2-base; 1-(2-tert.-butoxy-2-oxoethyl)-5-methoxyl group-2-Methyl-1H-indole-3-base; 5-methoxyl group-2-methyl isophthalic acid-(pyridin-3-yl methyl)-1H-indol-3-yl; 5-methoxyl group-1; 2-dimethyl-1H-indol-3-yl; 5-methoxyl group-2-methyl isophthalic acid-(2-tetramethyleneimine-1-base ethyl)-1H-indol-3-yl; 5-methoxyl group-2-methyl isophthalic acid-(2-morpholine-4-base ethyl)-1H-indol-3-yl; the 5-methyl isophthalic acid; 2-benzoisoxazole-3-base; 5-(dimethylamino)-2-Methyl-1H-indole-3-base; 6-methoxyl group-1-cumarone-3-base; quinoline-6-base; isoquinoline 99.9-6-base; 5-methyl-4,5,6; 7-tetrahydrochysene-3H-imidazo [4; 5-c] pyridine-6-base; 5-methyl isophthalic acid-thionaphthene-3-base; 1-(carboxymethyl)-5-methoxyl group-2-Methyl-1H-indole-3-base; 5-methoxyl group-2-methyl isophthalic acid-[2-(1-methylpiperazine-4-yl)-2-oxoethyl]-1H-indol-3-yl; 7-methyl-5,6,7; 8-imidazolidine also [1; 2-a] pyrazine-2-base; the 5-[(dimethylamino) methyl]-2-Methyl-1H-indole-3-base; 4,5,6; 7-tetrafluoro-1H-indol-3-yl; 5-fluoro-2-Methyl-1H-indole-3-base; 1H-pyrrolo-[2; 3-b] pyridin-3-yl; IH-pyrrolo-[3,2-c] pyridin-3-yl; 5-methoxyl group-1H-pyrrolo-[2,3-c] pyridin-3-yl; the 2-methyl isophthalic acid; 2; 3,4-tetrahydroisoquinoline-1-base; 1H-imidazoles-1-base; 4-ethanoyl piperazine-1-base; 1-(N, N-dimethyl glycyl) azetidine-3-base; 1-(2-methoxy ethyl) azetidine-3-base; 3-methoxyl group azetidine-1-base and 1-azonia two ring [2.2.2] oct-3-yls.
In one embodiment, R
3Be azonia two ring [2.2.1] heptyl, azonia two ring [2.2.2] octyl groups, thiazolyl, pyrazolyl isoxazolyl, thiadiazolyl group, benzothienyl, diazosulfide base Ben Bing oxadiazole base, dihydro benzo furyl, thiazoline and pyrimidyl, dihydrobenzo Er Evil satellite-based, Er hydrogen benzoxazinyl, benzimidazolyl-, triazolopyrimidinyl, Er hydrogen benzoxazolyl, indolinyl, the dihydroquinazoline base, the dihydro phthalazinyl, indazolyl, the benzoisoxazole base, the benzotriazole base, the tetrahydro-b-carboline base, dihydro-iso indolyl, the Tetrahydronaphthyridderivates base, tetrazyl, thio-morpholinyl, azetidinyl, the different benzopyranyl of dihydro, the dihydrobenzopyrans base, tetrahydric quinoline group, indenyl, the dihydro-benzothiazole base, the Imidazothiazole base, naphthyridinyl, the tetrahydrochysene indazole base, the tetrahydro benzo thienyl, hexahydro naphthalene pyridine base, tetrahydropyridine and naphthyridinyl, tetrahydro isoquinolyl, imidazolidine and pyridyl, imidazolidine and pyrazinyl or pyrrolopyridinyl; Any above-mentioned ring is optional to be independently selected from (CH by one or more
2)
m(CO)
nR
dGroup replace.
Concrete preferred R
3Group is azonia two ring [2.2.1] heptyl; thiazolyl; the dimethylthiazole base; (kharophen) (methyl) thiazolyl; the trimethylammonium pyrazolyl; the dimethyl isoxazole base; the methyl thiazolium di azoly; benzothienyl; diazosulfide base Ben Bing oxadiazole base; dihydro benzo furyl; thiazoline and pyrimidyl; dihydrobenzo Er Evil satellite-based; (methyl) Er hydrogen benzoxazinyl; azonia two ring [2.2.2] octyl groups; benzimidazolyl-; triazolopyrimidinyl; the phenyl thiazole base; the chloro thiophene base; the oxo-dihydro benzoxazolyl; methoxyl group oxoindoline base; the ethyl benzo imidazole base; the oxo-dihydro quinazolyl; methyl oxo-dihydro phthalazinyl; the tolimidazole base; (trifluoromethyl) benzimidazolyl-; indazolyl; the benzoisoxazole base; the benzotriazole base; the tetrahydro-b-carboline base; dihydro-iso indolyl; the Tetrahydronaphthyridderivates base; the pyrrolidyl tetrazyl; the dioxo thio-morpholinyl; the methyl azetidine base; the different benzopyranyl of (piperidines volution) dihydro; (piperidines volution) dihydrobenzopyrans base; the chloro benzimidazole base; (oxo) Er hydrogen benzoxazolyl; (oxo) tetrahydric quinoline group; the chlorine indazolyl; (methoxyl group) (methyl) indenyl; methoxyl group benzo imidazolyl; (methoxyl group) (oxo) Er hydrogen benzoxazolyl; (oxo) dihydro-benzothiazole base; fluorobenzene and imidazolyl; (methyl) Tetrahydronaphthyridderivates base; the Imidazothiazole base; naphthyridinyl; the tetrahydrochysene indazole base; the tetrahydro benzo thienyl; (oxo) dihydro-iso indolyl; [(dimethylamino) ethyl] dihydro-iso indolyl; (benzyl) (oxo) hexahydro naphthalene pyridine base; tetrahydropyridine and naphthyridinyl; (ethanoyl) tetrahydro isoquinolyl; (methyl) tetrahydro isoquinolyl; tetrahydro isoquinolyl; methyl benzo isoxazolyl; (methyl) imidazolidine and pyridyl; the methyl benzothienyl; (methyl) imidazolidine and pyrazinyl; pyrrolopyridinyl; (methoxyl group) pyrrolopyridinyl; (dimethyl glycyl) azetidinyl; (methoxy ethyl) azetidinyl and methoxyl group azetidinyl.
In one embodiment, R
3Be azonia two ring [2.2.1] heptan-2-base; 1,3-thiazoles-5-base; 2,4-dimethyl-1; 3-thiazole-5-base; 2-(kharophen)-4-methyl isophthalic acid, 3-thiazole-5-base; 1,3; 5-trimethylammonium-1H-pyrazoles-4-base; 3,5-dimethyl isoxazole-4-base; the 4-methyl isophthalic acid, 2; 3-thiadiazoles-5-base; thionaphthene-3-base; 2,1,3-diazosulfide-5-base; 2; 1,3-Ben Bing oxadiazole-4-base; 2,3-dihydro-1-cumarone-5-base; 6; 7-dihydro-5H-[1,3] thiazole [3,2-a] pyrimidin-3-yl also; 2; 3-dihydro-1,4-Ben Bing Er Evil star-6-base; 4-methyl-3,4-dihydro-2H-1; 4-benzoxazine-7-base; azonia two ring [2.2.2] suffering-4-bases; 1H-benzoglyoxaline-1-base; [1,2,4] triazolo [1; 5-a] pyrimidine-6-base; 4-phenyl-1,3-thiazoles-2-base; 5-chloro-1-thionaphthene-3-base; 2-oxo-1,3-benzoxazole-3 (2H)-Ji; 5-methoxyl group-2-oxo-2; 3-dihydro-1H-indol-3-yl; 6-methoxyl group-2-oxo-2,3-dihydro-1H-indol-3-yl; 2-ethyl-1H-benzoglyoxaline-1-base; 2-oxo quinazoline-1-(2H)-Ji; 4-methyl isophthalic acid-oxo phthalazines-2 (1H)-Ji; 2-methyl isophthalic acid H-benzoglyoxaline-1-base; 2-(trifluoromethyl)-1H-benzoglyoxaline-1-base; 1H-indazole-1-base; 1,2-benzoisoxazole-3-base; 1H-1; 2,3-benzotriazole-1-base; 2,3; 4; 9-tetrahydrochysene-1H-β-Ka Lin-4-base; 2,3-dihydro-1H-isoindole-2-base; 1,2; 3; 4-tetrahydrochysene-1,8-naphthyridine-5-base; 5-tetramethyleneimine-1-base-2H-tetrazolium-2-base; 1,1-dioxo thiomorpholine-4-base; 1-methyl azetidine-3-base; 1; 4 '-piperidines volution-3; the different chromene of 4-dihydro-3-base; 2,4-piperidines volution-3,4-dihydrobenzopyrans-4-base; 5-chloro-1H-benzoglyoxaline-3-base; 2-oxo-1; 3-benzoxazole-3 (2H)-Ji; 2H-indazole-2-base; 1; 4 '-piperidines volution-2,3-dihydro indenes-3-base; 2-oxo-1,2; 3; 4-tetrahydroquinoline-4-base; 5-chloro-1H-indazole-3-base; 5-methoxyl group-2-methyl isophthalic acid H-indenes-3-base; 5-methoxyl group-1H-benzimidazolyl-2 radicals-Ji; 1H-benzimidazolyl-2 radicals-Ji; 5-methoxyl group-2-oxo-1,3-benzoxazole-3 (2H)-Ji; 2-oxo-1,3-benzothiazole-3 (2H)-Ji; 6-fluoro-1H-benzimidazolyl-2 radicals-Ji; 5; 6; 7,8-naphthane-1-base; 3-methyl-5,6; 7; 8-tetrahydrochysene-1,8-naphthyridine-2-base; imidazo [2,1-b] [1; 3] thiazole-6-base; 1-thionaphthene-2-base; 1; 8-naphthyridine-2-base; 1,2,3; 4-tetrahydrochysene-1; 8-naphthyridine-7-base; 4,5,6; 7-tetrahydrochysene-1H-indazole-3-base; 4; 5,6,7-tetrahydrochysene-1-thionaphthene-3-base; 1-oxo-1; 3-dihydro-2H-isoindole-2-base; 2-[2-(dimethylamino) ethyl]-3-oxo-2; 3-dihydro-1H-isoindole-4-base; 6-benzyl-2-oxo-1,2,5; 6; 7,8-six hydrogen-1,6-naphthyridine-3-base; 6; 7; 8, the 9-tetrahydropyridine is [2,3-b]-1 also; 6-naphthyridine-7-base; 2-ethanoyl-1; 2,3,4-tetrahydroisoquinoline-1-base; the 2-methyl isophthalic acid; 2; 3,4-tetrahydroisoquinoline-3-base; 1,2; 3; 4-tetrahydroisoquinoline-2-base; the 5-methyl isophthalic acid, 2-benzoisoxazole-3-base; 5-methyl-4,5; 6; 7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-base; 5-methyl isophthalic acid-thionaphthene-3-base; 7-methyl-5,6; 7; the 8-imidazolidine is [1,2-a] pyrazine-2-base also; 1H-pyrrolo-[2,3-b] pyridin-3-yl; 1H-pyrrolo-[3; 2-c] pyridin-3-yl; 5-methoxyl group-1H-pyrrolo-[2; 3-c] pyridin-3-yl; the 2-methyl isophthalic acid, 2,3; 4-tetrahydroisoquinoline-1-base; 1-(N, N-dimethyl glycyl) azetidine-3-base; 1-(2-methoxy ethyl) azetidine-3-base; 3-methoxyl group azetidine-1-base or 1-azonia two ring [2.2.2] oct-3-yls.
In one embodiment, R
3Be azetidinyl, it is chosen wantonly and is independently selected from (CH by one or more
2)
m(CO)
nR
dGroup replace.Preferably, described optional substituting group is C
1-6Alkyl, particularly methyl.
In one embodiment, R
3Be 1-methyl azetidine-3-base, 1-(N, N-dimethyl glycyl) azetidine-3-base, 1-(2-methoxy ethyl) azetidine-3-base or 3-methoxyl group azetidine-1-base.
In one embodiment, R
3Be 1-methyl azetidine-3-base.
Preferred R
4Be hydrogen.
Preferred R
5Be C
1-6Alkyl, particularly methyl.Other preferred R
5Group is a hydrogen.
Preferred R
6And R
8Be hydrogen, C independently
1-6Alkyl or optional replace contain 1,2 or 3 heteroatomic 5 yuan or 6 yuan of saturated or fractional saturation heterocycle that are independently selected from N, O and S; Perhaps R
6And R
8Form oxo group together.
More especially, R
6Be hydrogen, C
1-4Alkyl or morpholinyl, and R
8Be hydrogen or C
1-4Alkyl; Perhaps R
6And R
8Form oxo group together.
Particularly, R
6Be hydrogen, methyl or morpholine-4-base, and R
8Be hydrogen or methyl; Perhaps R
6And R
8Form oxo group together.
In one embodiment, R
6Be hydrogen, C
1-6Alkyl or contain 1,2 or 3 heteroatomic 5 yuan or 6 yuan of saturated or fractional saturation heterocycle that are independently selected from N, O or S, described heterocycle is optional by C
1-6Alkyl replaces.
Concrete R
6Group comprises hydrogen, methyl and morpholinyl.R most preferably
6Be hydrogen, methyl or morpholine-4-base.
In one embodiment, R
6Be hydrogen.
Preferred R
8Be hydrogen or C
1-6Alkyl.More especially, R
8Be hydrogen or methyl.
In one embodiment, R
8Be hydrogen.
In one embodiment, R
6And R
8Form oxo group together.
In one embodiment, R
aBe hydrogen, C
1-6Alkyl or C
1-6Alkyl-carbonyl.Preferred R
aBe hydrogen, methyl or ethanoyl.
In one embodiment, R
cBe hydrogen or methyl.
In one embodiment, R
eBe hydrogen, C
1-6Alkyl or C
1-6Alkyl-carbonyl.Preferred R
eBe hydrogen, methyl or ethanoyl.
In one embodiment, R
hBe hydrogen, C
1-6Alkyl or C
6-10Aryl C
1-6Alkyl.Preferred R
hBe methyl or benzyl.
In one embodiment, R
kBe NHSO
2R
g, pyrazolyl, piperidyl, morpholinyl or tetrazyl, any above-mentioned ring is optional by C
1-6Alkyl replaces, particularly methyl.Preferred R
kBe dimethyl pyrazole base, piperidyl, morpholinyl, pyrazolyl, tetrazyl or (methylsulfonyl) amino.
The α 1 carbon asymmetric center of preferred The compounds of this invention has the S three-dimensional chemical configuration.In one embodiment, described α 1 carbon asymmetric center has the R three-dimensional chemical configuration.
The present invention also provides formula II compound:
Wherein:
R
1, R
3, R
5, R
6, R
8, X, p and t define suc as formula I;
D represents not exist, CH
2, CH
2CH
2Perhaps CH=CH;
A represents CH or N;
Y represents NR
e, O or S;
Z represents N or CR
f
R
7Expression C
1-6Alkyl, halo C
1-6Alkyl, hydroxyl, N (R
b)
2, hydroxyl C
1-6Alkyl, C
1-6Alkoxyl group, C
3-7Cycloalkyl, C
1-6Alkyl S (O)
mR
g, thienyl, furyl or pyridyl;
R
bExpression hydrogen, C
1-4Alkyl, hydroxyl, C
1-4Alkoxyl group, C
1-6Alkyl S (O)
wR
g, SO
2R
g, phenyl, benzyl, thiazolyl or thiadiazolyl group, any above-mentioned ring is optional to be replaced by amino;
R
eExpression hydrogen or C
1-6Alkyl;
R
fExpression hydrogen, C
1-6Alkyl or optional quilt are up to two and are selected from halogen, cyano group, C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkyl or halo C
1-6The C that the group of alkoxyl group replaces
6-10Aryl;
R
gBe C
1-6Alkyl, halo C
1-6Alkyl, amino, C
1-6Alkylamino or two (C
1-6Alkyl) amino;
W is 0,1 or 2;
Perhaps its pharmacy acceptable salt or tautomer.
In one embodiment:
D does not exist;
R
7Be C
1-6Alkyl, halo C
1-6Alkyl, hydroxyl or N (R
b)
2
R
bBe hydrogen, C
1-4Alkyl, hydroxyl, C
1-4Alkoxyl group, SO
2R
g, phenyl, benzyl, thiazolyl or thiadiazolyl group, any above-mentioned ring is optional to be replaced by amino;
R
gBe C
1-6Alkyl or halo C
1-6Alkyl;
Perhaps its pharmacy acceptable salt or tautomer.
Formerly in a kind of embodiment of embodiment:
R
7Be C
1-6Alkyl, hydroxyl or N (R
b)
2
R
8Be hydrogen; With
R
bBe hydrogen, C
1-4Alkyl, hydroxyl or optional by the amino phenyl that replaces.
The The compounds of this invention that one class is favourable has the three-dimensional chemical configuration of formula III:
R wherein
1, R
3, R
5, R
6, R
7, R
8, A, D, X, Y, Z, p and t define suc as formula II.
About the preferred compound of formula II and III such as previous rule qualification.
In one embodiment:
D does not exist;
R
7Be C
1-6Alkyl, halo C
1-6Alkyl, hydroxyl or N (R
b)
2
R
bBe hydrogen, C
1-4Alkyl, hydroxyl, C
1-4Alkoxyl group, SO
2R
g, phenyl, benzyl, thiazolyl or thiadiazolyl group, any above-mentioned ring is optional to be replaced by amino;
R
gBe C
1-6Alkyl or halo C
1-6Alkyl;
Perhaps its pharmacy acceptable salt or tautomer.
Formerly in a kind of embodiment of embodiment:
R
7Be C
1-6Alkyl, hydroxyl or N (R
b)
2
R
8Be hydrogen; With
R
bBe hydrogen, C
1-4Alkyl, hydroxyl or optional by the amino phenyl that replaces.
For fear of producing query, R
1But can be connected on any the position of substitution of ring.
In one embodiment, D does not exist.
In one embodiment, A is N, and Y is NR
ePerhaps O and Z are N or CR
f
In another embodiment, A is N, and Y is NR
eAnd Z is CR
f
In another embodiment, A is CH, and Y is that S and Z are CR
f
In another embodiment, A and Z are that N and Y are NR
e
In another embodiment, Y is O.
Preferred R
1Be phenyl, naphthyl, thienyl, isoxazolyl, pyridyl, benzothienyl or thiazoltriazol base, they are chosen wantonly by one or two and independently are selected from cyano group, bromine, chlorine, fluorine, methyl, trifluoromethyl, methoxyl group, difluoro-methoxy or phenyl groups replacement.Other preferred R
1Group is hydrogen and optional dihydrobenzo Er Evil satellite-based, benzothiazolyl, quinolyl or the isoquinolyl that replaces.Other preferred R
1Group comprises hydroxyl, (benzyl) (methyl) amino, dimethylamino, methoxycarbonyl, ethanoyl, cyclohexyl, bromine and optional substituted quinoxaline base, morpholinyl, tetrahydro isoquinolyl, indyl, dibenzo [b, d] furyl, naphthyridinyl or dihydroquinoline base.
Preferred R
3Be dimethylamino; phenyl; naphthyl; pyrrolidyl; piperidyl; azonia two ring [2.2.1] heptyl; azonia two ring [2.2.2] octyl groups; piperazinyl; morpholinyl; thienyl; thiazolyl; imidazolyl; pyrazolyl isoxazolyl; thiadiazolyl group; pyridyl; indyl; benzothienyl; diazosulfide base Ben Bing oxadiazole base; dihydro benzo furyl; thiazoline and pyrimidyl; isoquinolyl; dihydrobenzo Er Evil satellite-based and Er hydrogen benzoxazinyl, any above-mentioned ring is optional by one; two or three are independently selected from following group and replace: chlorine; fluorine; methyl; sec.-propyl; cyano group; methoxyl group; difluoro-methoxy; carboxyl; nitro; amino-sulfonyl; kharophen; the methylpiperazine base; pyridyl; the methylthiazol base; (methyl) (trifluoromethyl) pyrazolyl isoxazolyl; methoxycarbonyl and morpholinyl.The optional substituting group of on the described ring other comprises bromine, phenyl, oxo, ethyl, trifluoromethyl and pyrrolidyl.The optional substituting group of on the described ring other comprises hydroxyl, piperidines volution, the tertiary butyl, oxyethyl group, benzyloxy, dimethyl aminoethyl, benzyl, ethanoyl (tertbutyloxycarbonyl) methyl, pyridylmethyl, pyrrolidyl ethyl, morpholinyl ethyl, dimethylamino, carboxymethyl, [(methylpiperazine base) carbonyl] methyl, dimethylaminomethyl, (dimethylaminomethyl) carbonyl and methoxy ethyl.Other preferred R
3Group is a tert.-butoxy, cyclopentyl, methyl, trifluoromethyl, methoxyl group, methylamino, amino, diethylamino, hydroxyl or optional replace be selected from following ring: benzimidazolyl-, benzofuryl, triazolopyrimidinyl, Er hydrogen benzoxazolyl, indolinyl, the dihydroquinazoline base, the dihydro phthalazinyl, indazolyl, quinolyl, the benzoisoxazole base, the benzotriazole base, the tetrahydro-b-carboline base, dihydro-iso indolyl, the Tetrahydronaphthyridderivates base, tetrazyl, benzyloxy, thio-morpholinyl and azetidinyl, optional substituting group as defined above.Other preferred R
3Group is the ring that is selected from following optional replacement: the different benzopyranyl of dihydro, dihydrobenzopyrans base, dihydro indenyl, tetrahydric quinoline group, indenyl, benzothiazolyl, dihydro-benzothiazole base, tetralyl, Imidazothiazole base, naphthyridinyl, tetrahydrochysene indazole base, tetrahydro benzo thienyl, hexahydro naphthalene pyridine base, tetrahydropyridine and naphthyridinyl, tetrahydro isoquinolyl, imidazolidine and pyridyl, imidazolidine and pyrazinyl and pyrrolopyridinyl, optional substituting group as defined above.
Preferred R
5Be methyl.Other preferred R
5Group is a hydrogen.
Preferred R
6Be hydrogen, methyl or morpholinyl.
Preferred R
7Be methyl, ethyl, hydroxyl or N (R
b)
2Other preferred R
7Group is a trifluoromethyl.Other preferred R
7Group is butyl, propyl group, sec.-propyl, (methyl) propyl group, methylol, methoxyl group, cyclopropyl, methyl sulfinyl methyl, thienyl, methylsulfonyl methyl, pyridyl, furyl and aminosulfonyl ylmethyl.
In one embodiment, R
7Be C
1-6Alkyl.
In another embodiment, R
7Be methyl or ethyl.
Preferred R
bBe hydrogen, methyl, hydroxyl or aminophenyl.Other preferred R
bGroup comprises ethyl, sec.-propyl, methoxyl group, methylsulfonyl, ethylsulfonyl, trifyl, phenyl, benzyl, thiazolyl and thiadiazolyl group.Other preferred R
bGroup is methylmercaptoethyl and oxyethyl group.
Thus, concrete preferred R
7Group comprises methyl, ethyl, hydroxyl, methylamino, hydroxylamino and (aminophenyl) amino.The R that other is concrete
7Group comprises trifluoromethyl, amino, dimethylamino, isopropylamino, phenyl amino, benzylamino, methylsulfonyl amino, methoxymethyl amino, trifyl amino, ethylsulfonylamino, ethylamino, thiazolyl amino and thiadiazolyl group amino.The R that other is concrete
7Group comprises butyl, propyl group, (methylthio group) ethylamino, methoxyl group amino, oxyethyl group amino, propyl group, (methyl) propyl group, methylol, methoxyl group, cyclopropyl, methyl sulfinyl methyl, thienyl, methylsulfonyl methyl, pyridyl, furyl and aminosulfonyl ylmethyl.
Preferred R
eBe hydrogen or methyl.
Preferred R
fBe hydrogen, C
1-6Alkyl or C
6-10Aryl.More especially, R
fBe hydrogen, methyl or phenyl.Further concrete R
fGroup is a naphthyl, particularly the 2-naphthyl.
Preferred R
gBe methyl, ethyl or trifluoromethyl.Other R
gGroup is amino.
Preferred w is 1 or 2.
The present invention also provides formula IA the intermediate of represented formula I compound:
R wherein
pBe R
4Perhaps suitable protecting group is such as Boc;
R
1, R
2, R
4, Het and q as defined above;
Perhaps its pharmacy acceptable salt or tautomer.
In one embodiment, D does not exist.
In one embodiment, R
pBe hydrogen or Boc.
About the preferred compound of formula IA such as previous rule qualification.
The present invention also provides formula IB compound:
Wherein D, R
2As above define with X about formula I;
R
1For containing the unsaturated or fractional saturation heterocycle of heteroatomic 8-13 unit that is independently selected from O, N and S; Any above-mentioned ring is optional to be independently selected from following group replacement by one or more: cyano group, halogen, nitro, oxo, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkyl-carbonyl, C
1-6Alkoxy carbonyl, carboxyl, C
6-10Aryl, C
6-10Aryloxy, C
6-10Aryl carbonyl and N (R
a)
2, R wherein
aBe independently selected from hydrogen, C
1-6Alkyl, C
6-10Aryl, C
1-6Alkyl-carbonyl and C
6-10Aryl carbonyl; C
1-6Alkyl N (R
a)
2(CO)
dR
k, wherein d is 0 or 1;
R
kBe C
1-6Alkoxyl group, NHSO
2R
g, contain the saturated or fractional saturation heterocycle of 1,2 or 3 heteroatomic 5 yuan or 6 yuan that are independently selected from N, O and S or contain 1,2,3 or 4 heteroatoms that is independently selected from N, O and S but 5 membered unsaturated heterocycles that heteroatoms is O or S at the most wherein; Any above-mentioned ring is optional to be independently selected from halogen and C by one or more
1-6The group of alkyl replaces;
R
gBe C
1-6Alkyl, halo C
1-6Alkyl, amino, C
1-6Alkylamino or two (C
1-6Alkyl) amino;
R
3Be azonia two ring [2.2.1] heptyl, azonia two ring [2.2.2] octyl groups, thiazolyl, pyrazolyl isoxazolyl, thiadiazolyl group, benzothienyl, diazosulfide base Ben Bing oxadiazole base, dihydro benzo furyl, thiazoline and pyrimidyl, dihydrobenzo Er Evil satellite-based, Er hydrogen benzoxazinyl, benzimidazolyl-, triazolopyrimidinyl, Er hydrogen benzoxazolyl, indolinyl, the dihydroquinazoline base, the dihydro phthalazinyl, indazolyl, the benzoisoxazole base, the benzotriazole base, the tetrahydro-b-carboline base, dihydro-iso indolyl, the Tetrahydronaphthyridderivates base, tetrazyl, thio-morpholinyl, azetidinyl, the different benzopyranyl of dihydro, the dihydrobenzopyrans base, tetrahydric quinoline group, the dihydro-benzothiazole base, the Imidazothiazole base, naphthyridinyl, the tetrahydrochysene indazole base, the tetrahydro benzo thienyl, hexahydro naphthalene pyridine base, tetrahydropyridine and naphthyridinyl, tetrahydro isoquinolyl, imidazolidine and pyridyl, imidazolidine and pyrazinyl or pyrrolopyridinyl; Any above-mentioned ring is optional to be independently selected from (CH by one or more
2)
m(CO)
nR
dGroup replace;
M is 0,1,2 or 3;
N is 0,1 or 2; With
R
dBe halogen, cyano group, C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, carboxyl, C
1-6Alkoxy carbonyl, nitro, amino-sulfonyl, (C
1-6Alkyl-carbonyl) amino, morpholinyl, piperazinyl, thiazolyl, pyrazolyl, isoxazolyl, pyridyl, oxo, halo C
1-6Alkyl, phenyl or pyrrolidyl, hydroxyl, piperidines volution, C
6-10Aryl C
1-6Alkoxyl group, two (C
1-6Alkyl) amino, C
1-6Alkyl-carbonyl or two (C
1-6Alkyl) amino C
1-6Alkyl; Any above-mentioned ring is optional to be independently selected from C by one or more
1-6Alkyl and halo C
1-6The group of alkyl replaces;
Perhaps its pharmacy acceptable salt or tautomer.
About the embodiment of preferred equivalents as before having been limited about formula I, II and III of formula IB, they fall within the scope of formula IB.
In one embodiment, R
11,2,3 or 4 the unsaturated or fractional saturation heterocycle of heteroatomic 8-13 unit that is independently selected from O, N and S that contains for optional replacement.
In one embodiment:
R
1Be optional benzothienyl, thiazoltriazol base, dihydrobenzo two Evil satellite-baseds, benzothiazolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrahydro isoquinolyl, indyl, dibenzo [b, d] furyl, naphthyridinyl or the dihydroquinoline base of replacing; With
R
3Be the optional azetidinyl that replaces.
In one embodiment:
R
1Be optional substd quinolines base, isoquinolyl, quinoxalinyl, tetrahydro isoquinolyl, naphthyridinyl or dihydroquinoline base; With
R
3Be optional substituted azetidine base.
In one embodiment:
R
1Be 2 methoxy quinoline-3-base; With
R
3Be 1-methyl azetidine-3-base.
Preferred R
2Be C
1-6Alkyl, particularly methyl or ethyl.
Preferred D is direct key.
Preferred X is C.
Within the scope of the present invention, the present invention also comprises the N-oxide compound with following formula (I) compound.Usually, described N-oxide compound can form on any available nitrogen-atoms.The N-oxide compound can be prepared by ordinary method, such as, in the presence of wet oxidation aluminium, make the reaction of formula I compound and oxone.
Within the scope of the present invention, the present invention includes the prodrug of above-mentioned formula (I) compound.Usually, described prodrug will be the functionality derivative that can convert the formula I compound of required formula I compound in vivo easily to.The selection of suitable prodrug derivant and the ordinary method of preparation are described in, for example, " Design of Prodrugs ", chief editor H.Bundgaard, Elsevier is in 1985.
Prodrug can be the pharmacology inertia derivative of biologically active substance (" parent drug " or " parent molecule "), and it need carry out, and conversion has the delivery performance of improvement with release active medicine and it in the body with respect to the parent drug molecule.Conversion can be in the described body, the result of some metabolic processes for example, and such as the chemistry or the enzymic hydrolysis effect of carboxylicesters, phosphoric acid ester or sulfuric ester, or the reduction of responsive functional group or oxygenizement.
In its scope, comprise the solvated compounds and the salt thereof of formula I compound in the present invention, for example, hydrate.
The compounds of this invention can have asymmetric center, chiral axis and chirality face (as E.L.Eliel and S.H.Wilen, Stereochemistry of Carbon Compounds, John Wiley ﹠amp; Sons, New York, 1994, described in the pages 1119-1190), and can exist for racemoid, racemic mixture and as single diastereomer and all possible isomer and composition thereof, comprise optically active isomer, all these steric isomers all are included in the scope of the present invention.In addition, compound disclosed herein can be used as tautomer and exists, and its two kinds of tautomeric forms all are intended to be included in the scope of the present invention, even if only a kind of tautomeric structure is illustrated.
Described compound can exist with different isomeric form, and they all are included in the scope of the present invention.
As any variable (R for example
1And R
2Or the like) when occurring more than one time in any structure, its definition when each time occurs is independent of the definition when other occur each time.And, to have only when combination can produce stable compound the time, the combination of substituting group and variable is only permission.From substituting group be drawn into line the loop systems represent shown in key can be connected any replacement on the annular atoms.If described loop systems is a multi-loop system, this key intention only is connected on any suitable carbon atom of immediate ring so.
Be to be understood that, those of ordinary skills can select substituting group on the The compounds of this invention and replacement form, thereby provide chemical property stable and can be by the raw material that can obtain easily by technology known in the art and the following stated method synthetic compound easily.If substituting group self is replaced more than a group, should be appreciated that so described a plurality of group can be on identical carbon atoms or different carbon atom, as long as obtain rock steady structure.Phrase " optional replace " should be understood to be equivalent to phrase " be not substituted or replaced by one or more substituting group ", and in this case, preferred embodiment will have 0～3 substituting group.More especially, there is 0～2 substituting group.Substituting group on saturated, fractional saturation or unsaturated heterocycle can be connected on any commutable position.
" alkyl " means and comprises having the radical of saturated aliphatic alkyl of specifying carbonatoms purpose side chain and straight chain as used herein.For example, " C
1～C
6Alkyl " definition be to be included in the group that has 1,2,3,4,5 or 6 carbon atom in straight chain or the branched structure.For example, " C
1～C
6Alkyl " specifically comprise methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group and hexyl or the like.Preferred alkyl is a methyl.Term " cycloalkyl " is meant to have monocycle, two ring or the many ring fillings aliphatic hydrocarbyls that specify number carbon atom.For example, " C
7-10Cycloalkyl " comprise cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl and cyclohexyl or the like.In embodiment of the present invention, term " cycloalkyl " comprises the above group of just having described, and comprises monocycle unsaturated aliphatic alkyl in addition.For example, defined in this embodiment " cycloalkyl " comprises cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutene base and 7,7-dimethyl two ring [2.2.1] heptyl or the like.Preferred cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
" alkoxyl group " expression is by the described carbonatoms purpose alkyl that has of oxo bridge connection.Thus, " alkoxyl group " comprises the definition of above alkyl.The example of suitable alkoxyl group comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, sec-butoxy and tert.-butoxy.Preferred alkoxyl group is a methoxyl group.
Term " halo C
1-6Alkyl " and " halo C
1-6Alkoxyl group " be meant that one or more (particularly, 1～3) hydrogen atom is by the C of halogen atom (particularly fluorine or chlorine atom) replacement
1-6Alkyl or C
1-6Alkoxyl group.Preferred fluoro C
1-6Alkyl and fluoro C
1-6Alkoxyl group, particularly fluoro C
1-3Alkyl and fluoro C
1-3Alkoxyl group, for example CF
3, CHF
2, CH
2F, CH
2CH
2F, CH
2CHF
2, CH
2CF
3, OCF
3, OCHF
2, OCH
2F, OCH
2CH
2F, OCH
2CHF
2Perhaps OCH
2CF
3, and CF the most particularly
3, OCF
3And OCHF
2
Term " hydroxyl C
1-6Alkyl " be meant the C that one or more (particularly, 1～3) hydrogen atom has been replaced by hydroxyl
1-6Alkyl.Preferred CH
2OH, CH
2CHOH and CHOHCH
3
Term " C as used herein
2-6Thiazolinyl " be meant the straight chain or the side chain non-aromatic hydrocarbon base that contain 2～6 carbon atoms and at least one carbon-carbon double bond.Carbon-carbon double bond of preferred existence, and can have non-fragrant carbon-carbon double bond up to four.Thiazolinyl comprises vinyl, propenyl, butenyl and 2-methyl butene base.The straight chain of thiazolinyl or a chain portion can contain two keys, and if be indicated as substituted alkenyl, can be substituted so.Preferred thiazolinyl comprises vinyl and propenyl.
Term " C
2-6Alkynyl " be meant and contain 2～6 carbon atoms and at least one carbon carbon triple-linked straight chain or branched hydrocarbyl.Wherein can exist up to three carbon carbon triple bonds.Described alkynyl comprises ethynyl, proyl, butynyl and 3-methyl butynyl or the like.The straight chain of alkynyl or a chain portion can contain triple bond, and if be indicated as substituted alkynyl, it can be substituted so.Preferred alkynyl comprises ethynyl and proyl.
" C as used herein
6-10Aryl " be meant the monocycle or the bicyclic carbocyclic of any stable 6～10 atoms, wherein at least one ring is an aromatic nucleus.The example of above-mentioned aryl unit comprises phenyl, naphthyl, tetralyl, indanyl, tetrahydro benzo [7] annulene, indenyl and tetrahydro indenyl.Preferred aryl groups is phenyl or naphthyl, particularly phenyl.
Concrete heterocyclic example of the present invention is a benzimidazolyl-; the cumarone diketo; benzofuryl; benzo furazan base; the benzopyrazoles base; the benzotriazole base; benzothienyl; benzoxazolyl; benzoxazole ketone group; benzothiazolyl; the diazosulfide base; benzo dioxolyl Ben Bing oxadiazole base; the benzoisoxazole base; the benzisothiazole base; benzopyranyl; chromanyl; the isochroman base; carbazyl; carbolinyl; the cinnolines base; epoxy group(ing); furyl; the furazan base; imidazolyl; indolinyl; indyl; indolizine base (indolizinyl); indolinyl; isoindolinyl; indazolyl; isobenzofuran-base; pseudoindolyl; isoquinolyl; isothiazolyl isoxazolyl; naphtho-pyridyl oxadiazole base oxazolyl oxazolinyl isoxazoline-3-yl; the oxygen cyclobutyl; purine radicals; pyranyl; pyrazinyl; pyrazolyl; pyridazinyl; the pyridopyridine base; pyridazinyl; pyridyl; pyrimidyl; triazinyl; the tetrazine base; pyrryl; quinazolyl; quinolyl; quinoxalinyl; quinolizinyl; THP trtrahydropyranyl; tetrahydro thiapyran base; tetrahydro isoquinolyl; tetrazyl; the tetrazolo pyridyl; thiadiazolyl group; thiazolyl; thienyl; triazolyl; azetidinyl; 1, the 4-dioxane; six hydrogen azatropylidene bases; piperazinyl; piperidyl; the pyridin-2-ones base; pyrrolidyl; imidazolinyl; pyrazolinyl; pyrrolinyl; morpholinyl; thio-morpholinyl; the dihydrobenzo imidazolyl; dihydro benzo furyl; the dihydrobenzo thienyl; Er hydrogen benzoxazolyl; the dihydrofuran base; the glyoxalidine base; indolinyl; the dihydro-isoxazole base; dihydro isothiazolyl Er Qing oxadiazole base dihydro-oxazole base; the dihydro pyrazinyl; the pyrazoline base; the dihydropyridine base; the dihydro-pyrimidin base; the pyrrolin base; the dihydroquinoline base; the dihydro tetrazyl; the thiodiazoline base; dihydro-thiazolyl; the dihydro-thiophene base; the dihydro triazolyl; the dihydro azetidinyl; the different benzopyranyl of dihydro; the glyoxalidine ketone group; dihydro triazole ketone group; dihydrobenzo Er Evil satellite-based; thiazoline and pyrimidyl; the methylenedioxyphenyl formyl radical; tetrahydrofuran base; tetrahydro-thienyl; tetrahydric quinoline group; thiazolidonyl; the imidazoles ketone group; the isoindoline ketone group; the octahydro quinolizinyl; the octahydro pseudoindoyl; imidazopyridyl; the azabicyclic suberyl; the chromene ketone group; triazolopyrimidinyl; Er hydrogen benzoxazinyl; the thiazoltriazol base; azonia two suberyl; azonia two ring octyl groups; phthalazinyl; naphthyridinyl; quinazolyl; pteridyl and N-oxide compound thereof.Other concrete heterocycle comprises dihydroquinazoline base, dihydro phthalazinyl, dihydro-iso indolyl, Tetrahydronaphthyridderivates base, tetrahydro-b-carboline base and N-oxide compound thereof.Other concrete heterocycle comprises dibenzofuran group, naphthyridinyl, dihydrobenzopyrans base, dihydro-benzothiazole base, Imidazothiazole base, tetrahydrochysene indazole base, tetrahydro benzo thienyl, hexahydro naphthalene pyridine base, tetrahydropyridine and naphthyridinyl, imidazolidine and pyridyl, imidazolidine and pyrazinyl, pyrrolopyridinyl and N-oxide compound thereof.The heterocyclic radical substituting group can connect through carbon atom or heteroatoms.
Preferred 4 yuan of saturated heterocyclics are azetidinyl.
Saturated or the fractional saturation heterocycle of preferred 5 yuan or 6 yuan is pyrrolidyl, piperidyl, piperazinyl, morpholinyl, azonia two ring [2.2.1] heptyl and azonia two ring [2.2.2] octyl groups.Further preferred heterocycle is a thio-morpholinyl.
Preferred 5 membered unsaturated heterocycles are thienyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, thiadiazolyl group, oxazolyl and triazolyl.Further preferred heterocycle is tetrazyl, furyl He oxadiazole base.
Preferred 6 membered unsaturated heterocycles are pyridyl.
Preferred 8-10 unit is saturated, fractional saturation or unsaturated heterocycle are benzothienyl, isoquinolyl, indyl, diazosulfide base, Ben Bing oxadiazole base, thiazoltriazol base, dihydrobenzo Er Evil satellite-based, thiazoline and pyrimidyl, Er hydrogen benzoxazinyl and dihydro benzo furyl.Further preferred heterocycle is benzothiazolyl, quinolyl, isoquinolyl, benzimidazolyl-, benzofuryl, Er hydrogen benzoxazolyl, indolinyl, dihydroquinazoline base, dihydro phthalazinyl, indazolyl, benzoisoxazole base, benzotriazole base, dihydro-iso indolyl, Tetrahydronaphthyridderivates base and triazolopyrimidinyl.Further preferred heterocycle is quinoxalinyl, tetrahydro isoquinolyl, dibenzo [b, d] furyl, naphthyridinyl, dihydroquinoline base, the different benzopyranyl of dihydro, dihydrobenzopyrans base, tetrahydric quinoline group, dihydro-benzothiazole base, Imidazothiazole base, tetrahydrochysene indazole base, tetrahydro benzo thienyl, hexahydro naphthalene pyridine base, imidazolidine and pyridyl, imidazolidine and pyrazinyl and pyrrolopyridinyl.
Preferred 13 yuan of fractional saturation heterocycles are the tetrahydro-b-carboline base.
Preferred 14 yuan of fractional saturation heterocycles are tetrahydropyridine and naphthyridinyl (naphthy ridinyl).The first fractional saturation alkyl of preferred 6-13 is tetralyl and dihydro indenyl.
Term " halogen " is meant fluorine, chlorine, bromine and iodine as used herein, wherein preferred fluorine, chlorine and bromine.
Particular compound in the scope of the invention comprises:
1-methyl-3-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } carbonyl) piperidines two (trifluoroacetate);
2-((1S)-1-{[(4-p-methoxy-phenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-[(1S)-1-(([[2-(dimethyl amido) ethyl] (methyl) amino] alkylsulfonyl } amino)-7-oxo octyl group]-5-phenyl-1H-imidazoles-1-two (trifluoroacetate);
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
1-methyl-4-(the 2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } ethyl) piperazine two or three (trifluoroacetate);
1-methyl-2-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } carbonyl) piperidines two (trifluoroacetate);
1-(the 3-oxo-3-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } propyl group) piperidines two (trifluoroacetate)
2-((1S)-1-{[(1-methylpyrrolidin-3-yl) carbonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-two (trifluoroacetate);
1-methyl-4-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } carbonyl) piperidines two (trifluoroacetate);
2-{ (1S)-7-oxo-1-[(2-thienyl carbonyl) amino] octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-7-oxo-1-[(1,3-thiazole-5-base carbonyl) amino] octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(4-methyl isophthalic acid, 2,3-thiadiazoles-5-yl) carbonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-1-[(2,3-dihydro-1,4-Ben Bing Er Evil star (dioxin-)-and 6-base alkylsulfonyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(4-cyano-phenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-1-[(2-naphthalene sulfonyl base) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(2,4-dimethyl-1,3-thiazoles-5-yl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-1-[(1-thionaphthene-3-base alkylsulfonyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(4-chloro-phenyl-) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(3-p-methoxy-phenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
1,2-dimethyl-4-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } alkylsulfonyl)-1H-imidazoles-1-two (trifluoroacetate);
2-((1S)-1-{[(3,5-dimethyl isoxazole-4-yl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
4-[({1-[5-(2-p-methoxy-phenyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
4-[({1-[5-(3-p-methoxy-phenyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
4-[({1-[5-(4-fluorophenyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
4-[({1-[5-(4-chloro-phenyl-)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
4-[({1-[5-(4-bromophenyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
4-[({1-[5-(2-chloro-phenyl-)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
4-[({1-[5-(3, the 4-dichlorophenyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
4-[({1-[5-(4-cyano-phenyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
4-[({1-[5-(3-cyano-phenyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
4-({ [1-(4,5-phenylbenzene-1H-imidazoles-1--2-yl)-7-oxo octyl group] amino } carbonyl)-1-methyl piperidine two (trifluoroacetate);
4-({ [1-(4,5-phenylbenzene-1,3-oxazole-2-yl)-7-oxo octyl group] amino } carbonyl)-1-methyl piperidine trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-muriate;
1-methyl-4-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } carbonyl) the piperidines dichloride;
1-methyl-4-[4-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } carbonyl) phenyl] piperazine two or three (trifluoroacetate);
3-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } carbonyl)-1-pyridine-2-phenylpiperidines two (trifluoroacetate);
3-(2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } ethyl)-6,7-dihydro-5H-[1,3] thiazole [3,2-a] pyrimidine-4-two (trifluoroacetate) also;
2-(the 3-oxo-3-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } propyl group)-2-azonia two ring [2.2.1] heptane two (trifluoroacetate);
4-(the 2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino }-1-pyridin-3-yl ethyl) morpholine-4-three (trifluoroacetate);
1-methyl-4-([(1S)-and 1-(4-methyl-5-phenyl-1H-imidazoles-1--2-yl)-7-oxo octyl group] amino } carbonyl) piperidines two (trifluoroacetate);
4-([(1S)-and 1-(5-xenyl-4-base-1H-imidazoles-1--2-yl)-7-oxo octyl group] amino } carbonyl)-1-methyl piperidine two (trifluoroacetate);
1-methyl-4-[({ (1S)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl] piperidines two (trifluoroacetate);
4-[({ (1S)-1-[5-(3-chloro-phenyl-)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
4-{[((1S)-and 1-{5-[3,5-two (trifluoromethyl) phenyl]-1H-imidazoles-1--2-yl }-7-oxo octyl group) amino] carbonyl }-1-methyl piperidine two (trifluoroacetate);
The 1-methyl-4-{[((1S)-7-oxo-1-{5-[3-(trifluoromethyl) phenyl]-1H-imidazoles-1--2-yl } octyl group) amino] carbonyl } piperidines two (trifluoroacetate);
2-((1S)-1-{[(3-cyano-phenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-7-oxo-1-[(benzenesulfonyl) amino] octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
4-methyl-7-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } alkylsulfonyl)-3,4-dihydro-2H-1,4-benzoxazine-4-two (trifluoroacetate);
2-[(1S)-1-({ [2-(kharophen)-4-methyl isophthalic acid, 3-thiazole-5-yl] alkylsulfonyl } amino)-7-oxo octyl group]-5-phenyl-IH-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(5-chloro-2-thienyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
1,3,5-trimethylammonium-4-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } alkylsulfonyl)-1H-pyrazoles-1-two (trifluoroacetate);
2-[(1S)-1-({ [5-(2-methyl isophthalic acid, 3-thiazole-4-yl)-2-thienyl] alkylsulfonyl } amino)-7-oxo octyl group]-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-1-[({5-[1-methyl-3-(trifluoromethyl)-1H-pyrazoles-5-yl]-the 2-thienyl } alkylsulfonyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(5-isoxazole-3-base-2-thienyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
The 1-methyl-4-{[((1S)-7-oxo-1-{5-[4-(trifluoromethyl) phenyl]-1H-imidazoles-1--2-yl } octyl group) amino] carbonyl } piperidines two (trifluoroacetate);
4-{[((1S)-1-{5-[4-(difluoro-methoxy) phenyl]-1H-imidazoles-1--2-yl }-7-oxo octyl group) amino] carbonyl }-1-methyl piperidine two (trifluoroacetate);
4-[({ (1S)-1-[5-(3, the 4-difluorophenyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
2-((1S)-1-{[(2-nitrophenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(3-nitrophenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-[(1S)-1-({ [4-(kharophen) phenyl] alkylsulfonyl } amino)-7-oxo octyl group]-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(2-cyano-phenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(2-chloro-4-cyano-phenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(3-fluoro-4-nitrophenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-[(1S)-1-({ [2-(methoxycarbonyl)-3-thienyl] alkylsulfonyl } amino)-7-oxo octyl group]-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(2,5-Dimethoxyphenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(3-fluorophenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(3-cyano group-4-fluorophenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-[(1S)-1-({ [4-(difluoro-methoxy) phenyl] alkylsulfonyl } amino)-7-oxo octyl group]-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-[(1S)-1-({ [3-(difluoro-methoxy) phenyl] alkylsulfonyl } amino)-7-oxo octyl group]-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-1-[(2,1,3-diazosulfide-5-base alkylsulfonyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-1-[(2,3-dihydro-1-cumarone-5-base alkylsulfonyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-morpholine-4-base-5-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } alkylsulfonyl) pyridine two (trifluoroacetate);
2-{ (1S)-1-[(2,1,3-Ben Bing oxadiazole-4-base alkylsulfonyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(4-fluorophenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(4-nitrophenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(2-fluorophenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(3,4-Dimethoxyphenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(3,4-difluorophenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
5-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } alkylsulfonyl) isoquinoline 99.9 two (trifluoroacetate);
2-((1S)-1-{[(4-carboxyl phenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
1-methyl-4-[({ (1S)-7-oxo-1-[5-(3-thienyl)-1H-imidazoles-3--2-yl] octyl group } amino) carbonyl] piperidines two (trifluoroacetate);
2-[2-((1S)-1-{[(1-methyl piperidine-4-yl) carbonyl] amino }-7-oxo octyl group)-1H-imidazoles-3--5-yl] pyridine three (trifluoroacetate);
4-[({ (1S)-1-[5-(5-chloro-3-methyl isophthalic acid-thionaphthene-2-yl)-1H-imidazoles-3--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
1-methyl-4-[({ (1S)-7-oxo-1-[5-(3-phenyl-isoxazole azoles-5-yl)-1H-imidazoles-3--2-yl] octyl group } amino) carbonyl] piperidines two (trifluoroacetate);
1-methyl-4-{[((1S)-1-{5-[6-methyl-2-(trifluoromethyl) [1,3] thiazole is [3,2-b] [1,2,4] triazole-5-yl also]-1H-imidazoles-3--2-yl }-7-oxo octyl group) amino] carbonyl } piperidines two (trifluoroacetate);
1-methyl-4-[({ (1S)-1-[1-methyl-4-(2-naphthyl)-1H-imidazoles-3--2-yl]-7-oxo octyl group } amino) carbonyl] piperidines two (trifluoroacetate);
2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-{ (1S)-1-[5-(2-naphthyl)-4H-1,2,4-triazole-3-yl]-7-oxo nonyl } ethanamide;
2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-[7-oxo-1-(4-phenyl-2-thienyl) nonyl] ethanamide;
4-[({ (1S)-1-[5-(1-thionaphthene-3-yl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
2-{ (1S)-1-[(3, the 4-difluoro benzoyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[4-(kharophen) benzoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[4-(amino-sulfonyl) benzoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
4-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } carbonyl) pyridine two (trifluoroacetate);
3-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } carbonyl) pyridine two (trifluoroacetate);
2-((1S)-1-{[(3,5-dimethyl isoxazole-4-yl) carbonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-1-[(2,3-dihydro-1,4-Ben Bing Er Evil star-6-base carbonyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-1-[(3-nitro benzoyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-1-[(3-cyano group benzoyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-1-[(4-cyano group benzoyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
1-methyl-4-({ [7-oxo-1-(4-phenyl-2-thienyl) nonyl] amino } carbonyl) piperidines trifluoroacetate;
4-[({ (1S)-6-carboxyl-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl] hexyl } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
2-((1S)-6-carboxyl-1-{[(3-nitrophenyl) alkylsulfonyl] amino } hexyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
4-[({ (1S)-6-carboxyl-1-[5-(3-p-methoxy-phenyl)-1H-imidazoles-1--2-yl] hexyl } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
2-((1S)-6-carboxyl-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino } hexyl)-5-(3-p-methoxy-phenyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-6-carboxyl-1-{[(3-nitrophenyl) alkylsulfonyl] amino } hexyl)-5-(3-p-methoxy-phenyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-6-carboxyl-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino } hexyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-7-(hydroxyl amino)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-1-[(3-fluoro-4-nitro benzoyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-cyano group-5-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } carbonyl) pyridine two (trifluoroacetate);
2-((1S)-1-{[(4-cyano-phenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
5-(2-naphthyl)-2-((1S)-1-{[(3-nitrophenyl) alkylsulfonyl] amino }-7-oxo octyl group)-1H-imidazoles-1-trifluoroacetate;
2-[(1S)-1-([[2-(ethyl of dimethyl amido-ammonio-)] (methyl) amino] alkylsulfonyl } amino)-7-oxo octyl group]-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate);
5-(2-naphthyl)-2-{ (1S)-7-oxo-1-[(1,3-thiazole-5-base carbonyl) amino] octyl group }-1H-imidazoles-1-trifluoroacetate;
5-(3-chloro-phenyl-)-2-((1S)-1-{4-cyano-phenyl) alkylsulfonyl] amino }-7-oxo octyl group)-1H-imidazoles-1-trifluoroacetate;
5-(3-chloro-phenyl-)-2-((1S)-1-{[(3-nitrophenyl) alkylsulfonyl] amino }-7-oxo octyl group)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(4-cyano-phenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-(3-p-methoxy-phenyl)-1H-imidazoles-1-trifluoroacetate;
5-(3-p-methoxy-phenyl)-2-((1S)-1-{[(3-nitrophenyl) alkylsulfonyl] amino }-7-oxo octyl group)-1H-imidazoles-1-trifluoroacetate;
5-(3-p-methoxy-phenyl)-2-{ (1S)-7-oxo-1-[(1,3-thiazole-5-base carbonyl) amino] octyl group }-1H-imidazoles-1-trifluoroacetate;
2-((1S)-7-[(2-aminophenyl) amino]-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
5-(3-p-methoxy-phenyl)-2-[(1S)-1-([(3S)-and 1-methylpyrrolidin-3-yl] carbonyl } amino)-7-oxo octyl group]-1H-imidazoles-1-two (trifluoroacetate);
(3S)-3-[({ (1S)-1-[5-(3-p-methoxy-phenyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
(3S)-1-sec.-propyl-3-[({ (1S)-1-[5-(3-p-methoxy-phenyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl] piperidines two (trifluoroacetate);
5-(3-chloro-phenyl-)-2-[(1S)-1-([(3R)-and 1-methylpyrrolidin-3-yl] carbonyl } amino)-7-oxo octyl group]-1H-imidazoles-1-two (trifluoroacetate);
2-[(1S)-1-([(3R)-and 1-methylpyrrolidin-3-yl] carbonyl } amino)-7-oxo octyl group]-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate);
4-methyl-2-[({ (1S)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl] morpholine-4-two (trifluoroacetate);
4-[({ (1S)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-azonia two ring [2.2.2] octanes two (trifluoroacetate);
4-[2-((1S)-1-[5-(3-chloro-phenyl-)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino)-1-methyl-2-oxoethyl] morpholine-4-two (trifluoroacetate);
2-[(1S)-and 1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-(methylamino)-7-oxo heptyl]-5-(2-naphthyl)-1H-indazole-1-trifluoroacetate;
5-(the 3-p-methoxy-phenyl-2-[(1S)-1-([(3R)-and 1-methylpyrrolidin-3-yl] carbonyl } amino)-7-oxo octyl group]-1H-imidazoles-1-two (trifluoroacetate);
(3R)-3-[({ (1S)-1-[5-(3-p-methoxy-phenyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
5-(3-chloro-phenyl-)-2-[(1S)-1-([(3S)-and 1-methylpyrrolidin-3-yl] carbonyl } amino)-7-oxo octyl group]-1H-imidazoles-1-two (trifluoroacetate);
2-[(1S)-1-([(3S)-and 1-methylpyrrolidin-3-yl] carbonyl } amino)-7-oxo octyl group]-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate);
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
1-methyl-4-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } carbonyl) piperidines two (trifluoroacetate);
And pharmaceutically acceptable free alkali, salt, alternative salt and steric isomer.
More specific compound in the scope of the invention is:
2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-{ (1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl } ethanamide;
2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-{ (1S)-1-[5-(2-naphthyl)-1,3-oxazole-2-yl]-7-oxo nonyl } ethanamide;
5-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-2-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-[7-oxo-1-(2-phenyl-1,3-thiazoles-5-yl) nonyl] ethanamide;
2-((1S)-1-{[(1-methyl piperidine-4-yl) carbonyl] amino }-7-oxo nonyl)-4-phenylpyridine two (trifluoroacetate);
(7S)-and 7-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl] enanthic acid;
(7S)-and 7-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl] heptamide;
(7S)-and 7-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-[5-(2-naphthyl)-4H-1,2,4-triazole-3-yl] enanthic acid;
(7S)-and 7-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-[5-(2-naphthyl)-4H-1,2,4-triazole-3-yl] heptamide;
2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-{ (1S)-1-[5-(2-naphthyl)-1,2,4-oxadiazole-3-yl]-7-oxo nonyl } ethanamide;
2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-{ (1S)-1-[3-(2-naphthyl)-1,2,4-oxadiazole-5-yl]-7-oxo nonyl } ethanamide;
2-{ (1S)-1-[(methoxycarbonyl) amino]-7-oxo nonyl }-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(dimethylamino) carbonyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
3-nitro-N-[7-oxo-1-(4-phenyl-2-furyl) octyl group] benzsulfamide;
2-((1S)-7-[(ethylsulfonyl) amino]-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
5-(2-naphthyl)-2-((1S)-8,8,8-three fluoro-1-{[(5-methoxyl groups-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo octyl group)-1H-imidazoles-1-trifluoroacetate;
3-nitro-N-[7-oxo-1-(4-phenyl-1,3-thiazoles-2-yl) octyl group] benzsulfamide;
2-((1S)-7-amino-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-7-(dimethylamino)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-7-(sec.-propyl amino)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-7-anilino-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-7-(benzylamino)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-the 7-[(methyl sulphonyl) amino]-7-oxo heptyl }-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
1-methyl-4-[({ (1S)-1-[5-(2-naphthyl)-4H-1,2,4-triazole-3-yl]-7-oxo nonyl } amino) carbonyl] the piperidines trifluoroacetate;
(3S)-and 1-methyl-3-[({ (1S)-1-[5-(2-naphthyl)-4H-1,2,4-triazole-3-yl]-7-oxo nonyl } amino) carbonyl] the tetramethyleneimine trifluoroacetate;
(3S)-and 1-methyl-3-[({ (1S)-1-[5-(2-naphthyl)-4H-1,2,4-triazole-3-yl]-7-oxo nonyl } amino) carbonyl] the piperidines trifluoroacetate;
N-{ (1S)-1-[5-(2-naphthyl)-4H-1,2,4-triazole-3-yl]-7-oxo nonyl }-1,3-thiazoles-5-carboxylic acid amides;
4-cyano group-N-{ (1S)-1-[3-(2-naphthyl)-1H-1,2,4-triazole-5-yl]-7-oxo nonyl } benzsulfamide;
2-((1S)-7-[methoxyl group (methyl) amino]-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
1-methyl-4-[({ (1S)-7-(methylamino)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo heptyl } amino) carbonyl] piperidines two (trifluoroacetate);
4-[({ (1S)-7-(hydroxyl amino)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo heptyl } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
2-{ (1S)-6-carboxyl-1-[(1,3-thiazole-5-base carbonyl) amino] hexyl }-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
4-[({ (1S)-7-[(2-aminophenyl) amino]-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo heptyl } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
2-[(1S)-6-carboxyl-1-([(3R)-and 1-methylpyrrolidin-3-yl] carbonyl } amino) hexyl]-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate);
2-[(1S)-6-carboxyl-1-([(3S)-and 1-methylpyrrolidin-3-yl] carbonyl } amino) hexyl]-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate);
2-((1S)-6-carboxyl-1-{[(dimethylamino) alkylsulfonyl] amino } hexyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
4-[({ (1S)-7-[methoxyl group (methyl) amino]-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo heptyl } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo-7-{[(trifluoromethyl) alkylsulfonyl] amino } heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-7-(ethylamino)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
(3S)-and 3-[({ (1S)-1-[3-(3, the 5-dichlorophenyl)-1H-1,2,4-triazole-5-yl]-7-oxo nonyl } amino) carbonyl]-1-crassitude trifluoroacetate;
4-[({ (1S)-1-[3-(3, the 5-dichlorophenyl)-1H-1,2,4-triazole-5-yl]-7-oxo nonyl } amino) carbonyl]-1-azonia two ring [2.2.2] octane trifluoroacetates;
N-{ (1S)-1-[3-(3, the 5-dichlorophenyl)-1H-1,2,4-triazole-5-yl]-7-oxo nonyl }-2-(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanamide;
2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-{ (1S)-1-[3-(3-p-methoxy-phenyl)-1H-1,2,4-triazole-5-yl]-7-oxo nonyl } ethanamide;
2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-[7-oxo-1-(4-phenyl-1,3-thiazoles-2-yl) octyl group] ethanamide;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate;
2-{ (1S)-1-[(1H-indol-3-yl ethanoyl) amino]-7-oxo nonyl }-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-bromo-IH-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-fluoro-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate;
1-[2-((1S)-1-[5-(2-naphthyl)-1H-imidazoles-3--2-yl]-7-oxo nonyl } amino)-the 2-oxoethyl]-1H-benzoglyoxaline-3-two (trifluoroacetate);
2-((1S)-1-{[(7-methoxyl group-1-cumarone-2-yl) carbonyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-1H-indoles-2-yl) carbonyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-fluoro-1H-indoles-2-yl) carbonyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate;
6-[2-((1S)-1-[5-(2-naphthyl)-1H-imidazoles-3--2-yl]-7-oxo nonyl } amino)-the 2-oxoethyl] [1,2,4] triazolo [1,5-a] pyrimidine-4-two (trifluoroacetate);
5-(2-naphthyl)-2-((1S)-7-oxo-1-{[(4-phenyl-1,3-thiazoles-2-yl) ethanoyl] amino } nonyl)-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-chloro-1-thionaphthene-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(4-chloro-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate;
5-(2-naphthyl)-2-((1S)-7-oxo-1-{[(2-oxo-1,3-benzoxazole-3 (2H)-yl) ethanoyl] amino } nonyl)-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-oxo-2,3-dihydro-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(6-methoxyl group-2-oxo-2,3-dihydro-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate;
2-ethyl-1-[3-((1S)-1-[5-(2-naphthyl)-1H-imidazoles-3--2-yl]-7-oxo nonyl } amino)-the 3-oxopropyl]-IH-benzoglyoxaline-3-two (trifluoroacetate);
5-(2-naphthyl)-2-{ (1S)-1-[(1-naphthyl ethanoyl) amino]-7-oxo nonyl }-1H-imidazoles-3-trifluoroacetate;
5-(2-naphthyl)-2-{ (1S)-1-[(2-naphthyl ethanoyl) amino]-7-oxo nonyl }-1H-imidazoles-3-trifluoroacetate;
5-(2-naphthyl)-2-((1S)-7-oxo-1-{[(2-oxo quinazoline-1 (2H)-yl) ethanoyl] amino } nonyl)-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(4-methyl isophthalic acid-oxo naphthyridine-2 (1H)-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate;
5-(2-naphthyl)-2-{ (1S)-7-oxo-1-[(phenyl acetyl) amino] nonyl }-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(2,6-dichlorophenyl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(2,4-dichlorophenyl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate;
2-[(1S)-1-({ [2-fluoro-6-(trifluoromethyl) phenyl] ethanoyl } amino)-7-oxo nonyl]-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate;
2-[(1S)-1-({ [2-fluoro-3-(trifluoromethyl) phenyl] ethanoyl } amino)-7-oxo nonyl]-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate;
2-[(1S)-and 1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo-7-(1,3-thiazoles-2-base is amino) heptyl]-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate;
2-[(1S)-and 1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo-7-(1,3,4-thiadiazoles-2-base is amino) heptyl]-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate;
The 2-methyl isophthalic acid-[2-((1S)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo nonyl } amino)-the 2-oxoethyl]-IH-benzoglyoxaline-3-two (trifluoroacetate);
1-[2-((1S)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo nonyl } amino)-the 2-oxoethyl]-2-(trifluoromethyl)-1H-benzoglyoxaline-3-two (trifluoroacetate);
2-{ (1S)-1-[(1H-indazolyl-1-base ethanoyl) amino]-7-oxo nonyl }-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
3-[2-((1S)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo nonyl } amino)-the 2-oxoethyl] quinoline two (trifluoroacetate);
2-((1S)-1-{[(dimethylamino) (oxo) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-1-[(1,2-benzoisoxazole-3-base ethanoyl) amino]-7-oxo nonyl }-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(2-Methyl-1H-indole-1-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-1-[(1H-1,2,3-benzotriazole-1-base ethanoyl) amino]-7-oxo nonyl }-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(5-cyano-1 H-indol--1-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(dimethyl amido (ammonio)) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate);
1-methyl-4-[({ (1S)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo nonyl } amino) carbonyl] piperidines two (trifluoroacetate);
4-[({ (1S)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo nonyl } amino) carbonyl]-1-azonia two ring [2.2.2] octanes two (trifluoroacetate);
(7S)-and 7-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-N-methyl-7-[5-(2-naphthyl)-4H-1,2,4-triazole-3-yl] heptamide;
4-[({ (1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl } amino) carbonyl]-1-azonia two ring [2.2.2] octane trifluoroacetates;
2-ethyl-1-[3-((1S)-and 1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl } amino)-the 3-oxopropyl]-1H-benzoglyoxaline-3-trifluoroacetate;
6-[2-((1S)-and 1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl } amino)-the 2-oxoethyl] [1,2,4] triazolo [1,5-a] pyrimidine-3-trifluoroacetate;
1-methyl-4-[({ (1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl } amino) carbonyl] the piperidines trifluoroacetate;
(3R)-and 1-methyl-3-[({ (1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl } amino) carbonyl] the tetramethyleneimine trifluoroacetate;
(4R)-4-[({ (1S)-1-[5-(2-naphthyl)-1H-imidazoles-3--2-yl]-7-oxo nonyl } amino) carbonyl]-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-2-two (trifluoroacetate);
(7S)-and 7-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-N-methyl-7-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl] heptamide;
4-[({ (1S)-6-carboxyl-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl] hexyl } amino) carbonyl]-1-methyl piperidine trifluoroacetate;
(7S)-and 7-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-7-[(1,3-thiazole-4-base carbonyl) amino] enanthic acid;
4-[({ (1S)-1-[5-(2,3-dihydro-1,4-Ben Bing Er Evil star-6-yl)-1H-imidazoles-3--2-yl]-7-oxo nonyl } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-{ (1S)-1-[4-(2-naphthyl)-1,3-oxazole-2-yl]-7-oxo nonyl } ethanamide;
2-((1S)-7-(methylamino)-7-oxo-1-{[(1-pyridine-2-phenylpiperidines-3-yl) carbonyl] amino } heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-[2-((1S)-7-(methylamino)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo heptyl } amino)-the 2-oxoethyl]-2,3-dihydro-1H-isoindole two (trifluoroacetate);
2-{ (1S)-7-(methylamino)-7-oxo-1-[(piperidines-1-base ethanoyl) amino] heptyl }-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
4-[({ (1S)-7-(methylamino)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo heptyl } amino) carbonyl]-1-azonia two ring [2.2.2] octanes two (trifluoroacetate);
5-[({ (1S)-7-(methylamino)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo heptyl } amino) carbonyl]-1,2,3,4-tetrahydrochysene-1,8-naphthyridines-1-two (trifluoroacetate);
2-((1S)-7-(methylamino)-7-oxo-1-{[(5-tetramethyleneimine-1-base-2H-tetrazolium-2-yl) ethanoyl] amino } heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-7-(methylamino)-7-oxo-1-[(1,3-thiazole-5-base carbonyl) amino] heptyl }-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-7-(methylamino)-1-{[(4-methyl isophthalic acid, 2,3-thiadiazoles-5-yl) carbonyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-7-(methylamino)-7-oxo-1-[(pyridin-3-yl carbonyl) amino] heptyl }-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-7-(methylamino)-7-oxo-1-[(phenyl acetyl) amino] heptyl }-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
(7S)-7-([(3S)-and 1-methylpyrrolidin-3-yl] carbonyl } amino)-7-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl] enanthic acid;
(3S)-and 3-[({ (1S)-6-carboxyl-1-[5-(2-naphthyl)-4H-1,2,4-triazole-3-yl] hexyl } amino) carbonyl]-1-crassitude trifluoroacetate;
(3S)-and 3-[({ (1S)-7-amino-1-[5-(2-naphthyl)-4H-1,2,4-triazole-3-yl]-7-oxo heptyl } amino) carbonyl]-1-crassitude trifluoroacetate;
4-[({ (1S)-1-[5-(2,3-dihydro-1,4-Ben Bing Er Evil star-5-yl)-1H-imidazoles-3--2-yl]-7-oxo nonyl } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
4-[({ (1S)-1-[5-(1,3-benzothiazole-2-yl)-1H-imidazoles-3--2-yl]-7-oxo nonyl } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
4-[({ (1S)-1-[5-(1-thionaphthene-2-yl)-1H-imidazoles-3--2-yl]-7-oxo nonyl } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
2-[(1S)-and the 1-{[(benzylamino) carbonyl] amino }-7-(methylamino)-7-oxo heptyl]-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-[(1S)-1-({ [(4-p-methoxy-phenyl) amino] carbonyl } amino)-7-(methylamino)-7-oxo heptyl]-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-[(1S)-and 1-{[(cyclopentyl amino) carbonyl] amino }-7-(methylamino)-7-oxo heptyl]-5-(2-naphthyl)-IH-imidazoles-1-trifluoroacetate;
2-((1S)-7-(methylamino)-1-{[(3-nitrophenyl) alkylsulfonyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-[(1S)-and the 1-{[(4-cyano-phenyl) alkylsulfonyl] amino }-7-(methylamino)-7-oxo heptyl]-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-[(1S)-7-(methylamino)-1-([(3S)-and 1-methylpyrrolidin-3-yl] carbonyl } amino)-7-oxo heptyl]-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate);
2-[(1S)-7-(methylamino)-1-([(3R)-and 1-methylpyrrolidin-3-yl] carbonyl } amino)-7-oxo heptyl]-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate);
2-[(1S)-and the 1-{[(benzyloxy) carbonyl] amino }-7-(methylamino)-7-oxo heptyl]-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
1-methyl-4-[({ (1R)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo nonyl } amino) carbonyl] piperidines two (trifluoroacetate);
(3R)-and 3-[({ (1S)-6-carboxyl-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl] hexyl } amino) carbonyl]-1-crassitude trifluoroacetate;
5-methoxyl group-N-{ (1S)-7-(methylamino)-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-7-oxo heptyl }-1H-indoles-2-carboxylic acid amides;
(7S)-and the 7-{[(benzylamino) carbonyl] amino }-N-methyl-7-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl] heptamide;
2-((1R)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
4-[({ (1S)-1-[5-(4-methoxy quinoline-2-yl)-1H-imidazoles-3--2-yl]-7-oxo nonyl } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate);
3-[2-((1S)-1-{[(1-methyl piperidine-4-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] quinoline three (trifluoroacetate);
6-[2-((1S)-1-{[(1-methyl piperidine-4-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] quinoline three (trifluoroacetate);
1-methyl-4-([(1S)-and 7-oxo-1-(5-quinoline-2-base-1H-imidazoles-1--2-yl) nonyl] amino } carbonyl) piperidines two (trifluoroacetate);
4-([(1S)-and 1-(5-isoquinoline 99.9-3-base-1H-imidazoles-1--2-yl)-7-oxo nonyl] amino } carbonyl)-1-methyl piperidine two (trifluoroacetate);
1-methyl-N-{1-[2-(2-naphthyl)-1H-imidazoles-5-yl]-7-oxo nonyl } piperidines-4-carboxylic acid amides;
1-methyl-N-[7-oxo-1-(3-phenyl-1H-pyrazoles-5-yl) nonyl] piperidines-4-carboxylic acid amides;
2-[(1S)-1-(kharophen)-7-oxo nonyl]-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(1,3-dimethyl pyrrolidine-3-yl) carbonyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate);
4-[3-((1S)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo nonyl } amino)-the 3-oxopropyl] thiomorpholine-4-1,1-dioxide two (trifluoroacetate);
5-(2-naphthyl)-2-{ (1S)-7-oxo-1-[(trifluoroacetyl group) amino] nonyl }-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[2-(dimethyl amido (ammonio))-2-methylpropionyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate);
2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate);
2-[(1S)-and 1-{[3-(2-ethyl-1H-benzoglyoxaline-1-yl) propionyl] amino }-7-(methylamino)-7-oxo heptyl]-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
6-[2-((1S)-7-(methylamino)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo heptyl } amino)-the 2-oxoethyl] [1,2,4] triazolo [1,5-a] pyrimidine-3-two (trifluoroacetate);
2-((1S)-7-(methylamino)-7-oxo-1-{[(2-oxo quinazoline-1 (2H)-yl) ethanoyl] amino } heptyl)-5-(2-naphthyl)-IH-imidazoles-1-trifluoroacetate;
2-((1S)-7-(methylamino)-7-oxo-1-{[(2-oxo-1,3-benzoxazole-3 (2H)-yl) ethanoyl] amino } heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
1-ethyl-3-[({ (1S)-7-(methylamino)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo heptyl } amino) carbonyl] piperidines two (trifluoroacetate);
2-((1S)-1-{[methoxyl group (oxo) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[2-methyl-2-(methyl amido (ammonio)) propionyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate);
2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-[7-oxo-1-(3-phenyl-1H-pyrazoles-5-yl) nonyl] ethanamide;
1-methyl-4-([(1S)-and 7-oxo-1-(5-quinoline-2-base-1H-imidazoles-1--2-yl) nonyl] amino } carbonyl) the piperidines dichloride;
1-methyl-4-[({ (1S)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo nonyl } amino) (oxo) ethanoyl] piperazine-1-two (trifluoroacetate);
2-((1S)-1-{[morpholine-4-base (oxo) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-IH-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[amino (oxo) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[3-(diethyl amido (ammonio)) propionyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate);
2-((1S)-1-{[3-(dimethyl amido) propionyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate);
2-((1S)-1-{[(5-cyano-1 H-indol--3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-1-[(carboxyl carbonyl) amino]-7-oxo nonyl }-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-1-[(methyl sulphonyl) amino]-7-oxo nonyl }-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(dimethylamino) alkylsulfonyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
5-methoxyl group-2-methyl-3-(the 2-oxo-2-{[(1S)-7-oxo-1-(4-phenylpyridine-2-yl) nonyl] amino } ethyl)-IH-indoles two (trifluoroacetate);
2-ethyl-1-(the 3-oxo-3-{[(1S)-7-oxo-1-(4-phenylpyridine-2-yl) nonyl] amino } propyl group)-1H-3,1-benzoglyoxaline-1-two (trifluoroacetate);
1-methyl-N-{ (1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl } piperidines-4-carboxylic acid amides;
6-[2-((1S)-1-{[(1-methyl piperidine-4-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] the quinoline trichloride;
N-{ (1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl } quinine-4-carboxylic acid amides;
4-methoxyl group-2-[2-((1S)-1-{[(1-methyl piperidine-4-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-3--5-yl] the quinoline trichloride;
And pharmaceutically acceptable free alkali, salt, alternative salt and steric isomer.
Concrete intermediate in the scope of the invention comprises:
2-[(1S)-the 1-amido (ammonio)-6-carboxyl hexyl]-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate);
(1S)-and 1-[3-(2-naphthyl)-1H-1,2,4-triazole-5-yl]-7-oxo nonane-1-ammonium trifluoroacetate;
(1S)-1-[5-(2-naphthyl)-1H-imidazoles-2-yl]-7-oxo nonyl } t-butyl carbamate;
(1S)-7-oxo-1-(4-phenylpyridine-2-yl) ninth of the ten Heavenly Stems-1-ammonium trifluoroacetate;
2-[(1S)-the 1-amido (ammonio)-7-oxo octyl group]-5-(2-naphthyl)-1H-imidazoles-3-two (trifluoroacetate);
2-[(1S)-the 1-amido (ammonio)-7-oxo octyl group]-5-phenyl-1H-imidazoles-3-two (trifluoroacetate);
And pharmaceutically acceptable alkali, salt, alternative salt and steric isomer.
Further particular compound in the scope of the invention is:
2-{ (1S)-1-[(carboxyl carbonyl) amino]-7-oxo nonyl }-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[morpholine-4-base (oxo) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
5-(2-naphthyl)-2-{ (1S)-7-oxo-1-[(trifluoroacetyl group) amino] nonyl }-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-dichloride;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[4-(1H-pyrazol-1-yl) phenyl]-1H-imidazoles-3-trifluoroacetate;
5-(2 methoxy quinoline-3-yl)-2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-3-two (trifluoroacetate);
2-((1S)-1-{[3-(dimethyl amido (ammonio)) propionyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-dichloride;
4-methoxyl group-2-[2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] the quinoline trichloride;
N-{ (1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-5-oxo heptyl } quinine-4-carboxylic acid amides;
N-{ (1S)-1-[5-(4-methoxy quinoline-2-yl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl }-1-methyl azetidine-3-carboxylic acid amides;
5-(hydroxymethyl)-2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate;
4-{[2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] methyl } morpholine-4-two (trifluoroacetate);
2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[(1E)-3-methoxyl group-3-oxo third-1-alkene-1-yl]-1H-imidazoles-1-trifluoroacetate;
5-(2-carboxy ethyl)-2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate;
5-ethanoyl-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate;
5-cyclohexyl-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo undecyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-7-cyclopropyl-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-9-methyl-7-oxo decyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-8-hydroxyl-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-7-(2-furyl)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-[(1S)-and 1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-8-(methyl sulfinyl)-7-oxo octyl group]-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-[(1S)-and 1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-8-(methyl sulphonyl)-7-oxo octyl group]-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-8-(amino-sulfonyl)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
1-methyl-4-([(1S)-and 7-oxo-1-(4-phenyl-1H-imidazoles-3--2-yl)-7-pyridine-2-base heptyl] amino } carbonyl) piperidines two (trifluoroacetate);
2-((1S)-7-amino-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate;
2-((1S)-6-carboxyl-1-{[(dimethylamino) alkylsulfonyl] amino } hexyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate;
2-((1S)-7-(methylamino)-7-oxo-1-{[(1-pyridine-2-phenylpiperidines-3-yl) carbonyl] amino } heptyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate;
2-[(1S)-and the 1-{[(benzylamino) carbonyl] amino }-7-(methylamino)-7-oxo heptyl]-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate;
5-(2 methoxy quinoline-3-yl)-2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-3--L-tartrate;
2-((1S)-1-{[(1-Methyl-1H-indole-3-yl) carbonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-1H-indoles-2-yl) carbonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(6-fluoro-1H-indol-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-{ (1S)-1-[(1H-indol-3-yl ethanoyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-{ (1S)-1-[(1H-indol-3-yl carbonyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-bromo-1H-indol-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(7-methoxyl group-6,7-dihydro-1-cumarone-2-yl) carbonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-{ (1S)-1-[(1-naphthyl ethanoyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-fluoro-1H-indol-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-chloro-1H-indol-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-{ (1S)-1-[(1H-indoles-2-base carbonyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-fluoro-1H-indoles-2-yl) carbonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-1H-indol-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-hydroxyl-1H-indol-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(6-methoxyl group-2-oxo-2,3-dihydro-1H-indol-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-oxo-2,3-dihydro-1H-indol-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate;
6-(the 2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-3--2-yl) octyl group] amino } ethyl) [1,2,4] triazolo [1,5-a] pyrimidine-3-two (trifluoroacetate);
3-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-3--2-yl) octyl group] amino } carbonyl)-3,4-dihydro spiral shell [different chromene-1,4 '-piperidines] two (trifluoroacetates);
4-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-3--2-yl) octyl group] amino } carbonyl)-3,4-dihydro spiral shell [chromene-2,4 '-piperidines] two (trifluoroacetates);
5-chloro-2-(the 2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-3--2-yl) octyl group] amino } ethyl)-1H-3,1-benzoglyoxaline-3-two (trifluoroacetate);
2-((1S)-7-oxo-1-{[(2-oxo quinazoline-1 (2H)-yl) ethanoyl] amino } octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-((1S)-7-oxo-1-{[(2-oxo-1,3-benzoxazole-3 (2H)-yl) ethanoyl] amino } octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-{ (1S)-1-[(2H-indazolyl-2-base ethanoyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-3-trifluoroacetate;
3-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-3--2-yl) octyl group] amino } carbonyl)-2,3-dihydro spiral shell [indenes-1,4 '-piperidines] two (trifluoroacetates);
2-((1S)-7-oxo-1-{[(2-oxo-1,2,3,4-tetrahydroquinoline-4-yl) carbonyl] amino } octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-cyano-1 H-indol--1-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-{ (1S)-1-[(2-naphthyl ethanoyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-chloro-1-thionaphthene-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-chloro-1H-indazole-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate;
2-(2-{ (1S)-1-[(1-azonia two ring [2.2.2] sufferings-4-base carbonyl) amino]-7-oxo nonyl }-1H-imidazoles-1--5-yl)-4-methoxy quinoline three (trifluoroacetate);
4-methoxyl group-2-[2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] quinoline two (trifluoroacetate);
5-methoxyl group-N-{ (1S)-1-[5-(2-naphthyl)-1,3-oxazole-2-yl]-7-oxo nonyl }-1H-indoles-2-carboxylic acid amides;
1-methyl-4-[({ (1S)-1-[5-(2-naphthyl)-1,3-oxazole-2-yl]-7-oxo nonyl } amino) carbonyl] the piperidines trifluoroacetate;
4-[({ (1S)-1-[5-(2-naphthyl)-1,3-oxazole-2-yl]-7-oxo nonyl } amino) carbonyl]-1-azonia two ring [2.2.2] octane trifluoroacetates;
N, N, 2-trimethylammonium-1-((1S)-and 1-[5-(2-naphthyl)-1,3-oxazole-2-yl]-7-oxo nonyl } amino)-1-oxo third-2-ammonium (aminium) trifluoroacetate;
1-methyl-3-[({ (1S)-1-[5-(2-naphthyl)-1,3-oxazole-2-yl]-7-oxo nonyl } amino) carbonyl] the azetidine trifluoroacetate;
N-{ (1S)-1-[5-(2-naphthyl)-1,3-oxazole-2-yl]-7-oxo nonyl } ethanamide;
N, N-dimethyl-N '-(1S)-and 1-[5-(2-naphthyl)-1,3-oxazole-2-yl]-7-oxo nonyl } oxalamide;
8-[2-(1-{[(1-methyl piperidine-4-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] quinoline three (trifluoroacetate);
2-((1S)-1-{[(1-methyl piperidine-4-yl) carbonyl] amino }-7-oxo nonyl)-6-phenylpyridine two (trifluoroacetate);
N-{ (1S)-1-[5-(2-naphthyl)-1,3-oxazole-2-yl]-7-oxo nonyl }-2-(2-oxo quinazoline-1 (2H)-yl) ethanamide;
3-(2-ethyl-1H-benzoglyoxaline-1-yl)-N-{ (1S)-1-[5-(2-naphthyl)-1,3-oxazole-2-yl]-7-oxo nonyl } propionic acid amide;
N, N-dimethyl-2-((1S)-and 1-[5-(2-naphthyl)-1,3-oxazole-2-yl]-7-oxo nonyl } amino)-2-oxo second ammonium trifluoroacetate;
2-ethyl-1-(the 3-oxo-3-{[(1S)-7-oxo-1-(6-phenylpyridine-2-yl) nonyl] amino } propyl group)-1H-3,1-benzoglyoxaline-1-two (trifluoroacetate);
4-([(1S)-and 7-oxo-1-(6-phenylpyridine-2-yl) nonyl] amino } carbonyl)-1-azonia two ring [2.2.2] octanes two (trifluoroacetate);
2-((1S)-1-{[(benzylamino) carbonyl] amino }-7-oxo nonyl)-6-phenylpyridine trifluoroacetate;
2-((1S)-7-[methoxyl group (methyl) amino]-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-quinoxaline-2-base-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(3-methoxyl group-2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
5-{[benzyl (methyl) amido (ammonio)] methyl }-2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-two (trifluoroacetate);
2-{[2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] methyl }-1,2,3,4-tetrahydroisoquinoline two (trifluoroacetate);
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo decyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-p-methoxy-phenyl)-1H-imidazoles-3-trifluoroacetate;
2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(3-p-methoxy-phenyl)-1H-imidazoles-3-trifluoroacetate;
6-[2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3--5-yl] quinoline two (trifluoroacetate);
5-[2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3--5-yl]-2-toluquinoline two (trifluoroacetate);
5-[2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3--5-yl] quinoline two (trifluoroacetate);
5-[2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3--5-yl]-8-toluquinoline two (trifluoroacetate);
8-methoxyl group-5-[2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3--5-yl] quinoline two (trifluoroacetate);
5-(1-thionaphthene-7-yl)-2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate;
5-(1H-indoles-5-yl)-2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate;
5-[3-(3,5-dimethyl-1H-pyrazol-1-yl) phenyl]-2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate;
5-(3-methoxyl group-2-naphthyl)-2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-1-two (trifluoroacetate);
2-((1S)-1-{[(2-ethyl-5-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-5-quinoxaline-2-base-1H-imidazoles-1-two (trifluoroacetate);
2-((1S)-1-{[(2-ethyl-6-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
5-[4-(dimethyl amido (ammonio)) phenyl]-2-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-two (trifluoroacetate);
5-(2-fluoro-4-p-methoxy-phenyl)-2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate;
5-(3-fluoro-4-p-methoxy-phenyl)-2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate;
5-(3-carboxyl phenyl)-2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate;
5-xenyl-2-base-2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate;
5-dibenzo [b, d] furans-4-base-2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate;
2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[3-(piperidines-1-base carbonyl) phenyl]-1H-imidazoles-1-trifluoroacetate;
2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-quinoxalin-6-yl-1H-imidazoles-1-trifluoroacetate;
5-[(dimethyl amido (ammonio)) methyl]-2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-two (trifluoroacetate);
5-(1,4-dimethoxy-2-naphthyl)-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-{[2-(methylthio group) ethyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-7-(methoxyl group amino)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-7-(oxyethyl group amino)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(2-methyl-5-nitro-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-methyl isophthalic acid H-indenes-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(5-hydroxy-2-methyl-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[3-(propionyl of 5-methoxyl group-1H-benzimidazolyl-2 radicals-yl)] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-1-[(1-thionaphthene-3-base ethanoyl) amino]-7-oxo nonyl }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(2,5-dimethyl-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[3-(propionyl of 1H-benzimidazolyl-2 radicals-yl)] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(6-methoxyl group-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-1-[(1H-indoles-6-base ethanoyl) amino]-7-oxo nonyl }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(2-methyl isophthalic acid, 3-benzothiazole-5-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[3-(5-methoxyl group-2-oxo-1,3-benzoxazole-3 (2H)-yl) propionyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[3-(7-methoxyl group-1H-indol-3-yl) propionyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[3-(1,3-benzothiazole-2-yl) propionyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-oxo-2,3-dihydro-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(6-methoxyl group-2-oxo-2,3-dihydro-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(benzylamino) carbonyl] amino }-7-oxo nonyl)-4-phenylpyridine trifluoroacetate;
4-([(1S)-and 7-oxo-1-(4-phenylpyridine-2-yl) nonyl] amino } carbonyl)-1-azonia two ring [2.2.2] octanes two (trifluoroacetate);
2-((1S)-1-{[2-(dimethyl amido (ammonio))-2-methylpropionyl] amino }-7-oxo nonyl)-4-phenylpyridine two (trifluoroacetate);
5-(3,5-dimethoxy-2-naphthyl)-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(benzyloxy) carbonyl] amino }-7-oxo nonyl)-4-phenylpyridine trifluoroacetate;
2-((1S)-1-{[(1-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(7-fluoro-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(5-ethyl-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-(the 5-tertiary butyl-2-Methyl-1H-indole-3-yl)-N-[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-2-yl) nonyl] ethanamide;
2-((1S)-1-{[(5-oxyethyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-[5-(benzyloxy)-2-Methyl-1H-indole-3-yl]-N-[(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-2-yl) nonyl] ethanamide;
3-(1H-indoles-1-yl)-N-[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-2-yl) nonyl] propionic acid amide;
2-((1S)-1-{[(5-methoxyl group-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-7-oxo-1-{[3-(2-oxo-1,3-benzothiazole-3 (2H)-yl) propionyl] amino } nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-7-oxo-1-[(quinoline-3-base ethanoyl) amino] nonyl }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-7-oxo-1-[(quinoline-5-base ethanoyl) amino] nonyl }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[3-(propionyl of 6-chloro-1H-benzimidazolyl-2 radicals-yl)] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[3-(propionyl of 6-fluoro-1H-benzimidazolyl-2 radicals-yl)] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
N-[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-2-yl) nonyl]-2-(5,6,7,8-naphthane-1-yl) ethanamide;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-8-methyl-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-6-carboxyl-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino } hexyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-thienyl)-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(1-naphthyl)-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-quinoline-8-base-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-morpholine-4-base phenyl)-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(3-nitrophenyl)-1H-imidazoles-3-trifluoroacetate;
3-[2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3--5-yl] pyridine two (trifluoroacetate);
5-(3-cyano-phenyl)-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[3-(trifluoromethoxy) phenyl]-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[4-(trifluoromethoxy) phenyl]-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[4-(trifluoromethyl) phenyl]-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[3-(trifluoromethyl) phenyl]-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[2-(trifluoromethyl) phenyl]-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[2-fluoro-phenyl]-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[3-(oxyethyl group) phenyl]-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[4-(oxyethyl group) phenyl]-1H-imidazoles-3-trifluoroacetate;
5-[4-(kharophen) phenyl]-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate;
5-[2-(methoxycarbonyl) phenyl]-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[4-cyano group-phenyl]-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[5-(3-methyl-5,6,7,8-tetrahydrochysene-1,8-naphthyridines-2-yl) pentanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
6-(the 2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } ethyl) imidazo [2,1-b] [1,3] thiazole-4-two (trifluoroacetates);
2-{ (1S)-1-[(1-cumarone-5-base ethanoyl) amino]-7-oxo nonyl }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-1-[(1-thionaphthene-2-base ethanoyl) amino]-7-oxo nonyl }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(2-ethyl-1H-benzoglyoxaline-1-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate;
2-[2-((1S)-1-{[3-(dimethyl amido (ammonio)) propionyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl]-4-methoxy quinoline three (trifluoroacetate);
5-(4-chloro-phenyl-)-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate;
5-(3, the 4-dichlorophenyl)-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate;
5-(3-bromophenyl)-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate;
2-((1S)-7-methoxyl group-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-phenylethyl)-1H-imidazoles-1-trifluoroacetate;
7-(the 3-oxo-3-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } propyl group)-1,8-naphthyridines-1-two (trifluoroacetate);
7-(the 3-oxo-3-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } propyl group)-1,2,3,4-tetrahydrochysene-1,8-naphthyridines-1-two (trifluoroacetate);
N3, N3-dimethyl-N-[{ (1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl }-the α-Bing Ansuan acid amides;
2-{ (1S)-7-oxo-1-[(4,5,6,7-tetrahydrochysene-1H-indazolyl-3-base carbonyl) amino] nonyl }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-7-oxo-1-[(4,5,6,7-tetrahydrochysene-1-thionaphthene-3-base carbonyl) amino] nonyl }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-7-oxo-1-{[3-(1-oxo-1,3-dihydro-2H-isoindole-2-yl) propionyl] amino } nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-{ (1S)-1-[({2-[2-(dimethyl amido (ammonio)) ethyl]-3-oxo-2,3-dihydro-1H-isoindole-4-yl } carbonyl) amino]-7-oxo nonyl }-5-phenyl-1H-imidazoles-1-two (trifluoroacetate);
6-benzyl-2-oxo-3-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } carbonyl)-1,2,5,6,7,8-six hydrogen-1,6-naphthyridines-6-two (trifluoroacetate);
7-(the 4-oxo-4-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } butyryl radicals)-6,7,8, the 9-tetrahydropyridine is [2,3-b]-1 also, 6-naphthyridines-1-two (trifluoroacetate);
2-((1S)-1-{[(2-ethanoyl-1,2,3,4-tetrahydroisoquinoline-1-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-methyl-3-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } carbonyl)-1,2,3,4-tetrahydroisoquinoline two (trifluoroacetate);
2-(the 2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } ethyl)-1,2,3,4-tetrahydroisoquinoline two (trifluoroacetate);
4-[2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3--5-yl] pyridine two (trifluoroacetate);
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-nitrophenyl)-1H-imidazoles-3-trifluoroacetate;
5-(3-amido (ammonio) phenyl)-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-two (trifluoroacetate);
5-(2,3-dihydro-1,4-Ben Bing Er Evil star-6-yl)-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate;
5-(2, the 4-Dimethoxyphenyl)-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate;
5-[2-fluoro-5-(trifluoromethyl) phenyl]-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate;
5-[3-(amido (ammonio) methyl) phenyl]-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-two (trifluoroacetate);
5-[2-(amido (ammonio) methyl)-4-fluorophenyl]-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-two (trifluoroacetate);
5-xenyl-3-base-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate;
3-[2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3--5-yl] quinoline two (trifluoroacetate);
5-(3-carboxyl phenyl)-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[3-(1H-tetrazolium-5-yl) phenyl]-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(3-{[(methyl sulphonyl) amino] carbonyl } phenyl)-1H-imidazoles-3-trifluoroacetate;
2-((1R)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles third-1-two (trifluoroacetate);
2-[(1S)-1-({ [1-(2-tert.-butoxy-2-oxoethyl)-5-methoxyl group-2-Methyl-1H-indole-3-yl] ethanoyl } amino)-7-oxo nonyl]-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-[(1S)-1-({ [5-methoxyl group-2-methyl isophthalic acid-(pyridin-3-yl methyl)-1H-indol-3-yl] ethanoyl } amino)-7-oxo nonyl]-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-1,2-dimethyl-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-[(1S)-1-({ [5-methoxyl group-2-methyl isophthalic acid-(2-tetramethyleneimine-1-base ethyl)-1H-indol-3-yl] ethanoyl } amino)-7-oxo nonyl]-5-phenyl-1H-imidazoles-1-two (trifluoroacetate);
4-{2-[5-methoxyl group-2-methyl-3-(the 2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } ethyl)-1H-indoles-1-yl] ethyl } morpholine-4-two (trifluoroacetate);
2-((1S)-1-{[(5-methyl isophthalic acid, 2-benzoisoxazole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-[(1S)-1-([5-(dimethyl amido (ammonio))-2-Methyl-1H-indole-3-yl] ethanoyl } amino)-7-oxo nonyl]-5-phenyl-IH-imidazoles-1-two (trifluoroacetate);
1-methyl-4-[({ (1S)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo undecyl } amino) carbonyl] piperidines two (trifluoroacetate);
1-methyl-4-[({ (1S)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo decyl } amino) carbonyl] piperidines two (trifluoroacetate);
N-[1-(5-ethanoyl-1H-imidazoles-2-yl)-7-oxo nonyl]-2-(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanamide;
2-[2-((1S)-1-{[3-(dimethyl amido (ammonio)) propionyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl]-4-methoxy quinoline trichloride;
2-((1S)-1-{[(6-methoxyl group-1-cumarone-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
6-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } carbonyl) quinoline two (trifluoroacetate);
6-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } carbonyl) isoquinoline 99.9 two (trifluoroacetate);
5-methyl-6-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } carbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-3,5-two or three (trifluoroacetate);
2-(5-methyl isophthalic acid-thionaphthene-3-yl)-N-[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-2-yl) nonyl] ethanamide;
2-[(1S)-1-({ [1-(carboxyl methyl)-5-methoxyl group-2-Methyl-1H-indole-3-yl] ethanoyl } amino)-7-oxo nonyl]-5-phenyl-1H-imidazoles-1-trifluoroacetate;
4-{[5-methoxyl group-2-methyl-3-(the 2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } ethyl)-1H-indoles-1-yl] ethanoyl }-1-methylpiperazine-1-two (trifluoroacetate);
7-methyl-2-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } carbonyl)-5,6,7, the 8-imidazolidine is [1,2-a] pyrazine-4 also, 7-two or three (trifluoroacetate);
2-{ (1S)-1-[({5-[(dimethyl amido (ammonio)) methyl]-2-Methyl-1H-indole-3-yl } ethanoyl) amino]-7-oxo nonyl }-5-phenyl-1H-imidazoles-1-two (trifluoroacetate);
5-bromo-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate;
5-(4-carboxyl phenyl)-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate;
5-(3-hydroxy phenyl)-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate;
5-[2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] isoquinoline 99.9 two (trifluoroacetate);
5-{4-[(dimethyl amido (ammonio)) methyl] phenyl }-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-two (trifluoroacetate);
4-methoxyl group-2-[2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] quinoline three (trifluoroacetate);
5-(2-carboxyl phenyl)-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate;
5-[4-(dimethyl amido (ammonio)) phenyl]-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-two (trifluoroacetate);
2-((1S)-7-oxo-1-{[(4,5,6,7-tetrafluoro-1H-indol-3-yl) ethanoyl] amino } nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(5-fluoro-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
1-methyl-N-{ (1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl } azetidine-3-carboxylic acid amides;
2-{ (1S)-7-oxo-1-[(1H-pyrrolo-[2,3-b] pyridin-3-yl ethanoyl) amino] nonyl }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
4-([(1S)-and 6-carboxyl-1-(5-phenyl-1H-imidazoles-1--2-yl) hexyl] amino } carbonyl)-1-azonia two ring [2.2.2] octanes two (trifluoroacetate);
4-([(1S)-and 7-(methoxyl group amino)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) heptyl] amino } carbonyl)-1-azonia two ring [2.2.2] octanes two (trifluoroacetate);
1-methyl-4-([(1S)-and 7-oxo-1-(4-phenyl-1H-imidazoles-3--2-yl)-7-(2-thienyl) heptyl] amino } carbonyl) piperidines two (trifluoroacetate);
2-{ (1S)-7-oxo-1-[(1H-pyrrolo-[3,2-c] pyridin-3-yl ethanoyl) amino] nonyl }-5-phenyl-1H-imidazoles-1-trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-1H-pyrrolo-[2,3-c] pyridin-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate;
5-(2-fluorine quinoline-3-yl)-2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-3-two (trifluoroacetate);
2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-5-quinoxalin-6-yl-1H-imidazoles-3-two (trifluoroacetate);
8-methoxyl group-5-[2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-3--5-yl] quinoline three (trifluoroacetate);
5-[4-(dimethylamino) phenyl]-2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-3-two (trifluoroacetate);
The 2-methyl isophthalic acid-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } carbonyl)-1,2,3,4-tetrahydroisoquinoline two (trifluoroacetate);
5-(3-carboxyl phenyl)-2-{ (1S)-7-oxo-1-[(2-thienyl carbonyl) amino] nonyl }-1H-imidazoles-3-trifluoroacetate;
4-methoxyl group-2-(2-{ (1S)-1-[(3-morpholine-4--4-base propionyl) amino]-7-oxo nonyl }-1H-imidazoles-1--5-yl) the quinoline trichloride;
2-[2-((1S)-1-{[3-(1H-imidazoles-1--1-yl) propionyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl]-4-methoxy quinoline trichloride;
2-[2-((1S)-1-{[(4-ethanoyl piperazine-1--1-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl]-4-methoxy quinoline trichloride;
2-[2-((1S)-1-{[(dimethyl amido (ammonio)) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl]-4-methoxy quinoline trichloride;
4-methoxyl group-2-(2-{ (1S)-7-oxo-1-[(piperidines-1-base ethanoyl) amino] nonyl }-1H-imidazoles-1--5-yl) the quinoline trichloride;
4-methoxyl group-2-[2-((1S)-1-{[(4-methylpiperazine-4--1-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] the quinoline trichloride;
4-methoxyl group-2-[2-((1S)-1-{[(4-methylmorpholine-4--2-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] quinoline three (trifluoroacetate);
4-methoxyl group-2-[2-((1S)-1-{[3-(4-methylpiperazine-4--1-yl) propionyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] quinoline three (trifluoroacetate);
4-methoxyl group-2-[2-((1S)-1-{[(4-methylpiperazine-4--1-yl) (oxo) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] quinoline three (trifluoroacetate);
2-[(1S)-1-({ [1-(N, N-dimethyl glycyl) azetidine-3-yl] carbonyl } amino)-7-oxo nonyl]-5-(4-methoxy quinoline-2-yl)-1H-imidazoles-1-trifluoroacetate;
2-[(1S)-1-({ [1-(2-methoxy ethyl) azetidine-3-yl] carbonyl } amino)-7-oxo nonyl]-5-(4-methoxy quinoline-2-yl)-1H-imidazoles-1-two (trifluoroacetate);
1-methyl-3-[({ (1S)-1-[5-(1,8-naphthyridines-2-yl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl } amino) carbonyl] the azetidine formate;
1-methyl-3-[({ (1S)-1-[5-(1,6-naphthyridines-2-yl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl } amino) carbonyl] the azetidine formate;
1-methyl-3-[({ (1S)-1-[5-(1,6-naphthyridines-8-yl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl } amino) carbonyl] the azetidine formate;
3-((1S)-and 1-[5-(4-methoxy quinoline-2-yl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl } amino)-N, N-dimethyl-3-oxo third-1-ammonium formate;
4-[({ (1S)-1-[5-(4-methoxy quinoline-2-yl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl } amino) carbonyl]-1-azonia two ring [2.2.2] octane formate;
2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-5-(2-oxo-1,2-dihydroquinoline-3-yl)-1H-imidazoles-3-two (trifluoroacetate);
N-{ (1S)-1-[5-(4-methoxy quinoline-2-yl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl }-2-(1H-pyrrolo-[3,2-c] pyridin-3-yl) ethanamide;
5-(4-methoxy quinoline-2-yl)-2-{ (1S)-7-oxo-1-[(1H-pyrrolo-[3,2-c] pyridin-3-yl ethanoyl) amino] nonyl }-1H-imidazoles-1-trifluoroacetate;
5-(3-carboxyl phenyl)-2-((1S)-1-{[(1-methyl piperidine-4-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate;
5-(3-carboxyl phenyl)-2-{ (1S)-1-[(morpholine-4-base ethanoyl) amino]-7-oxo nonyl }-1H-imidazoles-3-trifluoroacetate;
5-(3-carboxyl phenyl)-2-{ (1S)-1-[(N, N-dimethyl glycyl) amino]-7-oxo nonyl }-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[(1-methyl piperidine-4-yl) carbonyl] amino }-7-oxo nonyl)-5-(3-{[(methyl sulphonyl) amino] carbonyl } phenyl)-1H-imidazoles-3-trifluoroacetate;
2-((1S)-1-{[3-(3-methoxyl group azetidine-1-yl) propionyl] amino }-7-oxo nonyl)-5-quinoxalin-6-yl-1H-imidazoles-1-two (trifluoroacetate);
3-([(1S)-and 7-oxo-1-(5-quinoxalin-6-yl-1H-imidazoles-3--2-yl) nonyl] amino } carbonyl)-1-azonia two ring [2.2.2] octanes two (trifluoroacetate);
4-([(1S)-and 7-oxo-1-(5-quinoxalin-6-yl-1H-imidazoles-1--2-yl) nonyl] amino } carbonyl)-1-azonia two ring [2.2.2] octanes two (trifluoroacetate);
5-(2 methoxy quinoline-3-yl)-2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-3-dichloride;
2-((1S)-1-{[(dimethyl amido (ammonio)) ethanoyl] amino }-7-oxo nonyl)-5-(4-methoxy quinoline-2-yl)-1H-imidazoles-1-dichloride;
3-[({ (1S)-1-[5-(2 methoxy quinoline-3-yl)-1H-imidazoles-2-yl]-7-oxo nonyl } amino) carbonyl]-1-methyl azetidine muriate;
N-{ (1S)-1-[5-(2 methoxy quinoline-3-yl)-1H-imidazoles-2-yl]-7-oxo nonyl }-1-methyl azetidine-3-carboxylic acid amides;
N-{ (1S)-7-[methoxyl group (methyl) amino]-1-[5-(2 methoxy quinoline-3-yl)-1H-imidazoles-2-yl]-7-oxo heptyl }-1-methyl azetidine-3-carboxylic acid amides;
And pharmaceutically acceptable free alkali, salt, alternative salt and steric isomer.
The formula I compound that the present invention includes free alkali form with and pharmacy acceptable salt and steric isomer.Some particular compound in this illustrations are the protonated salt of amine compound.Having the heterocyclic formula I compound that contains 2 or more a plurality of N atoms can carry out protonated on any, some or all N atom.Term " free alkali " is meant the amine compound into salt-independent shape.The pharmacy acceptable salt that the present invention comprised not only comprises for said particular compound and the salt of illustrations, and comprises all general pharmacy acceptable salts of the formula I compound of free form.The free form of the concrete salt of described compound can separate by using technology known in the art.For example, above-mentioned free form can obtain again by handling described salt with suitable dilute alkaline aqueous solution, and described dilute alkaline aqueous solution is such as rare NaOH, salt of wormwood, ammoniacal liquor and sodium bicarbonate aqueous solution.Can there be some difference in described free form by its corresponding salt form on some physicals, such as the solubleness in polar solvent, but on the other hand, based on the object of the invention, its bronsted lowry acids and bases bronsted lowry salt is that its corresponding free form pharmaceutically is equal to.
The The compounds of this invention pharmacy acceptable salt can be synthesized by the conventional chemical method by the The compounds of this invention that contains alkalescence or acidic moiety.Usually, the salt of basic cpd is prepared by ion exchange chromatography, perhaps by in the multiple combination of appropriate solvent or solvent, makes free alkali and stoichiometry or expects that with excessive formation the mineral acid or the organic acid reaction of salt are prepared.Similarly, the salt of acidic cpd is by obtaining forming with the reaction of suitable inorganic or organic bases.
Thus, the The compounds of this invention pharmacy acceptable salt comprises by making basic cpd of the present invention and conventional the non-toxic salt inorganic or The compounds of this invention that organic acid reaction forms.For example; conventional non-toxic salt comprises the salt that is obtained by mineral acid; hydrochloride for example; hydrobromate; vitriol; sulfamic salt; phosphoric acid salt and nitrate or the like; and by the salt of organic acid preparation, for example acetate; propionic salt; succinate; glycollate; stearate; lactic acid salt; malate; tartrate; Citrate trianion; ascorbate salt; pamoic; maleate; hydroxymaleic acid salt; the phenyl maleate; glutaminate; benzoate; salicylate; sulfanilate; 2-acetoxyl group-benzoate; fumarate; tosylate; mesylate; ethylene disulfonic acid salt; oxalate; isethionate and trifluoroacetate or the like.Preferred pharmacy acceptable salt of the present invention contains 1 equivalent formula (I) compound and the inorganic or organic acid of 1,2 or 3 equivalents.More especially, pharmacy acceptable salt of the present invention is trifluoroacetate or chloride salt, particularly trifluoroacetate.Preferred pharmacy acceptable salt of the present invention is a tartrate.
When The compounds of this invention was acidic cpd, suitable " pharmacy acceptable salt " was meant the salt that is prepared by pharmaceutically acceptable nontoxic alkali (comprising mineral alkali and organic bases).Comprise aluminium salt, ammonium salt, calcium salt, mantoquita, trivalent iron salt, divalent iron salt, lithium salts, magnesium salts, manganese salt, manganous salt, sylvite, sodium salt and zinc salt or the like by the mineral alkali salt that obtains of deriving.Preferred especially ammonium, calcium, magnesium, potassium and sodium salt.Comprise primary amine salt by the pharmaceutically acceptable organic nontoxic alkali salt that obtains of deriving, secondary amine salt, tertiary ammonium salt, replace amine salt (comprising naturally occurring replacement amine salt), cyclammonium salt and cation ion exchange resin salt, such as arginine, the trimethyl-glycine caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamide, 2-diethylaminoethanol, the 2-dimethylaminoethanol, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, glycosamine, glycosamine, Histidine, breathe out amine, Isopropylamine, Methionin, methyl glucoside amine, morpholine, piperazine, piperidines, versamid 900, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine and tromethane or the like.
The preparation of pharmacy acceptable salt and other general pharmacy acceptable salt is by people such as Berg as mentioned above, and " Pharmaceutical Salts ", J.Pharm.Sci., 1977,66:1-19 has carried out more comprehensively describing.
Should also be pointed out that, The compounds of this invention is inner salt or zwitterionic compound potentially, because under physiological condition, deprotonation acidic moiety (such as carboxyl) in the compound can become negatively charged ion, and this electric charge can be relative with cationic charge protonated or alkylation basic moiety (such as quaternary nitrogen atoms) and obtains internal balance subsequently.
The compounds of this invention can be used for the human body or the animal body methods of treatment of being undertaken by treatment.The compounds of this invention all has purposes in the multiple mankind and animal health application.The compounds of this invention is for being used for the treatment of histone deacetylase (HDAC) inhibitor of cancer and other disease.HDACs catalysis removes deacetylate from the protein lysine residue, comprises that histone and hdac inhibitor have shown different biological functions, comprises influencing genetic expression, cytodifferentiation, cell cycle progression, cessation of growth cessation and/or apoptosis.Referring to J.Med.Chem.2003,46:5097 and Curr.Med.Chem.2003,10:2343.
The compounds of this invention can be used for the treatment of cell breeding disease.The morbid state of method and composition treatment that can be by providing at this include but not limited to cancer (below be described further), neurodegenerative disease, schizophrenia and apoplexy.
Think to be specially adapted to treat cancer, comprise solid tumour, such as skin carcinoma, mammary cancer, the cancer of the brain, cervical cancer, carcinoma of testis or the like in this compound that provides, composition and method.Particularly, can include but not limited to by the cancer of The compounds of this invention, composition and method treatment: heart: (angiosarcoma, fibrosarcoma, rhabdosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and abnormal attitude knurl; Lung: bronchogenic carcinoma (squamous cell, not alienation minicell, not alienation maxicell, malignant adenoma), alveolar (bronchiolar) cancer, bronchial adenoma, sarcoma, lymphoma, chondroma progonoma, mesothelioma; Stomach and intestine: esophagus (squamous cell carcinoma, malignant adenoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas pancreas (ductal malignant adenoma, nesidioblastoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (malignant adenoma, lymphoma, carcinoid tumor, Karposi ' s sarcoma, leiomyoma, vascular tumor, the lipoma neurofibroma, fibroma), large intestine (malignant adenoma, the pipe adenoma, villous adenoma, progonoma, leiomyoma); Urogenital tract: kidney (malignant adenoma, Wilms' tumor of kidney [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transsitional cell carcinoma, malignant adenoma), prostate gland (malignant adenoma, sarcoma), testis (spermocytoma, abnormal attitude knurl, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, mesenchymal cell cancer, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver: liver cancer (hepatocellular carcinoma), cholangiocellular carcinoma, hepatoblastoma, angiosarcoma, adenoma, vascular tumor; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, pernicious giant cell tumor, chordome, osteocartilaginous exostosis, optimum chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor; Neural system: skull (osteoma, vascular tumor, granuloma, vitiligoidea, osteitis deformans), meninx (meningioma, meningiosarcoma, neurospongioma), brain (astrocytoma, medulloblastoma, neurospongioma, ependymoma, germinoma [pinealoma], glioblastoma are many types of, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal cord neurofibroma, meningioma, neurospongioma, sarcoma); Gynaecology: uterus (carcinoma of endometrium), uterine neck (cervical cancer, pre-tumour cervical atypism hyperplasia), ovary (ovarian cancer [serous cystadenocarcinoma, mucous cystoadenocarcinoma, general cancer], granuloma-theca cell tumour, the ovary sertoli-Leydig cell tumour, dysgerminoma, immature teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, malignant adenoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), uterine tube (cancer); Blood: blood (myelomatosis [acute and chronic], acute lymphoblastic leukemia, lymphocytic leukemia, marrow and bone marrow propagation disease, multiple myeloma, myelodysplastic syndrome) lymphogranulomatosis, non_hodgkin lymphoma [malignant lymphoma]; Skin: malignant melanoma, rodent cancer, squamous cell carcinoma, Karposi ' s sarcoma, moles dysplastic nevi, lipoma, vascular tumor, dermatofibroma, keloid, psoriasis; And suprarenal gland: neuroblastoma.Thus, as above given term " cancer cells " comprises and is subjected to any above-mentioned cell that symptom torments that is equal to.
Thus, the invention provides the formula I compound that is used to make the medicine for the treatment of cell breeding disease.
The present invention also provides the method for treatment cell breeding disease, this method comprise administration need its patient's significant quantity formula I compound or contain formula I compound compositions.
The compounds of this invention can also be used for the treatment of neurodegenerative disease, include but not limited to that polyglutamyl amine expands relevant neurodegeneration, Huntington's disease, Kennedy ' s disease, spinocerebellum ataxia, dentate nucleus rubrum pallidum Louis and examines atrophy (DRPLA), neurodegeneration, Machado-Joseph ' s disease, Alzheimer, Parkinson's disease, amyotrophic lateral sclerosis, statural spongiosus, Protein virus relative disease and multiple cerebral sclerosis (MS) that protein aggregation is relevant.Referring to WO 02/090534 and WO 03/083067.
Thus, the invention provides the formula I compound that is used to make treatment or prevents the medicine of neurodegenerative disease.
The present invention also provide the treatment or the prevention neurodegenerative disease method, this method comprise administration need its patient's significant quantity formula I compound or contain formula I compound compositions.
The compounds of this invention can also be used for the treatment of or prevent backwardness, particularly " X chromosome-relevant backwardness " and " Rubinstein-Taybi syndromes ".
Thus, the invention provides the formula I compound that is used to make the treatment or prevents retarded medicine.
The present invention also provide the treatment or prevent retarded method, this method comprise administration need its patient's significant quantity formula I compound or contain formula I compound compositions.
The compounds of this invention can also be used for the treatment of or prevent inflammatory schizophrenia, referring to WO02/090534.
Thus, the invention provides the formula I compound that is used to make the treatment or prevents schizoid medicine.
The present invention also provide the treatment or prevent schizoid method, this method comprise administration need its patient's significant quantity formula I compound or contain formula I compound compositions.
The compounds of this invention can also be used for the treatment of or prevent inflammatory diseases, includes but not limited to apoplexy, rheumatic arthritis, lupus erythematosus, ulcerative colitis and traumatic brain injury.Referring to people such as Leoni, PNAS, 99 (5): 2995-3000 (2002); People such as Suuronen, J.Neurochem.87:407-416 (2003) and Drug Discovery Today, 10:197-204 (2005).
Thus, the invention provides the formula I compound that is used to make treatment or prevents the medicine of inflammatory diseases.
The present invention also provide the treatment or the prevention inflammatory diseases method, this method comprise administration need its patient's significant quantity formula I compound or contain formula I compound compositions.
The compounds of this invention can also be used to suppress smooth muscle cell proliferation and/or migration, and can be used to prevent and/or treat restenosis thus, and for example the back restenosis is transplanted in angioplasty and/or expansion.
Thus, the invention provides the formula I compound of the medicine that is used to make treatment or prevention of restenosis.
The present invention also provides treatment or prevents the method for restenosis, this method comprise administration need its patient's significant quantity formula I compound or contain formula I compound compositions.
In one embodiment, by be provided in the expansion device or on it (for example, be coated on the expansion device) have the expansion device of one or more The compounds of this invention, smooth muscle cell proliferation and/or migration have obtained inhibition and postoperative restenosis has obtained preventing and/or treating.Described expansion device is used for the controllable release The compounds of this invention, thereby suppresses smooth muscle cell proliferation and/or migration and prevent and/or treat restenosis.
Narrow is the symptom relevant with angiostenosis with restenosis.Angiostenosis passage in time usually produces gradually.In contrast, the angiostenosis after restenosis is operated with blood vessel is interior is relevant, such as the angiostenosis behind balloon angioplasty and/or expansion transplanting or the blood vessel injury.
Generally carry out balloon angioplasty to open narrow blood vessel; Expansion combines after balloon angioplasty or with balloon angioplasty usually to be carried out, so that blood vessel keeps open.
Narrow blood vessel utilizes balloon angioplasty to be opened in the following manner: handle the most advanced and sophisticated conduit of air bag to narrow location and effectively the expanded balloon tip to enlarge the blood vessel of closure.In order to make closed blood vessel remain in opening, can will support partly to provide in the blood vessel in the spreader implantable intravascular to vessel open, thus restriction after balloon catheter removes, blood vessel retracts to the degree of its closure state.Restenosis is generally caused by damage suffered during the angioplasty, is subjected to for example influence of air bag expansion, atherectomy or artery laser-induced thermal etching treatment.For above-mentioned these operations, depend on vessel position, damage length and many other variablees, restenosis exists with about ratio of 30%～about 60%.This has just reduced the overall success ratio of relevant Noninvasive balloon angioplasty and expansion operation.
Restenosis can belong to multiple factor, comprises smooth muscle cell proliferation (SMC).The initial inner membrance mechanical injuries that SMC propagation is subjected to when being transplanted by balloon angioplasty and expansion cause.This process is characterised in that, early stage thrombocyte obtains activation and thrombus obtains formation, and SMC recovers and moves subsequently, and final cell is bred with extracellular matrix and accumulated.The endotheliocyte of damaged, SMCs, thrombocyte and scavenger cell secretion promote the cytokine and the somatomedin of restenosis.The expression of SMC propagation causes the final general way of neointimal propagation.Therefore, the purpose antiproliferative therapy that is to suppress to regulate in the cell cycle result can constitute the rational method of restenosis after the angioplasty.
The compounds of this invention can also be used as immunosuppressor or immunomodulator, and can be used for the treatment of in view of the above or epidemic prevention reaction or immune-mediated reaction and disease, such as the acute or chronic transplanting rejection (referring to WO 05/013958) of systemic lupus erythematous (SLE) and organ, tissue or Transplanted cells acceptor.
Can use the example of the autoimmune disease of The compounds of this invention to comprise that autoimmunization hematology illness (comprises hemolytic anemia disease, aplastic anemia, pure red blood corpuscle anemia and sudden thrombocytopenia), systemic lupus erythematous, thyroiditis, struma lymphomatosa, polychondritis, sclerodoma, Wegner granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, atopic dermatitis, vasculitis, Stevens-Yue Xun syndromes, sudden diarrhoea, autoimmunization inflammatory bowel (comprising ulcerative colitis and Crohn disease), incretory gland illness in eye, Graves disease, sarcoidosis, multiple cerebral sclerosis, the source property sent out sudamen liver cirrhosis, juvenile diabete (type i diabetes), type ii diabetes and relative disease, uveitis (preceding and back), keratoconjunctivitis sicca and Chun Fa keratoconjunctivitis, the internode lung fibrosis, psoriatic arthritis, glomerulonephritis (has or does not have nephrotic syndrome, comprise sudden nephrotic syndrome or little change ephrosis), the juvenile form dermatomyositis infects, the disease of autoantibody mediation, aplastic anemia, dust Wen syndromes, autoimmune hemolytic anemia, cause abnormal immune reaction and/or the activatory transmissible disease (immune disorder that brings out such as wound or pathogenic agent, for example comprise, infect the imbalance that causes) by hepatitis B and hepatitis C, infection of staphylococcus aureus, viral encephalitis, Sepsis, wherein damage the infection disease (for example leprosy) of bringing out by inflammatory responses; And circulatory diseases, such as arteriosclerosis, atherosclerosis, periarteritis nodosa and myocarditis.
Thus, the invention provides the formula I compound of the medicine that is used to make treatment or epidemic prevention disease.
The present invention also provides the treatment or the method for epidemic prevention disease, this method comprise administration need its patient's significant quantity formula I compound or contain formula I compound compositions.
The compounds of this invention can also be used for the treatment of or prevent other disease, such as diabetes, cardiovascular disorder and asthma.
The compounds of this invention can also be used for the treatment of or prevent cardiac hypertrophy and heart failure, as Cell, described in the 110:479-488 (2002).
In one embodiment, The compounds of this invention can be used for the treatment of or prevent neurodegenerative disease, schizophrenia, apoplexy, backwardness, Immunological diseases or asthma.
The compounds of this invention can be individually dosed or preferably in according to the pharmaceutical composition of standard drug practice collaborative pharmaceutically acceptable carrier, vehicle or thinner Combined Preparation to Mammals, preferred human.In one embodiment, The compounds of this invention can be administered to animal.Described compound can be taken orally or parenteral admin, comprises intravenous, intramuscular, endoperitoneal, subcutaneous, rectum and partial route of administration.
The present invention also provides the pharmaceutical composition that comprises one or more The compounds of this invention and pharmaceutically acceptable carrier.The pharmaceutical composition that contains described activeconstituents can for example, be tablet, tablet, lozenge, water or oil suspension, dispersible powder or granula, emulsion, hard or soft capsule or syrup or elixir for being applicable to the form of oral application.The pharmaceutical composition that is designed for oral application can be prepared according to any currently known methods that pharmaceutical composition is made in this area, and for pharmaceutically exquisite and good to eat preparation are provided, described composition can contain one or more reagent that is selected from sweeting agent, sweetener, tinting material and sanitas.Tablet contains the activeconstituents with the nontoxic pharmaceutically acceptable mixed with excipients that is fit to the manufacturing tablet.These vehicle can for, inert diluent for example is such as lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, for example Microcrystalline Cellulose, croscarmellose sodium, W-Gum or alginic acid; Tackiness agent, for example starch, gel, polyvinylpyrrolidone or gum arabic; And lubricant, for example Magnesium Stearate, stearic acid or talcum.Described tablet can not have dressing or they can carry out undesirable taste or delay disintegration and the absorption in gi tract of dressing with the shielding medicine by known technology, thereby the continuous action of long period is provided.For example, can use water-soluble taste masked material, such as hydroxypropyl-methylcellulose gum or hydroxypropylcellulose, the material of perhaps delaying time is such as ethyl cellulose, cellulose acetate butyrate.
The composition that is used for oral application can also exist as hard capsule, wherein activeconstituents is mixed with inert solid diluent (for example lime carbonate, calcium phosphate or kaolin), perhaps exist, wherein activeconstituents is mixed with water-soluble carrier (such as polyoxyethylene glycol) or oils medium (for example peanut oil, whiteruss or sweet oil) as soft capsule.
Aqueous suspensions contains the active substance with the mixed with excipients that is fit to the manufacturing aqueous suspensions.Described vehicle is a suspending agent, for example Xylo-Mucine, methylcellulose gum, Vltra tears, sodium alginate, polyvinylpyrrolidone, Tragacanth and Sudan Gum-arabic; Disperse or the naturally occurring phosphatide of wetting agent Ke Yishi, for example condensation product of the condensation product of Yelkin TTS or oxyalkylene and lipid acid (for example polyoxyethylene 8 stearate salt) or ethylene oxide and long chain aliphatic (for example 17 alkene oxygen base hexadecanols) or ethylene oxide and be derived from the partial ester of lipid acid and condensation product of hexitol (such as octadecanoic acid ester of polyethylene glycol) or ethylene oxide and be derived from the partial ester of lipid acid and the condensation product of hexitol acid anhydrides (for example polyethylene sorbitan monooleate).Described water suspension can also contain one or more sanitass, such as ethyl p-hydroxybenzoate or p-Hydroxybenzoate n-propyl; One or more tinting materials; One or more sweetener; With one or more sweeting agents, such as sucrose, asccharin or aspartame.
Oil suspension can obtain preparation by activeconstituents being suspended in vegetables oil (for example peanut oil, sweet oil, sesame oil or Oleum Cocois) or being suspended in the mineral oil (such as whiteruss).Described oil suspension can contain thickening material, for example beeswax, paraffinum durum or hexadecanol.Sweeting agent and sweetener such as act as listed above can be added wherein, thereby good to eat oral preparations is provided.These compositions can be preserved by adding antioxidant (such as butyl hydroxy anisol or alpha-tocopherol).
Being applicable to by adding dispersible powder and the granula that entry prepares aq suspension provides and dispersion agent or wetting agent, suspending agent and one or more sanitas blended activeconstituentss.The suitable dispersion agent or the illustration of wetting agent and suspending agent are as mentioned above.Can also there be other vehicle, such as sweeting agent, seasonings and tinting material.These compositions can be preserved by adding antioxidant (such as xitix).
Pharmaceutical composition of the present invention can also be the form of oil-water emulsifiers.Described oil phase can be vegetables oil (such as sweet oil or peanut oil), mineral oil (such as whiteruss) or their mixture.Examples of suitable emulsifiers can be naturally occurring phosphatide, such as soybean lecithin; The ester or the partial ester of deriving and obtaining by lipid acid and hexitol acid anhydrides, for example sorbitan monooleate; With the condensation product of described partial ester and ethylene oxide, polyoxyethylene sorbitan monooleate for example.Described emulsion can also contain sweeting agent, sweetener, sanitas and antioxidant.
Syrup and elixir can be prepared with sweeting agent (such as glycerine, propylene glycol, sorbyl alcohol or sucrose).Described preparation can also contain negative catalyst, sanitas, seasonings and tinting material and antioxidant.The pharmaceutical composition of The compounds of this invention can be the form of sterile injectable aqueous suspensions suspensoid.
Acceptable vehicle and operable solvent are water, Ringer's solution and isotonic sodium chlorrde solution.
Described sterile injectable preparation can also be a sterile injectable oil-in-water microemulsion, wherein activeconstituents is dissolved in the oil phase.For example, can at first activeconstituents be dissolved in the mixture of soya-bean oil and Yelkin TTS.Then, the gained oil solution is incorporated in the mixture of water and glycerine and and handles, thereby form microemulsion it.
Can injectable liquor or microemulsion be incorporated in patient's blood flow by local bolus injection.Additionally, advantageously described liquor of administration in a certain way or microemulsion, thus keep the stable circulation concentration of The compounds of this invention.In order to keep described constant density, can use continuous intravenously delivery apparatus.The example of described device is Deltec CADD-PLUS TM type 5400 intravenously pumps.
Described pharmaceutical composition is can be for the sterile injectable that is used for intramuscular and subcutaneous administration moisture or contain oil suspension.Described suspensoid can utilize above-mentioned suitable dispersion agent or wetting agent and suspending agent to prepare according to methods known in the art.Described injectable sterile preparation can also be at nontoxic parenteral acceptable diluent or injectable sterile solution or the suspension in the solvent, for example is 1,3 butylene glycol solution.In addition, usually aseptic, fixed oil are used as solvent or suspension medium.Based on above-mentioned purpose, any tasteless fixed oil can be used, and comprises synthetic list or triglyceride.In addition, in injectable formulation, can use such as oleic lipid acid.
Formula I compound can also carry out administration with the suppository form that is used for the described medicine of rectal administration.Thereby these compositions can by with medicine with at normal temperatures for solid but under rectal temperature for solid and will in rectum, melt the suitable nonirritant excipient that discharges medicine thus and mix and obtain preparing.Described material comprises the mixture of the fatty acid ester of the polyoxyethylene glycol of theobroma oil, glycerin cement, hydrogenated vegetable oil, various molecular weights and polyoxyethylene glycol.
For topical application, can use ointment, paste, jelly, liquor or suspensoid of containing formula I compound or the like.(based on application aims, topical application should comprise mouth wash shua and gargle.)
In addition, for The compounds of this invention, preferably can be with form administration in the nose, carrier and delivery apparatus in suitable nose is used in the part are perhaps through seeing through skin route, the skin surface patch form of utilizing those those of ordinary skills to know.For transdermal distribution system form administration, dosage will continue during the whole dosage regimen but not intermittent administration certainly.The compounds of this invention can be sent with the suppository form of using matrix, and described matrix is such as the mixture of the fatty acid ester of the polyoxyethylene glycol of theobroma oil, glycerin cement, hydrogenated vegetable oil, various molecular weights and polyoxyethylene glycol.
When will compound administration according to the present invention during to human subjects, every day, dosage be determined by the doctor that writes a prescription usually, and dosage is different according to the severity of age, body weight, sex and the reaction of individual patient and patient's symptom usually simultaneously.
In an example use, with the compound administration of sufficient quantity to the Mammals that carries out cancer therapy.Usually with every day about 0.1mg/kg body weight～about 60mg/kg body weight amount carry out administration, preferably every day 0.5mg/kg body weight～about 40mg/kg body weight.
The compounds of this invention can also be used in combination with known therapeutical agent and carcinostatic agent.Thus, the invention provides and be used for simultaneously, separate or formula (I) compound of order administration and the composition of known therapeutical agent and/or carcinostatic agent.For example, The compounds of this invention can be used for being used in combination with known carcinostatic agent.The combination of compound disclosed by the invention and other carcinostatic agent or chemotherapeutic is equally within the scope of the invention.The example of described reagent can be found in CancerPrinciples and V.T.Devita and S.Hellman (chief editor), the 6th edition (February 15,2001), Lippincott Williams ﹠amp; Among the Practice ofOncology of Wilkins Publishers.Those of ordinary skills can distinguish that the associating of which reagent is useful based on the characteristic and the related cancer of medicine.Described carcinostatic agent includes but not limited to following reagent: other hdac inhibitor, estrogenic agents, androgen receptor modifier, retinoid receptor modulators, cytotoxin/cytostatic agent, antiproliferative, prenyl-protein transferase inhibitor, HMG-CoA reductase inhibitor and other angiogenesis inhibitor, cell proliferation and the agent of existence signal suppressing, apoptosis bring out reagent and hinder the reagent of cell cycle chechpoint.When with the radiotherapy co-administered, The compounds of this invention is effective especially.
In one embodiment, The compounds of this invention can also be used for being used in combination with known carcinostatic agent, and described carcinostatic agent comprises following reagent: other hdac inhibitor, estrogenic agents, androgen receptor modifier, retinoid receptor modulators, cytotoxic agent, antiproliferative, prenyl-protein transferase inhibitor, HMG-CoA reductase inhibitor hiv protease inhibitor, reverse transcriptase inhibitors and other angiogenesis inhibitor.
The example of " other hdac inhibitor " comprises Vorinostat (SAHA), LAQ824, LBH589, PXD101, MS275, FK228, valproic acid, butyric acid and CI-994.
" estrogen receptor modulator " is meant interference or suppresses the compound that oestrogenic hormon is bonded to acceptor, and be irrelevant with mechanism.The example of estrogen receptor modulator is including but not limited to tamoxifen, raloxifene, indoles former times phenol, LY353381, LY117081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(piperidino) oxyethyl group] phenyl]-2H-1-chromene-3-yl]-phenyl-2,2-dimethyl propylene acid esters, 4,4 '-dihydroxy benaophenonel-2,4-dinitrophenyl-hydrazone and SH646.
" androgen receptor modifier " is meant interference or suppresses the compound that male sex hormone is bonded to acceptor, and be irrelevant with mechanism.The example of androgen receptor modifier comprise finasteride and other 5 inhibitor, Nilutamide, Drogenil, must catarrh amine, liarozole and Abiraterone acetate.
" retinoid receptor modulators " is meant interference or suppresses the compound that retinoid is bonded to acceptor, and be irrelevant with mechanism.The example of these retinoid receptor modulators comprise bexarotene, tretinoin, 13-suitable-vitamin A acid, 9-be suitable-vitamin A acid, a-Er Fujiajiniaoansuan, ILX23-7553, anti--N-(4 '-hydroxy phenyl) look yellow acid amides and the N-4-carboxyl phenyl is looked yellow acid amides.
" cytotoxic agent/cytostatics " is meant mainly and causes necrocytosis or suppress cell proliferation by direct interference cell function, perhaps suppress or the maiotic compound of interference cell, comprise alkylating reagent, tumour necrosis factor, intercalator, but hypoxemia activated compounds, microtubule inhibitor/microtubule stabilizer, the mitotic kinesins inhibitor, participate in the kinase inhibitor of mitotic division process, participate in the kinase inhibitor of somatomedin and cytokine signaling approach, antimetabolite, biological response modifier, hormone/hormone antagonist medicine, hemopoieticgrowth factor, monoclonal antibody targeted therapy medicine, topoisomerase enzyme inhibitor, proteoplast inhibitor and ubiquitin ligase enzyme inhibitor.
The example of cytotoxin reagent includes but not limited to sertenef; cachectin (cachectin); ifosfamide; tasonermin; lonidamine; carboplatin; altretamine; prednimustine; mitolactol; ranomustine; fotemustine; S 254; oxaliplatin; Temozolomide; heptan platinum; estramustine; Tosi acid improsulfan; trofosfamide; nimustine; dibrospidium chloride; pumitepa; Lip river platinum; husky platinum; porfiromycin (profiromycin); cis-platinum; Yiluo husband's literary composition; right ifosfamide; suitable-the amine dichloro (2-methyl-pyridine) closes platinum; the benzyl guanine; glufosfamide; GPX100; tetrachloroization is (trans; trans; trans)-two-m-(hexane-1; the 6-diamines)-m-[diamines-platinum (II)] two [diamines (chlorine) platinum (II)]; the smart ammonia of two aziridinyls; white arsenic; 1-(11-dodecyl amino-10-hydroxyl undecyl)-3, the 7-dimethyl xanthine; zorubicin; idarubicin; daunorubicin; bisantrene; mitoxantrone; pirarubicin; pinafide; valrubicin; amrubicin; antineoplaston; 3 '-deaminizating-3 '-morpholino-13-deoxidation generation-10-hydroxyl carminomycin; liposome anthracycline (annamycin); galarubicin; Elinafide; MEN10755 and 4-demethoxylation-3-deaminizating-3-aziridinyl-4-methyl sulphonyl-daunorubicin (referring to WO 00/50032).
But an example of hypoxemia activated compounds is a Win-59075.
The example of proteasome inhibitor includes but not limited to lactacystin, bortezomib, epoxomicin and peptide aldehyde, such as MG 132, MG 115 and PSI.
In one embodiment, The compounds of this invention can be united use with other hdac inhibitor, such as SAHA and proteasome inhibitor.
The example of microtubule inhibitor/microtubule stabilizer comprises taxol, vindesine sulfate, 3 ', 4 '-two dehydrogenations-4 '-deoxidation-8 '-navelbine, docetaxel, rhizomycin, dolastatin, according to western sour mivobulin, auristatin, Cemadotin, RPR109881, BMS184476, Vinflunine, depsipeptide class antitumour drug (cryptophycin), 2,3,4,5,6-five fluoro-N-(3-fluoro-4-p-methoxy-phenyl) benzsulfamide, F 81097, N, N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline(Pro)-t-butyl carboxamide, TDX258, Macrolide antitumour drug (epothilone) is (referring to for example United States Patent(USP) Nos. 6,284,781 and 6,288,237) and BMS188797.
Some examples of topoisomerase enzyme inhibitor are Hycamtin; hycaptamine; irinotecan; rubitecan; 6-ethoxy-c acyl group-3 '; 4 '-O-is outer-benzylidene-chartreusin; 9-methoxyl group-N; N-dimethyl-5-nitropyrazole also [3; 4; 5-kl] acridine-2-(6H) propionic acid amide; 1-amino-9-ethyl-5-fluoro-2; 3-dihydro-9-hydroxy-4-methyl-1H; 12H-benzo [de] furo [3 '; 4 ': b; 7]-indolizine also [1; 2b] quinoline-10; 13 (9H; 15H) diketone; lurtotecan; 7-[2-(N-isopropylamino) ethyl]-(20S) camptothecine; BNP1350; BNPI1100; BN80915; BN80942; the phosphoric acid Etoposide; teniposide; sobuzoxane; 2 '-dimethylamino-2 '-deoxidation-Etoposide; GL331; N-[2-(dimethylamino) ethyl]-9-hydroxyl-5; 6-dimethyl-6H-pyrido [4; 3-b] carbazole-1-methane amide; asulacrine; (5a; 5aB; 8aa; 9b)-9-[2-[N-[2-(dimethylamino) ethyl]-the N-methylamino-] ethyl]-5-[4-hydroxyl-3; the 5-Dimethoxyphenyl]-5; 5a; 6; 8; 8a; the 9-hexahydro furyl also (3 '; 4 ': 6; 7) naphtho-(2; 3-d)-1; 3-dioxole-6-ketone; 2; 3-(methylene-dioxy)-5-methyl-7-hydroxyl-8-methoxyl group benzo [c]-phenanthridines; 6; two [(2-aminoethyl) amino] benzo [g] isoquinoline 99.9-5 of 9-; the 10-diketone; 5-(amino third amino of 3-)-7; 10-dihydroxyl-2-(2-hydroxyethyl aminomethyl)-6H-pyrazolo [4; 5; 1-de] acridine-6-ketone; N-[1-[2 (diethylin) ethylamino]-7-methoxyl group-9-oxo-9H-thioxanthene-4-ylmethyl] methane amide; N-(2-(dimethylamino) ethyl) acridine-4-methane amide; 6-[[2-(dimethylamino) ethyl] amino]-3-hydroxyl-7H-indeno [2,1-c] quinoline-7-ketone and dimesna.
The mitotic kinesins inhibitor, the case description of particularly human mitotic kinesins KSP inhibitor is open in PCT
WO 01/30768, and WO 01/98278, and WO 02/056880, and WO 03/050,064, WO03/050,122, WO 03/049,527, WO 03/049,679, and WO 03/049,678, WO 03/039460, and WO 03/079973, WO03/099211, WO 2004/039774, and WO 03/105855, and WO 03/106417, WO 2004/087050, and WO 2004/058700, among WO 2004/058148 and WO 2004/037171 and US application US 2004/132830 and the US 2004/132719.In one embodiment, the mitotic kinesins inhibitor comprises but is not limited to KSP inhibitor, MKLP1 inhibitor, CENP-E inhibitor, MCAK inhibitor, Kifl4 inhibitor, Mphosphl inhibitor and Rab6-KIFL inhibitor.
" participate in the kinase inhibitor of mitotic division process " and include but not limited to aurora kinase inhibitor, Polo sample kinase inhibitor (PLK) (particularly PLK-1 inhibitor), bub-1 inhibitor and bub-R1 inhibitor.
" antiproliferative agents " comprises antisense rna oligonucleotide and antisense DNA oligonucleotide; such as G3139; ODN698; RVASKRAS; GEM231 and INX3001; also comprise antimetabolite; such as enocitabine; carmofur; Tegafur; pentostatin; doxifluridine; trimetrexate; fludarabine; capecitabine; Galocitabine; cytosine arabinoside octadecyl sodium phosphate; the fosteabine sodium hydrate; Raltitrexed; paltitrexid; emitefur; thiazole furan quinoline; Decitabine; Nolatrexed; pemetrexed; nelzarabine; 2 '-deoxidation-2 '-the methylene radical cytidine; 2 '-fluorine methylene radical-2 '-Deoxyribose cytidine; N-[5-(2; 3-dihydro-benzofuryl) alkylsulfonyl]-N '-(3, the 4-dichlorophenyl) urea; N6-[4-deoxidation-4-[N
2-[2 (E); 4 (E)-tetradecane diene acyls] glycyl amino]-L-glyceryl-B-L-mannose group-pyrans heptose base] VITAMIN B4; aplidine; ecteinascidin (ecteinascidin); troxacitabine; 4-[2-amino-4-oxo-4; 6; 7; 8-tetrahydrochysene-3H-Mi Dingbing [5; 4-b] [1; 4] thiazine-6-base-(S)-ethyl]-2; 5-Thenoyl-L-L-glutamic acid; aminopterin; 5 FU 5 fluorouracil; alanosine; acetate 11-ethanoyl-8-(carbamyl oxygen ylmethyl)-4-formyl radical-6-methoxyl group-14-oxa--1; 11-diaza Fourth Ring (the 7.4.1.0.0)-tetradecane-2; 4,6-triolefin-9-base ester; Tridolgosir; lometrexol; dexrazoxane; methioninase (methioninase); 2 '-cyano group-2 '-'-deoxy-n 4-palmityl-1-B-D-arabinofuranosyl adenin glycosyl cytosine(Cyt) and 3-aminopyridine-2-formaldehyde thiosemicarbazone.
The example of monoclonal antibody target therapeutic agent comprises that those have cytotoxic agent or the radioisotopic medicine that connects cancer cells monoclonal antibody specific or target cell monoclonal antibody specific.The example comprises tositumomab (Bexxar).
" HMG-CoA reductase inhibitor " is meant 3-hydroxy-3-methyl glutaryl-CoA-reductase." HMG-CoA reductase inhibitor " is meant 3-hydroxy-3-methylglutaric acid list acyl coenzyme A reductase inhibitor.The example of operable HMG-CoA reductase inhibitor includes but not limited to lovastatin (MEVACOR
Referring to U.S. Patent number 4,231,938,4,294,926 and 4,319,039), Simvastatin (ZOCOR
Referring to U.S. Patent number 4,444,784,4,820,850 and 4,916,239), Pravastatin (PRAVACHOL
Referring to U.S. Patent number 4,346,227,4,537,859,4,410,629,5,030,447 and 5,180,589), fluvastatin (LESCOL
Referring to U.S. Patent number 5,354,772,4,911,165,4,929,437,5,189,164,5,118,853,5,290,946 and 5,356,896), atorvastatin (LIPITOR
Referring to U.S. Patent number 5,273,995,4,681,893,5,489,691 and 5,342,952) and Cerivastatin (also claim rivastatin and BAYCHOL
Referring to U.S. Patent number 5,177,080).The structural formula of these compounds and the HMG-CoA reductase inhibitor that can be used for the inventive method in addition are described in M.Yalpani, " Cholesterol Lowering Drugs ", Chemistry ﹠amp; Industry is in pp.85～89 (on February 5th, 1996) and United States Patent (USP) Nos.4, in 782,084 and 4,885,314.Term " HMG-CoA reductase inhibitor " comprises all pharmaceutically acceptable lactones and open acid form (promptly as used herein, wherein thereby lactonic ring is opened and is formed free acid), and salt and ester-formin with compound of HMG-CoA reductase active, and therefore the purposes of above-mentioned salt, ester, open acid and lactone form all is included in the scope of the present invention.
" prenyl protein transferase inhibitor " is meant the compound that suppresses any one prenyl protein transferase or any prenyl protein transferase composition, described prenyl-protein transferase comprises farnesyl-protein transferase (FPTase), geranyl geranyl-protein transferase type i (GGPTase-I) and geranyl geranyl-protein transferase type-II (GGPTase-II also is called Rab GGPTase).
The example of prenyl-protein transferase inhibitor is disclosed in following discloses text and the patent:
WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S.Pat.No.5,420,245, U.S.Pat.No.5,523,430, U.S.Pat.No.5,532,359, U.S.Pat.No.5,510,510, U.S.Pat.No.5,589,485, U.S.Pat.No.5,602,098, European patent discloses 0 618 221, European patent discloses 0 675 112, European patent discloses 0 604 181, European patent discloses 0 696 593, WO 94/19357, and WO 95/08542, and WO 95/11917, WO 95/12612, and WO 95/12572, and WO 95/10514, U.S. Patent No. 5,661,152, WO 95/10515, WO 95/10516, and WO 95/24612, and WO 95/34535, WO 95/25086, WO 96/05529, and WO 96/06138, and WO 96/06193, WO 96/16443, WO 96/21701, and WO 96/21456, and WO 96/22278, WO96/24611, WO 96/24612, and WO 96/05168, and WO 96/05169, WO 96/00736, U.S. Patent No. 5,571,792, WO 96/17861, WO 96/33159, and WO 96/34850, and WO 96/34851, WO 96/30017, WO 96/30018, WO96/30362, and WO 96/30363, WO 96/31111, WO 96/31477, and WO 96/31478, and WO 96/31501, WO 97/00252, WO 97/03047, and WO 97/03050, and WO 97/04785, WO 97/02920, WO 97/17070, and WO 97/23478, WO97/26246, WO 97/30053, WO 97/44350, WO 98/02436 and U.S. Patent No. 5,532,359.Prenyl-protein transferase inhibitor to the example of angiopoietic effect referring to European J.of Cancer, Vol.35, No.9, pp.1394-1401 (1999).
" angiogenesis inhibitor " is meant the compound that suppresses neovascularization, and be irrelevant with mechanism.The example of angiogenesis inhibitor includes but not limited to that tyrosine kinase inhibitor is (such as tyrosine kinase receptor FIt-1 (VEGFR1) and FIk-1/KDR (VEGFR
2) inhibitor, epidermis source growth factor receptor inhibitors, inoblast source growth factor receptor inhibitors or platelet derived growth factor inhibitor, MMP (matrix metal proteolytic enzyme) inhibitor, integrin blocker, interferon alpha, IL-12, the many vitriol of piperylene, cyclooxygenase inhibitors (comprise such as the nonsteroidal anti-inflammatory (NSADDs) of Asprin and Ibuprofen BP/EP and the epoxy enzyme-2 inhibitor of examining former times and rofecoxib such as Seeley) (PNAS, the 89th volume, the 7384th page (1992); JNCI, the 69th volume, the 475th page (nineteen eighty-two); Arch.Opthalmol., the 108th volume, the 573rd page (nineteen ninety); Anat.R
eC., the 238th volume, the 68th page (1994); FEBS Letters, the 372nd volume, the 83rd page (nineteen ninety-five); Clin, Orthop. the 313rd volume, the 76th page (nineteen ninety-five); J.Mol.Endocrinol., the 16th volume, the 107th page (1996); Jpn.J.Pharmacol., the 75th volume, the 105th page (1997); Cancer R
eS., the 57th volume, the 1625th page (1997); Cell, the 93rd volume, the 705th page (1998); Intl.J.Mol.Med., the 2nd volume, the 715th page (1998 pages); J.Biol..Chem., the 274th, the 9116th page (1999)), the steroid antiphlogiston is (such as corticosteroid hormone, mineralocorticoid, dexamethasone, prednisone, prednisolone, radiosone, Betamethasone Valerate), the carboxyamino imidazoles, combretastatin A-4, the spiny dogfish polyamines, 6-O-chloracetyl-carbonyl-aspergillus fumigatus cedrol, thalidomide, angiostatin (angiostatin), troponin-1, the Angiotensin II antagonist is (referring to people such as Fernandez, J.Lab.Clin.Med.105:141-145 (1985)) and VEGF antibody (referring to Nature Biotechnology, the 17th volume, 963-968 page or leaf (in October, 1999); Kim etc., Nature, 362,841-844 (1993); WO 00/44777 and WO 00/61186).
Other adjusting or suppress vascularization and can comprise the reagent (referring to review in Clin.Chem.La.Med.38:679-692 (2000)) of adjusting or anticoagulant and fibrinolytic system with the therapeutical agent that The compounds of this invention is used in combination.The example of the reagent of above-mentioned adjusting or anticoagulant and fibrinolysis approach includes but not limited to that Vitrum AB (referring to Thromb.Haemost.80:10-23 (1998)), lower molecular weight Vitrum AB and carboxypeptidase U inhibitor (be also referred to as activity and can activate zymoplasm fibrinolysis inhibitor [TAFIa]) are (referring to Thrombosis R
eS.101:329-354 (2001)).The TAFIa inhibitor is described in open text WO 03/013,526 of PCT and U.S No.60/349, in 925 (being filed on January 18th, 2002).
" reagent of interference cell periodic inspection point " is meant the protein kinase that suppresses sensing cell cycle check position signal, thereby makes the compound of cancer cells to dna damage agent sensitivity.Described primordium comprises ATR, ATM, Chk1 and Chk2 kinase inhibitor and cdk and cdc kinase inhibitor, and its concrete illustration is 7-hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.
" cell proliferation and survival signal pathway inhibitor " is meant the pharmaceutical agent in the signal transduction cascade downstream that suppresses cell surface receptor and those surface receptors.Described reagent comprises EGFR inhibitor (for example Gefitinib and erlotinib), ERB-2 inhibitor (for example Herceptin), IGFR inhibitor (for example be disclosed among the WO 03/059951 those), the cytokine receptor inhibitor, the MET inhibitor, PI3K inhibitor (for example LY294002), the serine/threonine kinase inhibitor (includes but not limited to the Akt inhibitor, such as being disclosed in WO 03/086404, WO 03/086403, WO 03/086394, WO 03/086279, WO 02/083675, WO02/083139, AM inhibitor among WO 02/083140 and the WO 02/083138), Raf kinase inhibitor (for example BAY-43-9006), mek inhibitor (for example CI-1040 and PD-098059) and mTOR inhibitor (for example Wyeth CCI-779 and AriadAP23573).Described reagent comprises micromolecular inhibitor compound and antibody antagonist.
" apoptosis inducer " comprises the TNF receptor family member activator of (comprising the TRAIL acceptor).
The present invention also comprises the coupling with selective COX-2-2 inhibitor NSAID ' s.Based on this specification sheets, COX-2 selective depressant NSAID ' s is defined as with respect to COX-1, and the specificity that suppresses COX-2 is at least those inhibitor of 100 times, according to the IC of the COX-2 that measures by cell or microsome
50IC with COX-1
50Ratio weigh.
This compounds includes but not limited to the disclosed compound of following document:
U.S.Pat.5,474,995, U.S.Pat.5,861,419, U.S.Pat.6,001,843, U.S.Pat.6,020,343, U.S.Pat.5,409,944, U.S.Pat.5,436,265, U.S.Pat.5,536,752, U.S.Pat.5,550,142, U.S.Pat.5,604,260, U.S.5,698,584, U.S.Pat.5,710,140, WO 94/15932, U.S.Pat.5,344,991, U.S.Pat.5,134,142, U.S.Pat.5,380,738, U.S.Pat.5,393,790, U.S.Pat.5,466,823, U.S.Pat.5,633,272, and U.S.Pat.5,932,598, they all are hereby incorporated by.
Cox 2 inhibitor is 5-chloro-3-(4-methylsulfonyl) phenyl-2-(2-methyl-5-pyridyl) pyridine especially effectively in the methods of the invention; Perhaps its pharmacy acceptable salt.
Open as the special inhibitor of COX-2 and compound that can be used for thus among the present invention includes but not limited to: Parecoxib, CELEBREX
And BEXTRA
Perhaps its pharmacy acceptable salt.
Other example of angiogenesis inhibitor includes but not limited to: endostatin; ukrain; ranpirnase; IM862; (chloracetyl) carboxylamine 5-methoxyl group-4-[2-methyl-3-(3-methyl-2-butene base) Oxyranyle]-1-oxaspiro [2; 5] suffering-6-base ester; acetyldinanaline; 5-amino-1-[[3; 5-two chloro-4-(4-chlorobenzene formacyl) phenyl] methyl]-1H-1; 2; 3-triazole-4-methane amide; CM 101; squalamine; combretastatin; RPI4610; NX31838; sulfation phosphoric acid sweet dew pentose; 7; 7-(carbonyl-two [imino--N-methyl-4; 2-pyrrolo-carbonyl imino-[N-methyl-4; 2-pyrroles]-the carbonyl imino-]-two-(1; the 3-napadisilate) and 3-[(2, methylene radical 4-dimethyl pyrrole-5-yl)]-2-dihydroindolone (SU5416).
More than applied " integrin inhibitor " be meant selectivity antagonism, inhibition or antagonism physiology part and α ν β
3Integrin bonded compound; Selectivity antagonism, inhibition or antagonism physiology part and α ν β
5Integrin bonded compound; Antagonism, inhibition or antagonism physiology part and α ν β
3Integrin and α ν β
5Both bonded compounds of integrin; And the compound of the special integrin activity of antagonism, inhibition or the expression of antagonism capillary endothelial cell.This term also refers to α ν β
6, α ν β
8, α
1β
1, α
2β
1, α
5β
1, α
6β
1And α
6β
4The antagonist of integrin.This term also refers to α ν β
3, α ν β
5, α ν β
6, α ν β
8, α
1β
1, α
2β
1, α
5β
1, α
6β
1And α
6β
4The antagonist of any combination in the integrin.
Some specific exampless of tyrosine kinase inhibitor comprise: N-(trifluoromethyl)-5-methyl-isoxazole-4-methane amide, 3-[(2,4-dimethyl pyrrole-5-yl) methyl indenyl] Indolin-2-one, 17-(allyl amino)-17-goes the methoxy geldanamycin, 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-[3-(4-morpholinyl) propoxy-] quinazoline, N-(3-ethynyl phenyl)-6, two (2-the methoxy ethoxy)-4-quinazoline amine of 7-, BIBX1382,2,3,9,10,11,12-six hydrogen-10-(methylol)-10-hydroxyl-9-methyl-9,12-epoxy-1H-two indoles also [1,2,3-fg:3 ', 2 ', 1 '-kl] pyrrolo-[3,4-i] [1,6] benzodiazocine-1-ketone, SH
268, Sophoricol, STI571, CEP2563,4-(3-chloro-phenyl-amino)-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidyl methanesulfonates, 4-(3-bromo-4-hydroxyphenyl) amino-6,7-dimethoxyquinazoline, 4-(4 '-hydroxyphenyl) are amino-6,7-dimethoxyquinazoline, SU6668, STI571A, N-4-chloro-phenyl--4-(4-pyridylmethyl)-1-diaza naphthylamines and EMD121974.
Also be included in the inventive method with the coupling that is not other compound of anticancer compound.For example, the claimed compound of the application and the combination of PPAR-g agonist and PPAR-d agonist can be used for treating some malignant tumour.PPAR-g and PPAR-d are nuclear peroxisome proliferation-activated receptors g and nuclear peroxisome proliferation-activated receptors d.PPAR-γ has obtained report (referring to J.Cardiovasc.Pharmacol.1998 in the literature in expression on the endotheliocyte and the intervention in vascularization thereof; 31:909-913; J.Biol.Chem.1999; 274:9116-9121; Invest.Ophthalmol Vis.ScL 2000; 41:2309-2317).Recently, shown that the PPAR-gamma agonist is in the vascularization response of vitro inhibition to VEGF; Troglitazone and rosiglitazone maleate all suppress the development of retina neovascularization in the mouse.(Arch.Ophthamol.2001；119：709-717)。The example of PPAR-g agonist and PPAR-g/a agonist includes but not limited to thiazolidinedione (DRF for example
2725, CS-011, troglitazone, Rosiglitazone and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926,2-[(5,7-dipropyl-3-Trifluoromethyl-1,2-phenyl-isoxazole azoles-6-yl) oxygen base]-2 Methylpropionic acid (is disclosed in USSN09/782, in 856) and 2 (R)-7-(3-(2-chloro-4-(4-fluorophenoxy) phenoxy group) propoxy-)-2-ethyl chroman-2-formic acid (be disclosed in USSN 60/235, in 708 and 60/244,697).
Another embodiment of the present invention be compound disclosed by the invention and antiviral agent (such as, comprise the nucleoside analog of 9-(1,3-dihydroxy-2-third oxygen methyl) guanine) purposes of combination therapy cancer.Referring to WO 98/04290.
Another embodiment of the present invention is the purposes that compound disclosed by the invention and associating gene therapy are treated cancer.Described about the heredity strategy summary of treatment cancer referring to people such as people such as Hall (Am JHum Genet 61:785-789,1997) and Kufe (pp 876-889, BC Decker, Hamilton 2000 for Cancer Medicine, 5thEd).Gene therapy can be used to shift the tumour of any elimination gene.The example of described gene includes but not limited to p53, it can be through the transgenosis of recombinant virus mediation (for example, referring to U.S. Patent No. 6,069,134), uPA/uPAR antagonist (" Adenovirus-Mediated Delivery of auPA/uPAR Antagonist Suppresses Angiogenesis-Dependent TumorGrowth and Dissemination in Mice ", Gene Therapy, August 1998; 5 (8): 1105-13) and interferon-gamma (JImmunol 2000; 164:217-222) send.
The compounds of this invention can also be united the administration together of intrinsic many disease resistances (MDR) inhibitor, particularly relevant with translocator high level expression MDR.Described MDR inhibitor comprises p-glycoprotein (P-gp) inhibitor, such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833 (valspodar).
The compounds of this invention can be united use with the emesis agent, thereby treatment is used separately or use feeling sick or vomiting that The compounds of this invention can cause with radiotherapy, comprises acute, retardance, newcoming stage and feels sick earlier and tell.In order to prevent or treat vomiting, The compounds of this invention can be united use with other antiemetic, particularly unites use with following antiemetic: antagonists of neurokinine-1 receptor; 5HT3 receptor antagonist, for example ondansetron, granisetron, tropisetron and zatisetron; GABAB receptor stimulant, for example baclofen; Corticosteroid, for example dexamethasone, Kenalog, triamcinolone (Aristocort), nose pine (Nasalide), budesonide (Preferid), Benecorten or other are disclosed in U.S. Patent number 2,789,118,2,990,401,3,048,581,3,126,375,3,929,768,3,996,359,3,928,326 and 3,749, corticosteroid in 712, for example dopamine antagonist medicines such as thiodiphenylamine (as prochlorperazine, Fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol.In one embodiment, the emesis agent that is selected from antagonists of neurokinine-1 receptor, 5HT3 receptor antagonist and corticosteroid hormone is carried out administration as additive, the vomiting that is used for the treatment of or prevents to produce by the administration The compounds of this invention.
Be used for fully being described in following document with the antagonists of neurokinine-1 receptor of The compounds of this invention combined utilization, for example,
U.S.Pat.Nos.5,162,339,5,232,929,5,242,930,5,373,003,5,387,595,5,459,270,5,494,926,5,496,833,5,637,699,5,719,147; The open Nos.EP0 360 390,0 394 989,0 428 434,0 429 366 of European patent, 0 430 771,0 436 334,0 443 132,0 482 539,0 498 069,0,499 313,0 512 901,0 512 902,0 514 273,0 514 274,0 514 275,0 514 276,0 515 681,0 517 589,0 520555,0 522 808,0 528 495,0 532 456,0 533 280,0 536 817,0 545 478,0 558 156,0 577 394,0 585913,0 590 152,0 599 538,0 610 793,0 634 402,0 686 629,0 693 489,0 694 535,0 699 655,0 699 674,0 707 006,0 708 101,0 709 375,0 709 376,0 714 891,0 723 959,0 733 632 and 0 776 893; PCT
The open Nos.WO 90/05525,90/05729,91/09844,91/18899 of international monopoly, 92/01688,92/06079,92/12151,92/15585,92/17449,92/20661,92/20676,92/21677,92/22569,93/00330,93/00331,93/01159,93/01165,93/01169,93/01170,93/06099,93/09116,93/10073,93/14084,93/14113,93/18023,93/19064,93/21155,93/21181,93/23380,93/24465,94/00440,94/01402,94/02461,94/02595,94/03429,94/03445,94/04494,94/04496,94/05625,94/07843,94/08997,94/10165,94/10167,94/10168,94/10170,94/11368,94/13639,94/13663,94/14767,94/15903,94/19320,94/19323,94/20500,94/26735,94/26740,94/29309,95/02595,95/04040,95/04042,95/06645,95/07886,95/07908,95/08549,95/11880,95/14017,95/15311,95/16679,95/17382,95/18124,95/18129,95/19344,95/20575,95/21819,95/22525,95/23798,95/26338,95/28418,95/30674,95/30687,95/33744,96/05181,96/05193,96/05203,96/06094,96/07649,96/10562,96/16939,96/18643,96/20197,96/21661,96/29304,96/29317,96/29326,96/29328,96/31214,96/32385,96/37489,97/01553,97/01554,97/03066,97/08144,97/14671,97/17362,97/18206,97/19084,97/19942 and 97/21702;
With the open Nos.2 266 529,2 268 931,2 269 170,2 269 590,2 271774,2 292 144,2 293 168,2 293 169 of English Patent, and 2 302 689.The preparation of described compound fully is disclosed in above-mentioned patent and the open text, and they all are hereby incorporated by.
In one embodiment, be used for being selected from: 2-(R)-(1-(R)-(3 with the antagonists of neurokinine-1 receptor of The compounds of this invention combined utilization, 5-two (trifluoromethyl) phenyl) oxyethyl group)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H, 4H-1,2, the 4-triazole) methyl) morpholine or its pharmacy acceptable salt, this substance description is in U.S. Patent No. 5, in 719,147.
The compounds of this invention can also with together administration of the reagent that is used for the treatment of anaemia.Described treatment for anemia agent is that for example, red blood corpuscle generates receptor activators (for example Epoetin Alfa) continuously.
The compounds of this invention can also be used for the treatment of the together administration of reagent that neutrophilic leukocyte reduces.Described neutrophilic leukocyte reduces therapeutical agent, for example, regulates that neutrophil (such as, Filgrastim (G-CSF)) forms and the hemopoieticgrowth factor of function.The example of G-CSF comprises filgrastim.
The compounds of this invention also can be with for example immunostimulant administration of LEVAMISOLE HCL, isoprinosine and Zadaxin (Zadaxin).
The compounds of this invention can also be united with bisphosphonate (be interpreted as and comprise bisphosphonate, diphosphonate, di 2 ethylhexyl phosphonic acid and two phosphonic acids) and is used for the treatment of or preventing cancer (comprising osteocarcinoma).The example of bisphosphonate includes but not limited to: etidronic acid ester (Didronel), Pamidronic Acid ester (Aredia), clinic effect of alendronate ester (Fosamax), risedronic acid ester (Actonel), Zoledronate ester (Zometa), this phosphonic acid ester of dust (Boniva), because of card see acid esters or ineadronic acid ester, clodronate ester, EB-1053, minodronic acid ester, neridronic acid ester, piridronate and tiludronic acid comprise its any and all pharmacy acceptable salts, derivative, hydrate and composition thereof.
Thus, scope of the present invention comprises the compound and the purposes that is selected from second kind of following compound of claim of the present invention: estrogenic agents, androgen receptor modifier, the retinoid receptor modulators, cytotoxin/cytostatic agent, antiproliferative, prenyl-protein transferase inhibitor, the HMG-CoA reductase inhibitor, the hiv protease inhibitor, reverse transcriptase inhibitors, angiogenesis inhibitor, the PPAR-gamma agonist, the PPAR-delta agonists, antiviral agent, intrinsic many disease resistances inhibitor, the emesis agent, the reagent that is used for the treatment of anaemia, be used for the treatment of the reagent that neutrophilic leukocyte reduces, medicament for immunity enhancement, cell proliferation and the agent of survival signal suppressing, the reagent of interference cell periodic inspection point, apoptosis inducer and bisphosphonate.
Term relevant with The compounds of this invention " administration " and distortion (for example, " medication " compound) thereof, the meaning are that compound or compound prodrug are incorporated in the animal system that needs treatment.When The compounds of this invention or its prodrug and one or more other promoting agents (for example cytotoxic agent or the like) combination provide, should " administration " and distortion be interpreted as and comprise described compound or its prodrug and other reagent simultaneously and the order introducing.
The term of Shi Yonging " composition " intention comprises the product of the appointment composition that contains specified amount in this article, and anyly is designated as the branch combination directly or the product that obtains indirectly by specified amount.
Term " treatment significant quantity " is meant the amount that can cause the active substance or the pharmaceutical preparation of biological respinse or drug reaction in tissue, system, animal or the mankind as used herein, and this amount is explored by researchist, animal doctor, medical doctor or other clinicians.
Term " treatment cancer " or " treatment for cancer " thus be meant that administration suffers the Mammals that cancer symptoms torments and refers to alleviate the effect of cancer symptoms by kill cancer cell, and be meant the effect that growth of cancers and/or transfer are suppressed.
In one embodiment, the angiogenesis inhibitor that uses as second kind of compound is selected from tyrosine kinase inhibitor; epidermis derivative growth factor inhibitor; inoblast derivative growth factor inhibitor; the Thr6 PDGF BB inhibitor; MMP (matrix metalloproteinase) inhibitor; the integrin retarding agent; Interferon, rabbit-a; il-1 2; poly-sulfuric acid piperylene; cyclooxygenase inhibitors; the Carboxylamide triazole; combretastatin A-4; squalamine; 6-O-chloracetyl-carbonyl)-aspergillus fumigatus cedrol; Thalidomide; angiostatin; troponin-1 or VEGF antibody.In one embodiment, estrogenic agents is tamoxifen or raloxifene.
The scope of claim also comprises the treatment method for cancer, this method comprises the formula A compound of associating radiotherapy and/or second compound administration treatment significant quantity, and described second compound is selected from: other hdac inhibitor, estrogenic agents, androgen receptor modifier, the retinoid receptor modulators, cytotoxic agent/cytostatics, antiproliferative agents, the isopentene group protein transferase inhibitor, the HMG-CoA reductase inhibitor, the hiv protease inhibitor, reverse transcriptase inhibitors, angiogenesis inhibitor, the PPAR-g agonist, the PPAR-d agonist, antiviral agent, intrinsic multidrug resistance inhibitor, antiemetic, the medicine that is used for the treatment of anaemia, the medicine that is used for the treatment of neutrophilic granulocytopenia, immunostimulant, cell proliferation and the agent of survival signal suppressing, the medicine at the interference cell cycle outpost of the tax office, apoptosis inducer and diphosphonate.
Another embodiment of the present invention is the treatment method for cancer, comprises the formula I compound of the treatment significant quantity of administration and taxol or Herceptin coupling.
The present invention also comprises the method for treatment or preventing cancer, comprises the formula I compound of collaborative cox 2 inhibitor drug treatment significant quantity.
The present invention comprises also and being used for the treatment of or the pharmaceutical composition of preventing cancer that it comprises the formula I compound for the treatment of significant quantity and is selected from following compound: other hdac inhibitor, estrogenic agents, androgen receptor modifier, the retinoid receptor modulators, cytotoxin/cytostatic agent, antiproliferative, prenyl-protein transferase inhibitor, the HMG-CoA reductase inhibitor, the hiv protease inhibitor, reverse transcriptase inhibitors, angiogenesis inhibitor, the PPAR-gamma agonist, the PPAR-delta agonists, antiviral agent, cell proliferation and the agent of survival signal suppressing, the reagent of interference cell periodic inspection point, apoptosis inducer and bisphosphonate.
According to the instruction that is included in herein, these and other aspect of the present invention will be conspicuous.
All patent, publication and pending application applications of making mark all are hereby incorporated by.The shortenings that uses in following chemical process explanation and embodiment is as follows:
AcOH (acetate); BuLi (n-Butyl Lithium); BSA (bovine serum albumin); DBU (1,8-diazabicylo [5.4.0] 11-7-alkene); DCE (1, the 2-ethylene dichloride); DIPEA (diisopropylethylamine); DCM (methylene dichloride); DME (glycol dimethyl ether); DMEM (the improved Eagle substratum of Dulbecco); DMF (dimethyl formamide); DMSO (methyl-sulphoxide); DPPA (azide diphenyl phosphate); DTT (dithiothreitol (DTT)); EDC and EDCI (N-(3-dimethylaminopropyl)-N '-ethyl carbodiimide); EDCHCl (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride); EDTA (ethylenediamine tetraacetic acid (EDTA)); EGTA (egta); Em (emission); Eq. (equivalent); ES (electrospray); EtOAc (ethyl acetate); EtOH (ethanol); Ex (exciting); FACS (cell sorting of fluorescent activation); FITC (fluorescein isothiocyanate); Hepes ((N-(2-hydroxyethyl) piperazine)-N '-(2-ethanesulfonic acid)); HOBt (I-hydroxybenzotriazole); HPLC (high performance liquid chromatography); IPTG (isopropyl-); LEP (lysyl end peptidase); Lys C (lysyl C endo-protease); MeCN (acetonitrile); MeOH (methyl alcohol); MS (mass spectrum); NMR (nucleus magnetic resonance); NP40 (farming is according to younger brother P40); PBS (phosphate buffered saline (PBS)); PMSF (phenyl methanesulfonamide acyl fluorides); IPrOH (Virahol); PTSA (right-toluenesulphonic acids); PyBop (1H-1,2,3-benzotriazole-1-base oxygen base) (tripyrrole alkane-1-yl) phosphorus hexafluorophosphate); RP (anti-phase); RT (room temperature); SCX (Varian or Isolute Zeo-karb); SiO
2(silica gel); TEA (triethylamine); THF (tetrahydrofuran (THF)); TFA (trifluoroacetic acid); Tris-HCl (Tris hydroxymethyl ethylamine); And TSA (Trichostatin A).
Other shortenings comprises: App (apparent); PS-BEMP (2-tertbutylimido-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine); Py (pyridine); Sat.aq (saturated aqueous solution); SEM-Cl ([2-(chlorine methoxyl group) ethyl] (trimethylammonium) silane); TBAF (tetrabutyl ammonium fluoride); TBTU (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea tetrafluoro-methane); TFAA (trifluoroacetic anhydride); And TsCl (Tosyl chloride).Other shortenings is BOM (benzyloxymethyl).
Formula I compound can be prepared by making the reaction of formula IV compound and formula V compound:
Wherein D, R
1, R
2, R
3, R
4, R
5, R
6, R
8, X, Het, p, q and t be as defining about formula I, and L
1Be leavings group, such as hydroxyl or chlorine.Work as L
1For such as the leavings group of chlorine the time, described reaction usually at alkali (such as Et
3N) and solvent (such as DMF or DCM) exist down, approximately carrying out under the room temperature.Work as L
1When being the leavings group such as hydroxyl, wherein can also add coupling agent (such as EDCHCl) and alkali (such as Et
3N).Wherein can also there be other additive, such as HOBt and DIPEA.
Blocking group on the Het ring (such as SEM) and the locational dioxane of formula IV compound carbonyl can during reaction exist.Subsequently, can utilize standard method that compound is gone protection, such as, under refluxing, be added in such as the TBAF in the solvent of THF, perhaps approximately be added in such as the DCM in the solvent of THF and TFA or HCl (aqueous solution) under the room temperature.
Wherein Het is that the formula IV compound of imidazoles can be prepared in the following manner, makes formula VI compound:
Wherein D, R
1, R
2, R
4With q as defined above, and P is the protecting group such as Boc, reacts under about 150 ℃ in solvent (such as dimethylbenzene) usually with cyclization reagent such as ammonium acetate.
Formula VI compound can be prepared by making the reaction of formula VII compound and formula VIII compound:
Wherein D, R
1, R
2, R
4, q and P as defined above, and L
2Be leavings group, such as halogen, particularly bromine in the presence of alkali (such as cesium carbonate), at room temperature carries out in such as the solvent of DMF usually.
R wherein
4For the formula IV compound of hydrogen can be prepared in addition in the following manner, make formula IX compound:
Wherein D, R
1, R
2, Het and q as defined above, with azide reagent (such as, phenylbenzene azide phosphorus) reaction, this reaction is carried out in the presence of alkali (such as DBU) and in such as the solvent of toluene usually.Then, can carry out hydrogenation, thereby produce wherein R the gained trinitride
4Formula IV compound for hydrogen.For example, above-mentioned reaction can under nitrogen atmosphere, be carried out in such as the solvent of EtOAc and in the presence of the catalyzer such as Pd/ carbon at first under hydrogen atmosphere then.Additionally, can make gained trinitride and organophosphorus (such as PPh
3) in such as the solvent of THF and water, approximately reacting under the room temperature.Blocking group on the Het ring (such as SEM) and the locational dioxane of formula IX compound carbonyl can during reaction exist.
Formula IX compound can be prepared by making the reaction of formula X compound and formula XI compound:
Wherein D, R
1, R
2, Het and q as defined above, and L
3Be halogen atom, such as bromine, this reaction is carried out in such as the solvent of THF usually.
Its Chinese style IV compound can be prepared in addition in the following manner, makes formula XII compound:
Wherein D, R
1, R
2, R
4, Het, q and P as defined above, with oxygenant (crossing iodine alkane such as Dess-Martin) reaction, this reaction is being carried out under about room temperature in such as the solvent of DCM usually.
Wherein Het be triazole ring formula XII compound can by make formula XIII compound and formula XIV compound the reaction be prepared:
Wherein D, R
1, R
2, R
4, q and P as defined above, and R ' is C
1-6Alkyl, such as methyl, this reaction is approximately being carried out under the room temperature in such as the solvent of toluene usually.
Formula XIII compound can be prepared as follows, makes formula XV compound:
R wherein
2, R
4, q and P as defined above, and R " is C
1-6Alkyl, such as methyl, with the hydrazine hydrate reaction, this reaction is carried out under about 80 ℃ in such as the alcoholic solvent of Virahol usually.
Formula XV compound can be by making formula VII compound and reductive agent (such as BH
3Me
2S) reaction is prepared, and this reaction is carried out under about 0 ℃ in such as the solvent of THF usually.
Wherein Het is 1,3, and the formula IV compound of 4-oxadiazole can be prepared in the following manner, makes formula XVI compound:
Wherein D, R
1, R
2, R
4, q and P as defined above, with cyclizing agent (such as PS-BEMP and TsCl) reaction, this reaction is carried out under about 65 ℃ in such as the solvent of THF usually.
Formula XVI compound can be prepared as follows, makes formula XVII compound:
Wherein D, R
1, R
2, R
4, q and P as defined above, with oxygenant (crossing iodine alkane such as Dess-Martin) reaction, this reaction is being carried out under about room temperature in such as the solvent of DCM usually.
Formula XVII compound can be prepared by making the reaction of formula XIII compound and formula XVIII compound:
R
1-D-CO
2H
(XVIII)
Wherein D and R
1As defined above, this reaction is approximately being carried out under the room temperature in such as the DCM solvent in the presence of the coupling agent (such as HOBt and EDCHCl) usually.
Wherein the formula IV compound of Het Wei oxazole can be prepared in the following manner, makes formula XIX compound:
Wherein D, R
1, R
2, R
4, q and P as defined above, with cyclization reagent (such as hexachloroethane (C
2Cl
6) and triphenylphosphine (PPh
3)) reaction, this reaction is usually such as Et
3The alkali of N exists down, is approximately carrying out under the room temperature in such as the solvent of DCM.
Formula XIX compound can be prepared by making the reaction of formula VII compound and formula XX compound:
Wherein D and R
1As defined above.This reaction in the presence of coupling agent (such as HOBt and EDCHCl), is being carried out such as the alkali of DIPEA with in such as the solvent of DMF usually.
Formula XX compound can obtain preparation by the corresponding acylazide of hydrogenation of formula XXI:
Wherein D and R
1As defined above.This reaction in acid (such as HCl), in the presence of such as the Pd/ C catalyst and in such as methanol solvate, is being carried out under about room temperature usually.
Formula XXI compound can be by making formula VIII compound and trinitride source (such as NaN
3) reaction is prepared, this reaction is usually being carried out under about room temperature in such as the solvent of acetone.
Formula IX compound can be prepared in addition in the following manner, makes formula XXII compound and organometallic reagent reaction (such as BuLi, to promote halogen-lithium exchange), uses the quencher of formula XXIII compound subsequently:
Wherein D, R
1, R
2, q and Het as defined above, and L
2Be leavings group, such as halogen, bromine particularly.This reaction is usually carried out under approximately-78 ℃ in such as the solvent of THF.Wherein can there be protecting group, such as SEM, as discussed previously.
Formula XXII compound can be prepared by making the reaction of formula XXIV compound and formula XXV compound:
Wherein D, R
1And L
2Independently as defined above.This reaction is usually in such as the solvent of toluene and such as Pd (PPh
3)
4Catalyzer exist down and under refluxing, carry out.
Formula XXIII compound can be prepared as follows, makes formula XXVI compound:
R wherein
2With q as defined above, and R
xAnd R
yBe C independently
1-6Alkyl is such as methyl, and such as LiAlH
4Reductive agent reaction, this reaction is common to be carried out under approximately-78 ℃ in such as the solvent of THF.
Formula IX compound can be prepared by making formula XXVII compound and the organometallic reagent reaction that obtains by the agent treated formula XXVIII compound deriving of using such as tert-BuLi in addition:
Wherein D, R
1, R
2, q, Het, R
x, R
yAnd L
2As defined above.This reaction is usually carried out under approximately-78 ℃ in such as the solvent of THF and pentane.Subsequently, such as NaBH
4Reductive agent exist down and in such as the alcoholic acid solvent, approximately under the room temperature ketone changed into required alcohol.
R wherein
4For the formula IV compound of hydrogen can be prepared by making the organometallic reagent and the reaction of formula XXIX compound that are derived from formula XXII compound in addition:
R wherein
2With q as defined above, and P
1Be chiral adjuvant, such as tertiary butyl sulfonium compound.This reaction is usually carried out under approximately-78 ℃ in such as the solvent of THF.Subsequently, can be under acidic conditions (such as HCl), in such as methanol solvent under about room temperature with P
1Group (such as tertiary butyl sulfonium compound) is removed.
Formula XXIX compound can be prepared by making the reaction of formula XXIII compound and formula XXX compound:
P
1-NH
2
(XXX)
P wherein
1As defined above, this reaction is usually such as copper sulfate (CuSO
4) catalyzer exist down, in such as the solvent of DCM, approximately carrying out under the room temperature.
Formula XVI compound can be prepared by making the reaction of formula VII compound and formula XXXI compound in addition:
Wherein D and R
1As defined above.This reaction in the presence of coupling agent (such as EDCHCl and HOBt), is at room temperature carried out in such as the DMF solvent usually.
Wherein the formula XII compound of Het Wei oxadiazole can be prepared by making the reaction of formula XVIII compound and formula XXXII compound in addition:
R wherein
2, R
4, P and q as defined above.This reaction is usually in the presence of coupling agent (such as TBTU and HOBt), such as the alkali of DIPEA with in such as the DMF solvent, under about room temperature and be heated to then under about 110 ℃ and carry out.
Formula XXXII compound can be prepared as follows, makes formula XXXIII compound:
R wherein
2, R
4, P and q as defined above, with hydroxylamino reagent (such as NH
2OH-HCl) reaction, this reaction are carried out under refluxing in the presence of the alkali (such as KOH) in such as methanol solvent usually.
Formula XXXIII compound can be prepared as follows, makes formula XXXIV compound:
R wherein
2, R
4, P and q as defined above, with dewatering agent (such as TFAA) reaction, this reaction is usually such as Et
3The alkali of N exists down and exists, and carries out under about 0 ℃ in such as the solvent of DCM.Subsequently, can with such as other reductive agent in the methanol solvent (such as NaBH
4) add wherein, thereby reduction R
2Locational carbonyl.
Formula XXXIV compound can be prepared by making formula VII compound and amino source (such as bicarbonate of ammonia) reaction, and this reacts usually at pyridine and Boc
2O exists down, is approximately carrying out under the room temperature in such as the solvent of dioxane.
Wherein Het is 1,2, and the formula IV compound of 4-oxadiazole-5-base can be prepared by making the reaction of formula VII compound and formula XXXV compound:
Wherein D and R
1As defined above, this reaction is usually in the presence of coupling agent (such as TBTU and HOBt), such as the alkali of DIPEA with in the solvent such as DMF, under about room temperature, carry out under about 110 ℃ temperature then.
In addition, R wherein
2For the formula I compound of methyl can be prepared in the following manner, make formula XXXVI compound:
Wherein D, R
1, R
3, R
4, R
5, R
6, R
8, X, p, q, t and Het as defined above, with oxygenant (such as oxygen and CuCl) reaction, this is reflected at such as PdCl
2Catalyzer exist down and in such as the solvent of DMF, carry out.
Formula XXXVI compound can be prepared by making the reaction of formula V compound and formula XXXVII compound:
Wherein D, R
1, R
4, Het and q as defined above, carry out under the formerly described usually coupling condition of this reaction.
R wherein
4For the formula XXXVII compound of hydrogen can be prepared in the following manner, make formula XXXVIII compound:
Wherein D, R
1, Het and q as defined above, and such as PPh
3Organophosphorus in such as the solvent of THF and water, approximately reacting under the room temperature.
Formula XXXVIII compound can be prepared as follows, makes formula XXXIX compound:
Wherein D, R
1, Het and q as defined above, with azide reagent (such as, phenylbenzene azide phosphorus) reaction, this reaction is being carried out under about 50 ℃ in the presence of the alkali (such as DBU) and in such as the solvent of toluene usually.
Formula XXXIX compound can be prepared by making the reaction of formula X compound and formula XL compound:
L wherein
3With q as defined above, this reaction usually in the solvent such as THF, is carried out down and in the argon gas atmosphere at about 0 ℃.
Formula I compound can be prepared by making the reaction of formula XXV compound and formula XLI compound in addition:
R wherein
2, R
3, R
4, R
5, R
6, R
8, X, Het, p, q, t and L
2As defined above.This reaction usually in solvent such as n-BuOH, at catalyzer (such as Pd (OAc)
2, K
3PO
4And dicyclohexyl-(2 ', 6 '-dimethoxy-biphenyl-2-yl) phospene) exists down, under about 90 ℃, carry out.
During reaction, the blocking group on the Het (such as SEM) can exist, and is removed under aforesaid standard conditions subsequently.
Formula XXXI compound can be prepared by making the reaction of formula XLII compound and hydrazine monohydrate:
Wherein D and R
1As defined above, and L
4For suitable leavings group, such as methoxyl group.This reaction is carried out under about 80 ℃ in such as the solvent of Virahol usually.
Formula IX compound in addition can be by making formula X compound and being prepared by the formula XXVIII compound and the organometallic reagent reaction that obtains of deriving such as the reagent react of tert-butyl lithium.This reaction is usually such as Et
2Approximately carrying out under the room temperature in the solvent of O.Can as discussed previously the Het group be protected.
In addition, when X is C, t is 1 and R
5During for hydrogen, formula I compound can be prepared by making the reaction of formula IV compound and formula XLIII compound:
OCN-(CR
6R
8)
p-R
3
(XLIII)
R wherein
3, R
6, R
8With p as defined above.This reaction in the presence of alkali (such as DIPEA), is approximately being carried out under the room temperature in such as the solvent of DCM usually.
When synthesizing of intermediate and raw material was not described, these compounds can buy or can be obtained preparing by the extension method of commercial compound by standard method or this paper embodiment in market.
Formula I compound can be converted into other formula I compound by currently known methods or by method described in the embodiment.
Thus, R wherein
2For the formula I compound of hydroxyl can by with HN (R
b)
2Reaction changes into wherein R
2Be N (R
b)
2Formula I compound, this reaction is approximately being carried out under the room temperature in such as the solvent of DCM in the presence of the coupling agent (such as EDCl and DMAP) usually.Can also use HATU, it is usually such as 1, in the solvent of 4-dioxane.Can also be under about room temperature, use coupling agent, such as the alkali of DIPEA with such as the solvent of DMF such as ED.HCl and HoBt.
R wherein
2For the formula I compound of hydroxyl can be by being converted into wherein R with perfluoroalkyl acid anhydrides (such as TFAA) reaction
2Be the formula I compound of perfluoroalkyl, this reaction is being carried out under about 0 ℃ such as the alkali of pyridine with in the presence of such as the solvent of DCM usually.
R wherein
2Be N (R
b)
2Formula I compound can by with the agent treated formula H-C that uses such as n-BuLi
1-6Alkyl S (O)
wR
gThe organometallic reagent reaction that compound deriving obtains is converted into wherein R
2Be C
1-6Alkyl S (O)
wR
gCompound, this reaction is usually carried out under the temperature of-78 ℃～room temperature approximately in such as the solvent of THF.
R wherein
2Be N (R
b)
2Formula I compound can by with suitable organometallic reagent (such as by required R
2Organolithium or Grignard reagent that group is derived and obtained) reaction be converted into wherein at R
2The compound that has other group on the position.This reaction in the solvent such as THF, is carried out under the temperature of about-78 ℃～room temperature usually.
R wherein
2For the formula IV compound of hydrogen can be converted into wherein R by the organometallic reagent reaction that obtains with the agent treated formula XLIV compound deriving of using such as n-BuLi
2Be not the compound of hydrogen:
R
2-L
3
(XLIV)
R wherein
2And L
3As defined above.This reaction is carried out under about 0 ℃～room temperature in the presence of such as the solvent of THF usually.Then, utilize reagent such as Dess-Martin reagent, can be with the pure oxidation accepted way of doing sth IV compound that forms thus.If desired, can other functional group in the molecule be protected the suitable blocking group of usefulness as discussed previously.
During any building-up process as herein described, may need and/or can desirably protect sensitivity or active group on any molecule that relates to.This can be accomplished by conventional blocking group, is described in Protective Groups in Organic Chemistry, 3rd Edition, Greene T.W. and Wuts, P.G.M. such as those; Wiley Interscience, 1999 and Kocienski, P.J.Protecting Groups, Thieme, the blocking group in 1994.Subsequently, in the suitable stage, can utilize methods known in the art that these blocking groups are removed.For example, when having the BoC protecting group, can be removed by the reagent that adds such as TFA and DCM.Can also utilize standard method that compound is carried out hydrogenation, such as, under hydrogen atmosphere, in such as methanol solvent, use such as the catalyzer of Pd/C and handle.
As discussed previously, between the synthesis phase of formula I compound, can protect the Het group by protecting group such as SEM, can under standard conditions, be removed as mentioned above subsequently.
The example of the blocking group on other Het ring comprises the tertiary butyl (dimethyl) silicomethane methyl and BOM.Subsequently, can utilize standard method that the BOM group is removed, for example, under about room temperature, by adding such as BBr
3Reagent and be removed such as the solvent of toluene.
The compounds of this invention can be prepared by carrying out functionalized suitable processing alkyl chain at alpha-position with aminoderivative as described in the scheme 1.These derivatives can be prepared by those skilled in the art, and synthetic these heterocyclic methods are described in Alan Katritzky, Comprehensive Heterocyclic Chemistry. (Pergamon Press, New York, 1984) and Comprehensive Heterocylic Chemistry IL (Pergamon Press, New York, 1996) and in other document.Free amine group can with the acid derivative coupling, thereby form acid amides, it is known in the art making carboxylic acid (and acid derivative) and the method that the amine coupling forms carboxylic acid amides.Suitable method is described in, for example, and Jerry March, AdvancedOrganic Chemistry, the third edition, John Wiley ﹠amp; Sons, 1985, among the pp.370-376.In the presence of alkali, similarly react, thereby generate corresponding sulphonamide with SULPHURYL CHLORIDE, referring to Jerry March, Advanced Organic Chemistry, 4th version, John Wiley﹠amp; Sons, 1992, pp.496-499.In a comparable manner, the reaction of amine and sulphonamide chlorine generates corresponding sulphonamide.
Scheme 1
(these amino acid derivative can utilize the standard chemical process to be prepared by those skilled in the art by the protected amino ester of key; such as being described in Williams; R.M.Synthesis of Optically Active a-Amino Acids; Pergamon Press, the chemical process in 1989) route of synthetic side chain imidazoles is shown in the scheme 2.At alkali (Cs for example
2CO
3) exist down, can carry out alkylation and 150 ℃ are handled and be heated to the gained ester these acid with halogenated methyl ketone with the excessive acetic acid ammonium, thus the imidazoles that obtains expecting, described condition is described in Bioorg.Med.Chem.Lett.1996,6,1601, Tetrahedron 1996,52, in 10131 and J.Am.Chem.Soc.1981,103,3446.Removing protecting group can further carry out functionalized.The example comprises: by form acid amides with acid-respons in the presence of coupling agent; By in the presence of alkali, carrying out sulfonylation with the SULPHURYL CHLORIDE reaction; With by carrying out the sulfanilamide (SN) acidylate with sulphonamide chlorine and alkali reaction.
Scheme 2
The compounds of this invention can be as obtaining preparation by suitable heterocyclic aldehydes (commercially available or synthesized easily by the corresponding alcohol of oxidation) by the Yu Geshi reagent react as described in the scheme 3, and described Grignard reagent is from being prepared in backflow THF by corresponding alkyl bromide and magnesium chips under the standard conditions.The secondary alcohol that obtains thus can utilize the described conditions of people such as Thompson (J.Org.Chem..1993,58,5886-8),, thereby obtain trinitride with phenylbenzene azide phosphorus and DBU reaction.Under barometric point, use palladium/carbon to carry out hydrogenation, obtain racemic amines as catalyzer, then, its can with carboxylic acid, SULPHURYL CHLORIDE and the coupling of sulphonamide chlorine.Carry out deprotection with mineral acid at last, thereby discharge corresponding ketone.
Scheme 3
The modification of the route of synthetic side chain imidazoles is shown in the scheme 4,, with the mixture of ammonium acetate and acetate alkyl ammonium alkylation acid is handled down at 150 ℃ in dimethylbenzene at this, thereby is obtained comprising the mixture of product of the alkylation imidazoles of expectation.Then, can as discussed previously the gained compound be handled, thus the inhibitor that obtains expecting.
Scheme 4
The route that forms triazole is shown in the scheme 5, wherein at first the amino acid that has ketone is reduced and (for example uses BH
3-Me
2The S title complex), thereby forms alcohol, in alcoholic solvent, in the presence of hydrazine hydrate, ester group is converted into hydrazides then by heating.Then, the gained hydrazine can react with imino-ether, reaction at first at room temperature and reaction under 110 ℃ then, thereby the heterocycle that obtains expecting.Then, corresponding ketone is returned in the oxidation of gained alcohol, thereby obtain intermediate, can as discussed previously this intermediate be converted into required inhibitor.
Scheme 5
The method for preparing other analogue is shown in the scheme 6, with suitable functionalized alkiodide lithiumation Schollkopf derivative is carried out alkylation at this, after the weak acid hydrolysis, obtain chirality alpha-amino group ester (referring to people Synthesis 1982,866 such as U.Schollkopf).Make it carry out saponification reaction, thereby obtain chiral.This acid can as discussed previouslyly be converted into required imidazoles, at first carries out alkylation with α-bromoketone, with ammonium acetate it is handled in dimethylbenzene under 150 ℃ then.It is gone protection, and for example the DCM mixture with TFA makes it go protection, thereby discharges ammonium salt, makes it carry out coupling, thus the inhibitor that obtains expecting.
Scheme 6
By it being coupled to multiple N (R
b)
2Group, can further carry out carboxylic acid functionalized, thereby obtain acid amides and hydroximic acid as the expectation inhibitor, for example, use EDC as coupling agent, as 7 diagrams of scheme.
Scheme 7
Preparation 1,3, the synthetic route of 4-oxadiazole is shown in the scheme 8, wherein makes the hydrazides and second carboxylic acid carry out coupling easily, makes it carry out cyclisation then under dehydration conditions, thereby forms the heterocycle of expectation.Described suitable condition comprises the BEMP that uses toluene sulfonyl chloride and polymkeric substance load, and as people Synlett 2001,3 such as Brain, 382-384 is described.Subsequently, can remove protecting group and required inhibitor can as discussed previouslyly be synthesized from nitrogen-atoms.
Scheme 8
1,2 of isomery, the 4-oxadiazole can obtain preparation as described in scheme 9.Can make amino acid carry out coupling, thereby form primary amide, can use reagent and alkali to make it be dehydrated into nitrile subsequently such as trifluoroacetic anhydride.In some cases, reduction step need guarantee in functional group and the building-up process that oxidation step afterwards is compatible.The formation of aldoxime can use hydroxylamine hydrochloride accomplished in the presence of potassium hydroxide.The effect of cyclisation Wei oxadiazole can by use TBTU to carry out coupling as coupling agent and then reaction is heated to 110 ℃ accomplished, thereby the realization cyclic action, as people such as Poulin, Tetrahedron Letters 2001,42,1495-8 is described.In addition, for the synthesising different structure heterocycle, can overturn and a-amino acid and be derived from the reaction upset replacement form of heterocyclic aldoxime to the coupling form.
Scheme 9
Be equipped with in the situation of oxazole in system, another kind of alternative method is shown in the scheme 10, wherein makes alpha-amino group ketone and carboxylic acid coupling, can make under dehydration conditions at this acid amides that obtains then and carry out cyclisation once more, thereby form the heterocycle of expecting.A kind of method of carrying out cyclic action is to use hexachloroethane and triphenylphosphine, and as people Jjim.Chem.Soc 2004,126 such as Nicolaou, 10162-10173 is described.
Scheme 10
Other heterocyclic alternative method of introducing shown in the scheme 3 is shown in the scheme 11.For example, can make suitable Weinreb acid amides and organo-metallic substance reaction, thereby obtain corresponding ketone.Suitable organometallic compound comprises the organolithium material, it can be by halogen-lithium exchange reactions or in addition by with highly basic heterocycle being carried out deprotonation and obtaining easily, for example, referring to: L.Brandsma and H.Verkruijsse, Preparative Polar OrganometallicChemistry 1, Springer-Verlag.Described crucial ketone can also obtain preparation, thereby form heterocycle Weinreb acid amides by adding lithium alkylide (carrying out halogen-lithium exchange by alkyl iodide/alkyl bromide and tert-BuLi obtains) (as J.Am.Chem.Soc.1990,55,5404 and 5406 is described).These ketone can utilize the reductive agent such as sodium borohydride to be converted into required alcohol easily.
Described alcohol can also pass through aforesaid method, uses aldehyde to replace the Weinreb acid amides directly to be prepared, thereby can remove reduction step.
Scheme 11
This tactful alternative strategy relates to the methyl ketone group that uses the terminal olefin conduct to be shielded, and the latter can be deshielded easily by Wacker oxidation, shown in scheme 12.By forming Grignard reagent by ω-halo-1-alkene and they being added on the aldehyde, can easily alkene be incorporated in the inhibitor.Use DPPA and DBU as mentioned above, benzylalcohol can be accomplished to the conversion of corresponding amine, thereby form trinitride, carries out the Staudiger reaction with the reduction trinitride, thereby form required amine.Amine is carried out functionalized after, use oxygen and CuCl and catalysis PdCl
2, can be ketone with conversion of olefines easily, as Synthesis 1984, described in the 369-384.
Scheme 12
The variant of aforesaid method is to select the Ellman chemical process for use, thereby makes crucial amine to obtain forming in stereospecific mode, shown in scheme 13.Make aldehyde with (R)-(Sulfinamide) condensation, N-(R)-tertiary butyl sulfenimide (sulfinimine) thereby form for tertiary butyl sulfinyl amine.The addition of organometallic reagent on this imines can be accomplished in highly stereospecific mode, and described in following document: Tetrahedron 1999,55,8883-8904; J.Org.Chem.1999,64,1278-84 and J.Comb.Chem.2003,5,590-6 and can separate diastereomer as required.With acidic methanol chiral adjuvant is hydrolyzed, thereby obtains being applicable to the crucial Chiral Amine of further functionalization.
Scheme 13
Perfluoroalkyl ketone can obtain preparation as described in scheme 14, wherein corresponding carboxylic acid is carried out deprotonation, corresponding negatively charged ion and perfluoroalkyl diacetyl oxide (such as TFAA) are reacted in the presence of alkali (such as pyridine), thereby obtain perfluoroalkyl ketone, as TetrahedronLetters, 1992,33,1285-8 is described.
Scheme 14
In some cases, can be converted into other analogue by the inhibitor that the known simple functional group of those skilled in the art handles expectation.For example, can be with multiple R
xThe carboxylic acid that comprises in the group decomposes and coupling, thereby introduces amide group.Equally can be to R
xIn the group shielded amine go protection and undertaken by reaction functionalized, such as be coupled to carboxylic acid derivative or undertaken by reductive amination reaction functionalized, shown in scheme 15.
Scheme 15
The modification of scheme 13 is shown in the scheme 16; wherein to 2; 5-dibromo imidazoles is protected; carry out lithiumation by the bromo-lithium exchange of carrying out with BuLi subsequently; and it is added on the tertiary butyl sulfenimide of alkyl chain; thereby obtain non-enantiomer mixture, this mixture can obtain easily separating by chromatography.It is can be in acidic medium accomplished easily and can coupling introduce one of capping group to utilize chiral auxiliary(reagent) to be hydrolyzed.Cross-coupling reaction for example carries out the Suzuki reaction with boric acid under palladium catalysis, introduce R '-D-group and finally it is gone protection, discharges the inhibitor of expectation easily.
Scheme 16
Further modification is shown in the scheme 17, and wherein bromide can carry out cross-coupling with 1-(1-alkoxyl group thiazolinyl) stannic hydride in the presence of palladium (0) catalysis in the Stille reaction, then it is hydrolyzed, and partly is present in R thereby obtain ketone
1Compound in the-D-group.Additionally, if bromide and ene boric acid carry out cross-coupling in the Suzuki reaction, can carry out hydrogenation to having the products obtained therefrom that is present in the two keys in the inhibitor so, thereby obtain on D, having the derivative of alkyl.
Scheme 17
R
1Other modification on the-D-substituent characteristic can be accomplished by carry the hydroxyl and protected methyl in the building-up process shown in the scheme 18.To carrying out lithiumation and carry out quencher by DMF and on imidazoles, introduce aldehyde radical in the 2-position of imidazoles, this compound subsequently can with functionalized organolithium reagent reaction, comprise the side chain of inhibitor, thereby make up the nuclear of the molecule of expectation.Gained secondary alcohol is changed into corresponding trinitride and use PPh in the Staudinger reaction
3Being hydrolyzed discharges amine, can carry out coupling to it subsequently, thereby introduces an end envelope group.Then, this key structure unit can be prepared into aforesaid multiple inhibitor.For example: go protection that hydroxymethyl R is provided
1-D-group; Remove silicon protecting group and carry out oxidation then, obtain crucial aldehyde, can carry out it by reductive amination subsequently functionalized, thereby at R
1Introduce amine on the-D-side chain, this aldehyde can carry out homologization easily by reacting such as the Wittig olefination in addition, thereby forms unsaturated compound, they can be hydrogenated to their saturated counterpart subsequently.
Scheme 18
The alternative method of scheme 8 is shown in the above scheme 19, wherein makes the R that has expectation
1The hydrazides of-D-group and the coupling of activated amino acid derivative.Suitable pre-activation strategy comprises, before adding hydrazides, handles amino acid composition 10 minutes with EDCI and HOBt.Then, can under dehydration conditions, carry out cyclisation to the gained compound easily, such as the BEMP that uses toluene sulfonyl chloride and polymkeric substance load.Functional group is handled, thus the inhibitor that obtains expecting.
Scheme 19
Modification R
2The method of-group property is shown in the scheme 20, wherein uses organometallic reagent (generally being organolithium reagent or Grignard reagent) that the Weinreb acid amides is handled, thereby obtains a series of alkyl ketone and functionalised alkyl ketone.Specific examples is to use the organolithium reagent that is formed by chloroiodomethane.In this case, can handle the intermediate that forms thus with potassium acetate, thereby form acetoxy-methyl ketone, it forms methylol ketone by alkaline bleach liquor cleavage.
The variant (not shown) of these methods is to use aldehyde to replace the Weinreb acid amides.In this case, add organometallic reagent and need oxidation step afterwards, to obtain corresponding ketone, this can be by using Dess-Martin reagent accomplished.
Scheme 20
The modification of scheme 6 is shown in the above scheme 21, wherein by the careful blocking group of selecting, and such as using the Cbz-group as amino protecting group, can be by not contacting amino protecting group with the tertiary butyl ester cracking.This makes R
2The character of-group can change and in the end amino protecting group be removed and multiple capping group is introduced in the step subsequently.
Scheme 21
Compound in this illustrations is tested by measuring method as described below, finds their IC
50Value is less than 10 μ M.
HDACl and NE measure
Measure explanation:
Use HDAC_NE and HDACl to measure quantitative histone deacetylase (HDAC) activity.This is determined in the 96 hole microwell plates and carries out by the following method; HeLa nuclear extract or purifying HDACl with fixed concentration cultivate in advance to the compound of serial dilution, contain acetylize Methionin matrix/developer to wherein adding by what deacetylated effect produced fluorescence then.Under 37 ℃, carry out deacetylation enzyme reaction 60 minutes, terminate, use plate reader that fluorescence (ex 360nM, em 460nM) is measured then by adding developer solution.
HDAC matrix buffer system
The HDAC fluorescence activity is measured reagent available from BioMol R
e(Plymouth Meeting PA) and with Fluor-de-Lys TM matrix/developer system characterizes search Laboratories.Described reagent is included as the proprietary fluorescence matrix (KI-104) and the developer concentrated solution (KI-105) of 50mM mother liquor.
After adding special-purpose developer, the deacetylation of the lysine residue of Fluor-de-Lys matrix is carried out quantitatively by measuring fluorescence (ex 360nM, em 460nM).
Work reagent:
The TSA raw material: in 100% methyl-sulphoxide (DMSO), TSA provides with the form of 10mM mother liquor.Measure damping fluid: 25mM Tris/HCl pH8,137mM NaCl, 2.7mM KCl, 1mM MgCl
2, 0.1mg/ml BSA.
The matrix solution of dilution: before each time used, measure damping fluid with HDAC commercially available 50mM Fluor-de-Lys matrix (KI-104) is diluted to 150uM.In mensuration, ultimate density is 30uM.
The developer solution of dilution: commercially available 20X developer concentrated solution (KI-105) is gone into HDAC with dilution in 1: 167 measure in the damping fluid.With 2uM[final] TSA joins in this solution to strengthen the ability of its termination reaction.
HDAC_NE working solution: before each time used, the HeLa nuclear extract in the fresh sample is diluted in the mensuration damping fluid.In mensuration, ultimate density is 20ug/ml.
HDACl working solution: before each time used, the HDACl enzyme in the fresh enzyme sample is diluted in the mensuration damping fluid.In mensuration, ultimate density is 1-2nM.
Compound: the mensuration buffer soln that test compounds should be prepared into 10 * 5%DMSO.In reaction, final DMSO concentration is 0.5%.
Test design: describedly be reflected at that the final volume with the 50ul/ hole carries out in the 96 hole microplates, as described below:
-adding 5ul DMSO/ compound solution
HeLa NE or the HDACl (perhaps 35ul in negative control measure damping fluid) of-adding 35ul in measuring damping fluid
-at room temperature cultivated 10 minutes
-start reaction by the matrix solution that adds 10ul 150uM
-cultivated 1 hour down at 37 ℃
-by adding 50ul developer/4uM TSA solution stopped reaction
-at room temperature cultivated 10 minutes
-be determined at the fluorescence under Ex.360nM and the Em.460nM
The nucleus extraction scheme of HeLa cell (sticking connection or suspension)
About carrying out scheme that nucleus extracts (adhesion or suspension) from HeLa S3 cell referring to people 1999Anal.Biochem. such as Nare, 267:390-396.
The nucleus of adhesion HeLa S3 cell (0.5-1 * 109 cells) is prepared as follows: with twice of 1 * PBS washed cell, the cell scraping is gone among the 1X PBS, use the 1XPBS wash plate, collect and under 4 ℃, the rotation cell is 10 minutes under 800xg, with 1X PBS washed cell pill (pair cell is counted), under 4 ℃, rotation cell 10 minutes under 800xg goes in the liquid nitrogen and with it to be stored under-80 ℃ with the cell pill is freezing.
Suspension HeLa S3 cell (0.5-1 * 10
9Cell) nucleus is prepared as follows: under 4 ℃, by 10 minutes collecting cells of rotation under 800xg, with 1X PBS washed cell pill, under 4 ℃, the rotation cell is 10 minutes under 800xg, repeated washing step twice (pair cell is counted) goes in the liquid nitrogen and with it to be stored under-80 ℃ with the cell pill is freezing.
Cell pill resuspending is gone into lysis damping fluid (5ml/1 * 10
8Cell; Damping fluid contains: 0.25M sucrose, 0.45%NP40,10mM Tris-HCl (7.5), 10mM NaCl, 5mM MgCl
2, 0.1mM EGTA, 0.5mM PMSF, COMPLETE protease inhibitor cocktail), vortex 10 seconds and it was being placed 15 minutes upset damping fluid (25ml lysate/5ml damping fluid on ice; Damping fluid contains: 30% sucrose, 10mM Tris-HCl (7.5), 10mM NaCl, 3mM MgCl
2), 1, the upset damping fluid is 10 minutes under the 300xg, removes supernatant liquor/damping fluid under 4 ℃, it is suspended in lysis damping fluid neutralization the above rotation damping fluid for another example as mentioned above again, removes supernatant liquor/damping fluid.
Extract for nucleus, nucleus granule resuspending is extracted damping fluid (13.5ml/5ml nucleus granule in nucleus; Nucleus extracts damping fluid and contains: 50mM Hepes pH 7.4) on ice its supersound process was become suspension (1 minute, output is controlled to be 4～5), placed 30 minutes on ice, under 4 ℃ 100, under the 000xg with its centrifugal 1 hour, remain on ice, repeat supersound process/ice/centrifugation step more than twice, three kinds of supernatant liquors are collected in together and make its 50mM Hepes pH 7.4/10% glycerol of dialysing, in liquid nitrogen, its quick freezing formed suitable five equilibrium and it is stored under-80 ℃.
Extraction and the purifying of the FLAG-label H DACl that in the Hela cell, expresses
At DMEM, be supplemented with in antibiotic 10% foetal calf serum and the glutamine, on the 10cm culture dish, make HeLa cell with the of short duration transfection of pCDNA3-HDACl-FLAG grow to 80% and merge.Wash and its scraping is gone among the 2ml PBS with the cold PBS pair cell of 10ml.Under 4 ℃, under 800xg with cell centrifugation 5 minutes, with 30ml PBS it is washed and with its resuspending in 10ml PBS, to its count, centrifugal and under-80 ℃, carry out freezing again to it.
Hypotonic lysis damping fluid (the LB:20mM Hepes pH7.9 that refrigerated cell granule resuspending is contained the COMPLETE proteinase inhibitor in 1ml, 0.25mM EDTA 10% glycerol) and under freezing condition it was cultivated 15 minutes, in 2-ml DounceB homogenizer, it is carried out homogenizing (25 bumps) subsequently.150mM KCl and 0.5%NP-40 are joined in the above-mentioned homogenate, gained solution is carried out 30 seconds of supersound process (output 5/6, working cycle 90) and under 4 ℃ it cultivated 1 hour.Under 12000rpm and 4 ℃, carry out 30 minutes centrifugal after, collect supernatant liquor (soluble extract) and use BIORAD to measure protein concn is determined.
Anti--FLAG M2 affinity resin (Sigma) is with TBS washing three times and use the LB washed twice.Resin/mg the protein (2-3ug Flagged-HDACl) of 10 μ l LB-washing is joined in the soluble extract (1mL), and under 4 ℃, under gentleness is mixed with its overnight incubation.By centrifugal resin is collected then, with LB once with its washing, with the LB+0.1%NP40 washed twice and with elution buffer (50mM HepespH 7.4,5% glycerol, 100mM KC1,0.01%Triton X-100) washed twice.
By adding the excessive 10 times elution buffer that contains 100 μ g/ml 3XFLAG peptides (SIGMA), the HDAC of protein affinity purification is eluted from resin.By the Western engram analysis concentration of purifying HDAC is determined.
Other assay method is known in the document and can be carried out easily by those skilled in the art.
The present invention of following examples illustrations.
Embodiment 1
1-methyl-3-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino }
Carbonyl) piperidines two (trifluoroacetate) (A4)
Step 1:(2S)-and the 2-[(tertbutyloxycarbonyl) amino]-8-oxo n-nonanoic acid (A1)
At room temperature, with (2S)-2-[(tertbutyloxycarbonyl) amino]-8-oxo methyl pelargonate (1 equivalent) is dissolved in 1: 1 mixture of THF and water, and LiOH hydrate (1.2 equivalent) is added wherein and the gained mixture was stirred 30 minutes.Said mixture is distributed between 0.1M HCl and the DCM, and with its separation, the gained organic phase washes, carries out drying (Na with water
2SO
4) and under reduced pressure concentrate.Thus obtained water white oil A1 does not need to be further purified promptly to can be used in the next step.MS (ES) C
14H
25NO
5, desired value: 287, discovery value: 288 (M+H)
+
Step 2:[(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-2-yl) octyl group] carboxylamine uncle fourth
Ester (A2)
At room temperature, with A1 (1 equivalent) and Cs
2CO
3The EtOH solution stirring of (0.5 equivalent) 30 minutes under reduced pressure concentrates it then.2-bromoacetophenone (1 equivalent) is joined in the DMF solution of gained salt, and at N
2In, at room temperature the gained mixture was stirred 1 hour.By DMF being removed with the dimethylbenzene azeotropic.EtOAc is added wherein, the gained mixture is filtered and with EtOAc the gained resistates washed.The filtrate that under reduced pressure is combined concentrates.With the xylene solution reflux (bathing warm for 150 ℃) of gained oil and ammonium acetate (20 equivalent) 3 hours.With said mixture be cooled to room temperature, with EtOAc dilution and water (2 *), saturated NaHCO
3The aqueous solution and salt water washing.Above-mentioned gained solution is carried out drying (Na
2SO
4), under reduced pressure it is concentrated and on silica gel, the gained brown oil is carried out purifying by chromatography, with EtOAc/ sherwood oil (1.5: 1) wash-out, thereby obtain imidazoles A2 into water white oil.
1H NMR (300MHz, CDCl
3) δ: 10.50-9.60 (1H, m), 7.82-7.40 (2H, m), 7.38-7.29 (2H, m), and 7.22-7.15 (2H, m), 5.13 (1H, br.s), and 4.68-4.55 (1H, m), 2.39 (2H, t, J=7.2Hz), 2.22-2.06 (4H, m), 1.99-1.80 (1H, m), 1.60-1.50 (2H, m), 1.43 (9H, s), 1.40-1.27 (4H, m) .MS (ES) C
22H
31N
3O
3Desired value: 385, discovery value: 386 (M+H)
+.
Step 3:2-[(1S)-the 1-amido (ammonio)-7-oxo octyl group]-5-phenyl-1H-miaow
Azoles-1-two (trifluoroacetate) (A3)
Under 0 ℃, A2 (1 equivalent) is dissolved among the TFA/DCM (1: 1).Cooling bath is removed and at room temperature the gained mixture was stirred 60 minutes.Under reduced pressure solvent is removed, and again the gained resistates was positioned in the high vacuum 3 hours.The thick amine salt A3 of gained does not need to be further purified and can use.MS (ES) C
17H
23N
3O, desired value: 285, discovery value: 286 (M+H)
+
Step 4:1-methyl-3-([(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) suffering
Base] amino } carbonyl) piperidines two (trifluoroacetate) is (A4)
To A3 (1 equivalent) and Et
3The DMF solution that adds EDCHCl (1.2 equivalent), HOBt (1.2 equivalent) and 1-methyl piperidine-3-carboxylic acid (1.2 equivalent) in the DMF solution of N (2.2 equivalent).At room temperature, use H with said mixture jolting 16 hours
2O (+0.1%TFA) and MeCN (+0.1%TFA) as elutriant (C18 post), by the preparation RP-HPLC to the expectation material separate.Desired components is carried out lyophilize, thereby obtain the imidazoles A4 into water white oil, it obtains solidifying by placement.
1H NMR (300MHz, DMSO-d6) δ: 8.96-8.91 (1H, m), 7.98 (1H, s), 7.78 (2H, d, J=7.5Hz), 7.50 (2H, t, J=7.5Hz), 7.45-7.32 (1H, m), and 5.06-4.90 (1H, m), 3.16-2.67 (8H, m), 2.40 (2H, t, J=7.2Hz), 2.05 (3H, s), 2.03-1.16 (12H, m) .MS (ES) C
24H
34N
4O
2Desired value: 410, discovery value: 411 (M+H)
+.
Embodiment 2
2-((1S)-{ [(4-p-methoxy-phenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-miaow
Azoles-1-trifluoroacetate (B1)
To embodiment 1, A3 and Et
3Add 4-anisole SULPHURYL CHLORIDE (1.1 equivalent) in the DCM solution of N (1.1 equivalent).At room temperature above-mentioned reaction mixture was stirred 3 hours and use saturated NaHCO
3The aqueous solution washs said mixture.Under reduced pressure the gained organic phase is concentrated, and use H
2O (+0.1%TFA) and MeCN (+0.1%TFA) as elutriant (post: C18), by the preparation RP-HPLC the thick resistates of gained is carried out purifying.Desired components is carried out lyophilize, thereby obtain title compound B1 into water white oil.
1H NMR (300MHz, CD
3CN) δ: 8.87 (1H, d, J=9.3Hz), 7.60-7.52 (4H, m), 7.51-7.40 (3H, m), 7.31 (1H, s), 6.79-6.63 (2H, m), and 4.78-4.65 (1H, m), 3.51 (3H, s), 2.37 (2H, t, J=7.3Hz), 2.04 (3H, s), 1.89-1.78 (2H, m), 1.51-1.32 (3H, m), 1.31-1.14 (3H, m) .MS (ES) C
24H
29N
3O
4The S desired value: 455, discovery value: 456 (M+H)
+.
Embodiment 3
2-[(1S)-1-([[2-(dimethyl amido (ammonio)) ethyl] (methyl) amino]-sulphonyl
Base } amino)-7-oxo octyl group]-the 5-phenyl-1H-imidazoles-1-two (trifluoroacetate) is (C2)
Step 1:2-[(chlorosulfonyl) (methyl) amino]-N, N-dimethyl ethyl ammonium chloride (C1)
In 15 fens clock times, under 0 ℃, to the CHCl of SULPHURYL CHLORIDE (1.0 equivalent)
3Drip in the solution and add trimethylammonium quadrol (1.0 equivalent).After adding, cooling bath is removed and at room temperature the gained mixture is stirred and spend the night.Under reduced pressure solvent is removed, and the gained resistates was placed high vacuum 4 hours.Obtain thus to be the thick product of light yellow solid, it does not need to be further purified and can use.
Step 2:2-[(1S)-1-([[2-(dimethyl amido (ammonio)) ethyl] (methyl) ammonia
Base]-alkylsulfonyl } amino)-7-oxo octyl group]-5-phenyl-1H-imidazoles-1-two (trifluoroacetate)
(C2)
To embodiment 1, A3 and Et
3Add thick C1 (1.2 equivalent) in the DCM solution of N (4 equivalent).At room temperature said mixture was stirred 16 hours.Use H
2O (0.1%TFA) and MeCN (+0.1%TFA) (post: C18), RP-HPLC carries out purifying to said mixture by preparation as elutriant.Desired components is carried out lyophilize, thereby obtain title compound C2 into water white oil.
1H NMR (300MHz, DMSO-d
6) δ: 8.18 (1H, br.s), 7.87 (1H, br.s), 7.83-7.71 (2H, m), and 7.58-7.28 (3H, m), 4.64-4.45 (1H, m), and 3.41-3.16 (4H, m), 2.79 (6H, s), 2.63 (3H, s), 2.39 (2H, t, J=6.8Hz), 2.05 (3H, s), 1.98-1.78 (2H, m), 1.53-1.19 (6H, m) .MS (ES) C
22H
35N
5O
3The S desired value: 449, discovery value: 450 (M+H)
+.
Embodiment 4
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-the 7-oxo
Octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate (D1)
To embodiment 1, A3 and Et
3The DCM solution that adds EDC hydrochloride (1.2 equivalent), HOBt (1.2 equivalent) and (5-methoxyl group-2-Methyl-1H-indole-3-yl) acetate (1.2 equivalent) in the DCM solution of N (1 equivalent).At room temperature with said mixture jolting 1.5 hours, the gained reaction mixture diluted, uses saturated NaHCO with DCM then
3Solution washing, drying (Na
2SO
4), filter and under reduced pressure concentrate.Use H
2O (0.1%TFA) and MeCN (+0.1%TFA) (post: C18), RP-HPLC carries out purifying to the thick resistates of gained by preparation as elutriant.Desired components is carried out lyophilize, thereby obtain title compound D1 into white bulky powder.
1H NMR (400MHz, DMSO-d6+TFA) δ: 14.43 (2H, bs), 10.61 (1H, s), 8.59 (1H, d, J=6.6Hz), 8.05 (1H, s), 7.79-7.73 (2H, m), 7.56-7.48 (2H, m), 7.47-7.41 (1H, m), 7.10 (1H, d, J=8.6Hz), 6.96 (1H, d, J=2.4Hz), 6.60 (1H, dd, J=8.6,2.4Hz), 5.06-4.97 (1H, m), 3.68 (3H, s), 3.57 (1H, d, J=15.3Hz), 3.48 (1H, d, J=15.3Hz), 2.36-2.27 (5H, m), 2.03 (3H, s), 1.97-1.83 (2H, m), 1.43-1.13 (6H, m) .MS (ES) C
29H
34N
4O
3Desired value: 486, discovery value: 487 (M+H)
+.
Embodiment 5-31 is prepared according to reaction scheme that provides among the embodiment 1-4 and method.
| Embodiment | Title | (M+H) + | Method according to embodiment No |
| 5 | 1-methyl-4-(the 2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } ethyl) piperazine two or three (trifluoroacetate); | 426 | 1 |
| 6 | 1-methyl-2-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } carbonyl) piperidines two (trifluoroacetate); | 411 | 1 |
| 7 | 1-(the 3-oxo-3-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } propyl group) piperidines two (trifluoroacetate) | 425 | 1 |
| 8 | 2-((1S)-1-{[(1-methylpyrrolidin-3-yl) carbonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-two (trifluoroacetate); | 397 | 1 |
| 9 | 1-methyl-4-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } carbonyl) piperidines two (trifluoroacetate); | 411 | 1 |
| 10 | 2-{ (1S)-7-oxo-1-[(2-thienyl carbonyl) amino] octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 396 | 1 |
| 11 | 2-{ (1S)-7-oxo-1-[(1,3-thiazole-5-base carbonyl) amino] octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 397 | 1 |
| 12 | 2-((1S)-1-{[(4-methyl isophthalic acid, 2,3-thiadiazoles-5-yl) carbonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 412 | 1 |
| 13 | 2-{ (1S)-1-[(2,3-dihydro-1,4-Ben Bing Er Evil star (dioxin-)-and 6-base alkylsulfonyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 484 | 2 |
| 14 | 2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 487 | 4 |
| 15 | 2-((1S)-1-{[(4-cyano-phenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 451 | 2 |
| 16 | 2-{ (1S)-1-[(2-naphthalene sulfonyl base) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 476 | 2 |
| 17 | 2-((1S)-1-{[(2,4-dimethyl-1,3-thiazoles-5-yl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 461 | 2 |
| 18 | 2-{ (1S)-1-[(1-thionaphthene-3-base alkylsulfonyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 482 | 2 |
| 19 | 2-((1S)-1-{[(4-chloro-phenyl-) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 460 | 2 |
| 20 | 2-((1S)-1-{[(3-p-methoxy-phenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 456 | 2 |
| 21 | 1,2-dimethyl-4-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } alkylsulfonyl)-1H-imidazoles-1-two (trifluoroacetate); | 444 | 2 |
| 22 | 2-((1S)-1-{[(3,5-dimethyl isoxazole-4-yl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 445 | 2 |
| 23 | 4-[({1-[5-(2-p-methoxy-phenyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 441 | 1 |
| 24 | 4-[({1-[5-(3-p-methoxy-phenyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 441 | 1 |
| 25 | 4-[({1-[5-(4-fluorophenyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 429 | 1 |
| 26 | 4-[({1-[5-(4-chloro-phenyl-)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 445 | 1 |
| 27 | 4-[({1-[5-(4-bromophenyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 489 | 1 |
| 28 | 4-[({1-[5-(2-chloro-phenyl-)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 445 | 1 |
| 29 | 4-[({1-[5-(3, the 4-dichlorophenyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 479 | 1 |
| 30 | 4-[({1-[5-(4-cyano-phenyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 436 | 1 |
| 31 | 4-[({1-[5-(3-cyano-phenyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 436 | 1 |
Embodiment 32 and 33
4-([(1S)-and 1-(4,5-phenylbenzene-1,3-oxazole-2-yl)-7-oxo octyl group] amino } carbonyl)-1-
Methyl piperidine trifluoroacetate (E2a) and 4-([(1S)-(and 4,5-phenylbenzene-1H-imidazoles-1--
The 2-yl)-and 7-oxo octyl group] amino } carbonyl)-1-methyl piperidine two (trifluoroacetate) is (E2b)
Step 1:[(1S)-and 1-(4,5-phenylbenzene-1,3-oxazole-2-yl)-7-oxo octyl group] carboxylamine
The tert-butyl ester (E1a) and [(1S)-1-(4,5-phenylbenzene-1,3-imidazoles-2-yl)-7-oxo octyl group] amino
T-butyl formate (E1b)
At room temperature, with embodiment 1, A1 and Cs
2CO
3The EtOH solution stirring of (0.5 equivalent) 30 minutes under reduced pressure is concentrated into drying with it then.In the gained salt that is dissolved in DMF, add 2-bromo-1,2-phenylbenzene ethyl ketone (1 equivalent).At room temperature the gained mixture was stirred 1 hour, under reduced pressure DMF is removed then.EtOAc is added, the gained mixture is filtered and further with EtOAc strainer washed.The filtrate that under reduced pressure is combined concentrates.With gained oil and NH
4The xylene solution reflux of OAc (20 equivalent) (150 ℃ bathe temperature) 90 minutes is cooled to it room temperature then and dilutes with EtOAc.Gained solution H
2O (2 *), saturated NaHCO
3The aqueous solution and salt water washing are carried out drying (Na to it then
2SO
4) and under reduced pressure it is concentrated.Thus obtained brown oil does not need to be further purified promptly to can be used in the next step.
[(1S)-and 1-(4,5-phenylbenzene-1,3-oxazole-2-yl)-7-oxo octyl group] t-butyl carbamate: MS (ES) C
28H
34N
2O
4, desired value: 462, discovery value: 463 (M+H)
+
[(1S)-and 1-(4,5-phenylbenzene-1,3-imidazoles-2-yl)-7-oxo octyl group] t-butyl carbamate: MS (ES) C
28H
35N
3O
3, desired value: 461, discovery value: 462 (M+H)
+
Step 2:4-([(1S)-and 1-(4,5-phenylbenzene-1,3-oxazole-2-yl)-7-oxo octyl group] amino }-
Carbonyl)-1-methyl piperidine trifluoroacetate (E2a) and 4-([(1S)-and 1-(4,5-phenylbenzene-1H-
Imidazoles-1--2-yl)-and 7-oxo octyl group] amino } carbonyl)-1-methyl piperidine two (trifluoroacetate)
(E2b)
The mixture (E1a and E1b) that is obtained from the carbamate of previous steps is dissolved among the TFA/DCM (1: 1), and at room temperature said mixture was stirred 60 minutes.Under vacuum, solvent is removed, and the gained resistates is distributed in saturated NaHCO
3Between the aqueous solution and the DCM.The gained organic phase is carried out drying (Na
2SO
4), and under reduced pressure it is concentrated.The DMF solution that adds EDCHCl (1.2 equivalent), HOBt (1.2 equivalent) and 4-carboxyl-1-methyl piperidine muriate (1.2 equivalent) in the resistates that is obtained is subsequently to wherein adding Et
3N (1.2 equivalent).At room temperature said mixture was stirred 4 hours.Use H
2O (0.1%TFA) and MeCN (+0.1%TFA) as elutriant (post: C18), by the preparation RP-HPLC the said products is separated, thereby at first obtain imidazoles E2a and subsequently De Dao oxazole E2b.Desired components is carried out lyophilize, thereby obtain title compound into water white oil.
First component of wash-out: (4-([(1S)-and 1-(4,5-phenylbenzene-1H-imidazoles-1--2-yl)-7-oxo octyl group] amino } carbonyl)-1-methyl piperidine two (trifluoroacetate): MS (ES) C
30H
38N
4O
2Desired value: 486, discovery value: 487 (M+H)
+
Second component of wash-out: 4-([(1S)-and 1-(4,5-phenylbenzene-1,3-oxazole-2-yl)-7-oxo octyl group] amino } carbonyl)-1-methyl piperidine trifluoroacetate:
1H NMR (300MHz, DMSO-d6) δ: 9.50-9.13 (1H, m), 8.63 (1H, d, J=8.2Hz), 7.65-7.30 (10H, m), 5.01 (1H, m), 3.51-3.24 (2H, m), 3.22-2.84 (2H, m), 2.82-2.70 (3H, m), and 2.55-2-45 (1H, m), 2.41 (2H, t, J=3.6Hz), 2.05 (3H, s), 2.02-1.64 (6H, m), 1.54-1.19 (6H, m) .MS (ES) C
30H
37N
3O
3Desired value: 487, discovery value: 488 (M+H)
+.
Embodiment 34-86 is prepared according to the reaction scheme and the method that provide among the embodiment 1-4,32 and 33.
| Embodiment | Title | (M+H) + | Method according to embodiment No |
| 34 | 2-((1S)-1-{[(5-methoxyl group-2-methyl isophthalic acid H-indol-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-muriate; | 487 | 1 |
| 35 | 1-methyl-4-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } carbonyl) the piperidines dichloride; | 411 | 1 |
| 36 | 1-methyl-4-[4-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } carbonyl) phenyl] piperazine two or three (trifluoroacetate); | 488 | 1 |
| 37 | 3-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } carbonyl)-1-pyridine-2-phenylpiperidines two (trifluoroacetate); | 474 | 1 |
| 38 | 3-(2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } ethyl)-6,7-dihydro-5H-[1,3] thiazole [3,2-a] pyrimidine-4-two (trifluoroacetate) also; | 466 | 1 |
| 39 | 2-(the 3-oxo-3-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } propyl group)-2-azonia two ring [2.2.1] heptane two (trifluoroacetate); | 437 | 1 |
| 40 | 4-(the 2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino }-1-pyridin-3-yl ethyl) morpholine-4-three (trifluoroacetate); | 490 | 1 |
| 41 | 1-methyl-4-([(1S)-and 1-(4-methyl-5-phenyl-1H-imidazoles-1--2-yl)-7-oxo octyl group] amino } carbonyl) piperidines two (trifluoroacetate); | 425 | 32 |
| 42 | 4-([(1S)-and 1-(5-xenyl-4-base-1H-imidazoles-1--2-yl)-7-oxo octyl group] amino } carbonyl)-1-methyl piperidine two (trifluoroacetate); | 487 | 1 |
| 43 | 1-methyl-4-[({ (1S)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl] piperidines two (trifluoroacetate); | 461 | 1 |
| 44 | 4-[({ (1S)-1-[5-(3-chloro-phenyl-)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 445 | 1 |
| 45 | 4-{[((1S)-and 1-{5-[3,5-two (trifluoromethyl) phenyl]-1H-imidazoles-1--2-yl }-7-oxo octyl group) amino] carbonyl }-1-methyl piperidine two (trifluoroacetate); | 547 | 1 |
| 46 | The 1-methyl-4-{[((1S)-7-oxo-1-{5-[3-(trifluoromethyl) phenyl]-1H-imidazoles-1--2-yl } octyl group) amino] carbonyl } piperidines two (trifluoroacetate); | 479 | 1 |
| 47 | 2-((1S)-1-{[(3-cyano-phenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 451 | 2 |
| 48 | 2-{ (1S)-7-oxo-1-[(benzenesulfonyl) amino] octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 426 | 2 |
| 49 | 4-methyl-7-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } alkylsulfonyl)-3,4-dihydro-2H-1,4-benzoxazine-4-two (trifluoroacetate); | 497 | 2 |
| 50 | 2-[(1S)-1-({ [2-(kharophen)-4-methyl-1,3-thiazoles-5-yl] alkylsulfonyl } amino)-7-oxo octyl group]-5-phenyl-IH-imidazoles-1-trifluoroacetate; | 504 | 2 |
| 51 | 2-((1S)-1-{[(5-chloro-2-thienyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 466 | 2 |
| 52 | 1,3,5-trimethylammonium-4-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } alkylsulfonyl)-1H-pyrazoles-1-two (trifluoroacetate); | 458 | 2 |
| 53 | 2-[(1S)-1-({ [5-(2-methyl isophthalic acid, 3-thiazole-4-yl)-2-thienyl] alkylsulfonyl } amino)-7-oxo octyl group]-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 529 | 2 |
| 54 | 2-{ (1S)-1-[({5-[1-methyl-3-(trifluoromethyl)-1H-pyrazoles-5-yl]-the 2-thienyl } alkylsulfonyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 580 | 2 |
| 55 | 2-((1S)-1-{[(5-isoxazole-3-base-2-thienyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 499 | 2 |
| 56 | The 1-methyl-4-{[((1S)-7-oxo-1-{5-[4-(trifluoromethyl) phenyl]-1H-imidazoles-1--2-yl } octyl group) amino] carbonyl } piperidines two (trifluoroacetate); | 479 | 1 |
| 57 | 4-{[((1S)-1-{5-[4-(difluoro-methoxy) phenyl]-1H-imidazoles-1--2-yl }-7-oxo octyl group) amino] carbonyl }-1-methyl piperidine two (trifluoroacetate); | 477 | 1 |
| 58 | 4-[({ (1S)-1-[5-(3, the 4-difluorophenyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 447 | 1 |
| 59 | 2-((1S)-1-{[(2-nitrophenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 471 | 2 |
| 60 | 2-((1S)-1-{[(3-nitrophenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 471 | 2 |
| 61 | 2-[(1S)-1-({ [4-(kharophen) phenyl] alkylsulfonyl } amino)-7-oxo octyl group]-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 483 | 2 |
| 62 | 2-((1S)-1-{[(2-cyano-phenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 451 | 2 |
| 63 | 2-((1S)-1-{[(2-chloro-4-cyano-phenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 485 | 2 |
| 64 | 2-((1S)-1-{[(3-fluoro-4-nitrophenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 489 | 2 |
| 65 | 2-[(1S)-1-({ [2-(methoxycarbonyl)-3-thienyl] alkylsulfonyl } amino)-7-oxo octyl group]-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 490 | 2 |
| 66 | 2-((1S)-1-{[(2,5-Dimethoxyphenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 486 | 2 |
| 67 | 2-((1S)-1-{[(3-fluorophenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 444 | 2 |
| 68 | 2-((1S)-1-{[(3-cyano group-4-fluorophenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 469 | 2 |
| 69 | 2-[(1S)-1-({ [4-(difluoro-methoxy) phenyl] alkylsulfonyl } amino)-7-oxo octyl group]-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 492 | 2 |
| 70 | 2-[(1S)-1-({ [3-(difluoro-methoxy) phenyl] alkylsulfonyl } amino)-7-oxo octyl group]-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 492 | 2 |
| 71 | 2-{ (1S)-1-[(2,1,3-diazosulfide-5-base alkylsulfonyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 484 | 2 |
| 72 | 2-{ (1S)-1-[(2,3-dihydro-1-cumarone-5-base alkylsulfonyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 468 | 2 |
| 73 | 2-morpholine-4-base-5-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } alkylsulfonyl) pyridine two (trifluoroacetate); | 512 | 2 |
| 74 | 2-{ (1S)-1-[(2,1,3-Ben Bing oxadiazole-4-base alkylsulfonyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 468 | 2 |
| 75 | 2-((1S)-1-{[(4-fluorophenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 444 | 2 |
| 76 | 2-((1S)-1-{[(4-nitrophenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 471 | 2 |
| 77 | 2-((1S)-1-{[(2-fluorophenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 444 | 2 |
| 78 | 2-((1S)-1-{[(3,4-Dimethoxyphenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 486 | 2 |
| 79 | 2-((1S)-1-{[(3,4-difluorophenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 462 | 2 |
| 80 | 5-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } alkylsulfonyl) isoquinoline 99.9 two (trifluoroacetate); | 477 | 2 |
| 81 | 2-((1S)-1-{[(4-carboxyl phenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 470 | 2 |
| 82 | 1-methyl-4-[({ (1S)-7-oxo-1-[5-(3-thienyl)-1H-imidazoles-3--2-yl] octyl group } amino) carbonyl] piperidines two (trifluoroacetate); | 417 | 1 |
| 83 | 2-[2-((1S)-1-{[(1-methyl piperidine-4-yl) carbonyl] amino }-7-oxo octyl group)-1H-imidazoles-3--5-yl] pyridine three (trifluoroacetate); | 412 | 1 |
| 84 | 4-[({ (1S)-1-[5-(5-chloro-3-methyl isophthalic acid-thionaphthene-2-yl)-1H-imidazoles-3--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 515 | 1 |
| 85 | 1-methyl-4-[({ (1S)-7-oxo-1-[5-(3-phenyl-isoxazole azoles-5-yl)-1H-imidazoles-3--2-yl] octyl group } amino) carbonyl] piperidines two (trifluoroacetate); | 478 | 1 |
| 86 | 1-methyl-4-{[((1S)-1-{5-[6-methyl-2-(trifluoromethyl) [1,3] thiazole is [3,2-b] [1,2,4] triazole-5-yl also]-1H-imidazoles-3--2-yl }-7-oxo octyl group) amino] carbonyl } piperidines two (trifluoroacetate); | 540 | 1 |
Embodiment 87
1-methyl-4-[({ (1S)-1-[1-methyl-4-(2-naphthyl)-1H-imidazoles-3--2-yl]-the 7-oxo
Octyl group } amino) carbonyl] piperidines two (trifluoroacetate) is (F3)
Step 1:2-(2-naphthyl)-2-oxoethyl (2S)-2-[(tertbutyloxycarbonyl) amino]-the 8-oxo
Pelargonate (F1)
At room temperature, with embodiment 1, A1 and Cs
2CO
3The EtOH solution stirring of (0.5 equivalent) 30 minutes under reduced pressure is concentrated into drying with it then.In the DMF of gained salt solution, add 2-bromo-1-(2-naphthyl) ethyl ketone (1 equivalent).At room temperature the gained mixture was stirred 1 hour and under reduced pressure DMF removed.EtOAc is added wherein, the gained mixture is filtered, and strainer is washed with EtOAc.The filtrate that under reduced pressure is combined concentrates.Thus obtained water white oil does not need to be further purified promptly to can be used in the next step.MS (ES) C
26H
33NO
6, desired value: 455, discovery value: 456 (M+H)
+
Step 2:2-{ (1S)-1-[(tertbutyloxycarbonyl) amino]-7-oxo octyl group }-1-methyl-4-(2-naphthalene
Base)-1H-imidazoles-1-trifluoroacetate (F2)
In the xylene solution of F1, add NH
4OAc (10 equivalent) and MeNH
3OAc (10 equivalent).With said mixture reflux (150 ℃ bathe temperature) 90 minutes.Be cooled to after the room temperature, the gained mixture is with the EtOAc dilution and use H
2O and saturated NaHCO
3The aqueous solution washs.Under reduced pressure the gained organic phase is concentrated, and use H
2O (0.1%TFA) and MeCN (0.1%TFA) are as elutriant (post: C18), by preparation RP-HPLC the product of expectation is separated.Desired components is carried out lyophilize, thereby obtain product into water white oil.MS (ES) C
27H
35N
3O
3, desired value: 449, discovery value: 450 (M+H)
+
Step 3:1-methyl-4-[({ (1S)-1-[1-methyl-4-(2-naphthyl)-1H-imidazoles-1--2-
Base]-7-oxo octyl group } amino) carbonyl] piperidines two (trifluoroacetate) is (F3)
F2 is dissolved among the TFA/DCM (1: 1), and at room temperature said mixture was stirred 60 minutes.Under reduced pressure solvent is removed, and the gained resistates is distributed in saturated NaHCO
3Between the aqueous solution and the DCM.Drying (Na is separated, carried out to organic phase
2SO
4) and under reduced pressure it is concentrated.The DMF solution that adds EDCHCl (1.2 equivalent), HOBt (1.2 equivalent) and 4-carboxyl-1-methyl piperidine muriate (1.2 equivalent) in the resistates that is obtained is subsequently to wherein adding DIPEA (1.2 equivalent).At room temperature said mixture was stirred 2 hours, use H then
2(post: C18), RP-HPLC separates product F 3 by preparation as elutriant for O (0.1%TFA) and MeCN (0.1%TFA).Desired components is carried out lyophilize, thereby obtain the finished product into water white oil.
1H NMR (300MHz, DMSO-d6) δ: 9.62-9.20 (1H, m), 8.69 (1H, s), 8.29 (1H, s), and 8.01-7.81 (5H, m), 7.59-7.44 (2H, m), 5.05 (1H, m), 3.77 (3H, s), 3.50-3.22 (2H, m), 3.20-2.82 (2H, m), 2.81-2.70 (3H, m), 2.55-2.45 (1H, m), 2.41 (2H, t, J=3.6Hz), 2.06 (3H, s), and 2.02-1.64 (6H, m), 1.54-1.19 (6H, m) .MS (ES) C
29H
38N
4O
2Desired value: 474, discovery value: 475 (M+H)
+.
Embodiment 88
2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-{ (1S)-1-[5-(2-naphthyl)-4H-1,2,4-
Triazole-3-yl]-7-oxo nonyl } ethanamide (G5)
Step 1:(2S)-and the 2-[(tertbutyloxycarbonyl) amino]-8-hydroxydecanoic acid methyl esters (G1)
In nitrogen atmosphere, under 0 ℃, to (2S)-2-[(tertbutyloxycarbonyl) amino]-slowly add BH in the anhydrous THF solution of 8-oxo capric acid
3.Me
2The THF solution of S (2M, 2 equivalents).Under 0 ℃, said mixture was stirred 5 minutes, under 55 ℃, it was stirred 3 hours.To react quencher and it will be distributed in EtOAc and NaHCO with methyl alcohol
3Between the saturated aqueous solution.The gained organic phase is carried out drying (Na
2SO
4), and under reduced pressure it is concentrated.Thus obtained product does not need to be further purified promptly to can be used in the next step.MS (ES) C
16H
31NO
5, desired value: 317, discovery value: 318 (M+H)
+
Step 2:(2S)-and the 2-[(tertbutyloxycarbonyl) amino]-8-hydroxyl caprinoyl hydrazine (G2)
Be dissolved in G1 in the Virahol and with NH
2NH
2.H
2O (3 equivalent) adds wherein, under 80 ℃ said mixture is heated 16 hours then.Said mixture is cooled to room temperature, and it is distributed in DCM and H
2Between the O.The gained organism with the salt water washing, carry out drying (Na
2SO
4) and under reduced pressure concentrate.Thus obtained thick product does not need to be further purified promptly to can be used in the next step.MS (ES) C
15H
31N
3O
4, desired value: 317, discovery value: 318 (M+H)
+
Step 3:{ (1S)-7-hydroxyl-1-[3-(2-naphthyl)-1H-1,2,4-triazole-5-yl] nonyl } amino
T-butyl formate (G3)
The absolute methanol solution of 2-naphthyl cyanide is joined in the MeOH solution (31%, 1 equivalent) of NaOMe.Under 40 ℃,, at room temperature it was stirred 1 hour then said mixture heating 5 minutes.Said mixture placed down at 5 ℃ spend the night, neutralize with AcOH then and it is joined among the G2.At room temperature above-mentioned gained mixture was stirred 3 hours.Under reduced pressure solvent is removed, be suspended in the gained resistates in the dry toluene and under 110 ℃, be heated 2.5 hours.Be cooled to after the room temperature, between EtOAc and water, said mixture distributed.The gained organic phase with the salt water washing, carry out drying (Na
2SO
4) and under reduced pressure concentrate.Use the 50%EtOAc/ sherwood oil as elutriant, on silicon-dioxide, the gained resistates is carried out purifying, thereby obtain expected product into water white oil by flash chromatography.MS (ES) C
26H
36N
4O
3, desired value: 452, discovery value: 453 (M+H)
+
Step 4:{ (1S)-1-[3-(2-naphthyl)-1H-1,2,4-triazole-5-yl]-7-oxo nonyl } amino
T-butyl formate (G4)
In the anhydrous DCM solution of G3, add Dess-Martin and cross iodine alkane (1.5 equivalent).At room temperature said mixture was stirred 2 hours, then with saturated NaHCO
3The aqueous solution (contains Na
2S
2O
3(6 equivalent)) add wherein and the gained mixture was stirred 15 minutes.To respectively be separated, the gained water washs with DCM.The organic phase that is combined is carried out drying (Na
2SO
4) and under reduced pressure it is concentrated.Thus obtained product does not need to be further purified promptly to can be used in the next step.MS (ES) C
26H
34N
4O
3, desired value: 450, discovery value: 451 (M+H)
+
Step 5:2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-{ (1S)-1-[3-(2-naphthyl)-
1H-1,2,4-triazole-5-yl]-7-oxo nonyl } ethanamide (G5)
Be dissolved in G4 in DCM and TFA (1: the 1) mixture and at room temperature it stirred.After 20 minutes, under reduced pressure solvent is removed, and the gained resistates is distributed in saturated NaHCO
3Between the aqueous solution and the DCM.Drying (Na is separated, carried out to organic phase
2SO
4) and under reduced pressure it is concentrated.
The DMF solution (pre-mixing 3 minutes) that adds (5-methoxyl group-2-Methyl-1H-indole-3-yl) acetate (1.3 equivalent), HOBt (1.3 equivalent) and EDC.HCl (1.3 equivalent) in above-mentioned gained resistates is subsequently to wherein adding DIPEA (1.3 equivalent).At room temperature said mixture was stirred 3 hours.Use H
2(post: C18), RP-HPLC separates products obtained therefrom by preparation, desired components is carried out lyophilize, thereby obtain the finished product into water white oil as elutriant for O (0.1%TFA) and MeCN (0.1%TFA).
1H NMR (300MHz, DMSO-d6) δ: 10.57 (1H, s), 8.52 (1H, s), 8.39 (1H, d, J=7.5Hz), 8.18-7.18 (4H, m), 7.65-7.49 (2H, m), and 7.16-6.98 (2H, m), 6.64-6.54 (1H, m), 5.00 (1H, m), 3.67 (3H, s), 3.60-3.40 (2H, m), and 2.40-2.23 (7H, m), 1.98-1.72 (2H, m), 1.45-1.11 (6H, m), 0.89 (3H, t, J=7.3Hz) .MS (ES) C
33H
37N
5O
3Desired value: 551, discovery value: 552 (M+H)
+.
Embodiment 89
2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-[7-oxo-1-(4-phenyl-2-thienyl)
Nonyl] ethanamide (H4)
Step 1:6-(2-ethyl-1,3-dioxolane-2-yl)-1-(4-phenyl-2-thienyl) oneself-1-alcohol (H1)
Under Ar, in the anhydrous THF mixture of the Mg (2.5 equivalent) that stirs, add I
2(＞5mol%), and with the said mixture reflux, until solution become colourless till.Then, with 2-(5-bromine amyl group)-2-ethyl-1,3-dioxolane (2.2 equivalent) [Sanghee, people Synthesis 2003,14 such as K., 2194-2198] drips and adds wherein, after adding fully, the gained mixture heating up is refluxed 2.5 hours.The gained Grignard reagent is used for next step immediately.
Under 0 ℃ and Ar, the gained Grignard reagent is joined in the THF solution of 4-phenyl thiophene-2-formaldehyde (1 equivalent), and the gained mixture was stirred 30 minutes.By the saturated NH of slow adding
4Cl solution is above-mentioned reaction quencher, and with EtOAc the product of expectation extracted.The gained organic layer with the salt water washing, carry out drying (Na
2SO
4) and under reduced pressure concentrate.By column chromatography the thick product of gained is carried out purifying, use 90% sherwood oil/EtOAc to carry out wash-out, thus the pure H1 that obtains expecting.
1HNMR (300MHz, CD
3CN) δ: 7.60-7.50 (2H, d, J=7.3Hz), 7.42-7.32 (3H, m), and 7.33-7.27 (2H, m), 5.05-4.89 (1H, t, J=7.3Hz), 4.88-4.83 (1H, s), 3.94-3.89 (4H, s), 1.89-1.78 (2H, m), 1.65-1.55 (4H, m), 1.40-1.25 (6H, m), 0.90-0.80 (3H, m) .MS (ES) C
21H
28O
3The S desired value: 360, discovery value: 361 (M+H)
+.
Step
Rapid 2:2-[6-azido--6-(4-phenyl-2-thienyl) hexyl]-2-ethyl-1,3-dioxy penta Ring (H2)
Pure H1 is dissolved in the toluene, thereby forms 0.5M solution, subsequently phenylbenzene azide phosphorus (DPPA, 1.2 equivalents) and DBU (1.2 equivalent) are added wherein, and under 50 ℃ in stirring with the said mixture heated overnight.Be cooled to after the room temperature, EtOAc added wherein gained mixture H
2The 5%HCl solution washing is used in the O washing then.The gained organic layer with the salt water washing, carry out drying (Na
2SO
4) and under reduced pressure concentrate.By column chromatography the gained resistates is carried out purifying, use 50% sherwood oil/EtOAc to carry out wash-out, thereby obtain H2.
1H NMR (300MHz, CDCl
3) δ: 7.62-7.55 (2H, d, J=8.1Hz), 7.45-7.20 (5H, m), 4.65 (1H, t, J=7.3Hz), 3.95 (4H, s), 1.89-1.78 (2H, m), 1.65-1.55 (4H, m), 1.45-1.25 (6H, m), 0.9-0.8 (3H, m) .MS (ES) C
21H
27N
3O
2The S desired value: 385, discovery value: 386 (M+H)
+.
Step 3:[6-(2-ethyl-1,3-dioxolane-2-yl)-1-(4-phenyl-2-thienyl) hexyl]
Amine (H3)
H2 is dissolved among the MeOH with trinitride, and at H
2Under the atmosphere, in the presence of 10%Pd/C, it was stirred 1 hour.With H
2Atmosphere is removed and with N
2Introduce wherein.Above-mentioned reaction mixture is filtered, with the methanol wash catalyzer and under reduced pressure gained filtrate is concentrated.By column chromatography the gained resistates is carried out purifying, use 30% sherwood oil/EtOAc to carry out wash-out, thereby obtain amine H3.
1H NMR (300MHz, CDCl
3) δ: 7.54 (2H, d, J=7.6Hz), 7.45-7.35 (3H, m), 7.33-7.28 (2H, m), 4.67 (1H, t, J=7.0Hz), 3.90 (4H, s), 1.89-1.78 (2H, m), 1.65-1.55 (4H, m), 1.45-1.25 (6H, m), 0.90-0.80 (3H, m) .MS (ES) C
21H
29NO
2The S desired value: 359, discovery value: 360 (M+H)
+.
Step 4:2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-[7-oxo-1-(4-phenyl-2-
Thienyl) nonyl] ethanamide (H4)
In the DCM solution of (5-methoxyl group-2-methyl isophthalic acid-indol-3-yl) acetate (1.2 equivalent), HOBt (1.2 equivalent) and the EDCI (1.2 equivalent) that stir, add H3.At room temperature said mixture was stirred 16 hours.The gained reaction mixture in proper order with 0.25M HCl solution, 0.25M NaOH solution and salt water washing, carry out drying (Na
2SO
4) and under reduced pressure it is concentrated.With gained N-[6-(2-ethyl-1,3-dioxolane-2-yl)-1-(4-phenyl-2-thienyl) hexyl]-2-(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanamide is absorbed among 1M HCl solution (4 equivalent) and the THF, and at room temperature it was stirred 4 hours.With with said mixture and with EtOAc gained ketone being extracted among the 1M NaOH.The gained organism is with the salt water washing and under reduced pressure concentrate.Use H
2O (+0.1%TFA) and MeCN (+0.1%TFA) as elutriant (post: C18), by the preparation RP-HPLC gained mixture is carried out purifying.Desired components is carried out lyophilize, thereby obtain title compound H4 into water white oil.
1H NMR (300MHz, CD
3CN) δ: 9.00-8.90 (1H, br.s), 7.52 (2H, d, J=7.3Hz), 7.43-7.34 (3H, m), 7.32-7.22 (1H, m), 7.18 (1H, d, J=8.5Hz), 7.10 (1H, s), 6.97 (1H, s), 6.69 (1H, dd, J=8.6,2.0Hz), 6.60 (1H, d, J=8.6Hz), 5.17 (1H, q, J=6.0Hz), 3.76 (3H, s), 3.56-3.50 (2H, br.s), 2.45-2.30 (7H, m), and 1.90-1.20 (8H, m), 0.93 (3H, t, J=7.3Hz) .MS (ES) C
31H
36N
2O
3The S desired value: 516, discovery value: 517
| Embodiment | Title | (M+H) + | Method according to embodiment No |
| 90 | 4-[({ (1S)-1-[5-(1-thionaphthene-3-yl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 467 | 1 |
| 91 | 2-{ (1S)-1-[(3, the 4-difluoro benzoyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 426 | 1 |
| 92 | 2-((1S)-1-{[4-(kharophen) benzoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 447 | 1 |
| 93 | 2-((1S)-1-{[4-(amino-sulfonyl) benzoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 469 | 1 |
| 94 | 4-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } carbonyl) pyridine two (trifluoroacetate); | 391 | 1 |
| 95 | 3-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } carbonyl) pyridine two (trifluoroacetate); | 391 | 1 |
| 96 | 2-((1S)-1-{[(3,5-dimethyl isoxazole-4-yl) carbonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 409 | 1 |
| 97 | 2-{ (1S)-1-[(2,3-dihydro-1,4-Ben Bing Er Evil star-6-base carbonyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 448 | 1 |
| 98 | 2-{ (1S)-1-[(3-nitro benzoyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 435 | 1 |
| 99 | 2-{ (1S)-1-[(3-cyano group benzoyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 415 | 1 |
| 100 | 2-{ (1S)-1-[(4-cyano group benzoyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 415 | 1 |
| 101 | 1-methyl-4-({ [7-oxo-1-(4-phenyl-2-thienyl) nonyl] amino } carbonyl) piperidines trifluoroacetate; | 441 | 89 |
| 102 | 4-[({ (1S)-6-carboxyl-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl] hexyl } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 463 | 107 |
| 103 | 2-((1S)-6-carboxyl-1-{[(3-nitrophenyl) alkylsulfonyl] amino } hexyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 523 | 326 |
| 104 | 4-[({ (1S)-6-carboxyl-1-[5-(3-p-methoxy-phenyl)-1H-imidazoles-1--2-yl] hexyl } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 443 | 107 |
| 105 | 2-((1S)-6-carboxyl-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino } hexyl)-5-(3-p-methoxy-phenyl)-1H-imidazoles-1-trifluoroacetate; | 519 | 107 |
| 106 | 2-((1S)-6-carboxyl-1-{[(3-nitrophenyl) alkylsulfonyl] amino } hexyl)-5-(3-p-methoxy-phenyl)-1H-imidazoles-1-trifluoroacetate; | 503 | 107 |
Embodiment 107
2-((1S)-6-carboxyl-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }
Hexyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate (I6)
Step 1:6-[(2S, 5R)-5-sec.-propyl-3,6-dimethoxy-2,5-dihydro pyrazine-2-yl] oneself
Tert-butyl acrylate (I1)
In 10 fens clock times, to (the 2R)-2-of-78 ℃ stirrings sec.-propyl-3,6-dimethoxy-2 drips adding BuLi solution (1.6N hexane solution in the THF solution of 5-dihydro pyrazine (1.0 equivalent), 1.0 equivalent), and under-78 ℃ it is continued to stir 45 minutes.Then, in 5 fens clock times, add wherein, should react stirring and spend the night, and make it slowly be warming up to room temperature by the THF solution of sleeve pipe with pre-cooled 6-iodine hecanoic acid t-butyl ester (1.0 equivalent).Then, at room temperature above-mentioned reaction was stirred 1 hour again, by adding NH
4The Cl aqueous solution should react quencher.THF layer decant gone out and under reduced pressure it is concentrated, use EtOAc (3 *) that water mixture is extracted simultaneously.Dissolve oil-containing THF resistates again with the EtOAc extract, this solution with the salt water washing, carry out drying (Na
2SO
4) and under reduced pressure concentrate.The thick product of gained does not need to be further purified and can be directly used in (I1) in the next step.
Step 2:8-tertiary butyl 1-methyl (2S)-2-[(tertbutyloxycarbonyl) amino] suberate (I2)
I1 is dissolved among the THF (0.12M solution) and with ice bath it is cooled to 0 ℃; 1M HCl (4 equivalent) adding wherein and under uniform temp is stirred the gained mixture 20 minutes.1M NaOH (4 equivalent) is added wherein, and the gained water extracts with EtOAc, the organic phase of collection with brine treatment, carry out drying (Na
2SO
4) and under reduced pressure solvent is removed then.Thus obtained light yellow oil is dissolved in 1, in 4-dioxane/water (1: 1,0.09M solution), then with NaHCO
3(4 equivalent) and Boc
2O (2 equivalent) adds wherein and at room temperature the gained mixture is stirred and spend the night.Under reduced pressure dioxane is removed and the gained water extracts with EtOAc.The organic phase of collecting with the salt water washing, carry out drying (Na
2SO
4) and under reduced pressure concentrate.On silica gel, the gained amber oil is carried out purifying, carry out wash-out, thereby obtain title compound into water white oil with EtOAc/ sherwood oil (4: 1) by chromatography.
1HNMR (400MHz, CDCl
3) δ: 5.00 (1H, br.s), 4.30 (1H, br.s), 3.75 (3H, s), 2.21 (2H, t, J=7.4Hz), 1.70-1.80 (1H, m), 1.70-1.50 (3H, m), 1.45 (18H, s), 1.40-1.27 (4H, m) .MS (ES) C
18H
33NO
6Desired value: 359, discovery value: 360 (M+H)
+.
Step 3:(2S)-and 8-tert.-butoxy-2-[(tertbutyloxycarbonyl) amino]-8-oxo sad (I3)
At room temperature, I2 is dissolved in THF and H
2In the mixture of O (4: 1,0.35M solution), with LiOH-H
2O (1.1 equivalent) adds wherein, then the gained mixture is stirred 1.5 hours.1M HCl is added wherein, is 4-5 until the pH value, under reduced pressure THF is removed then.The gained water extracts with EtOAc (3 *), and the organic phase of collection is with the salt water washing and subsequently it is carried out drying (Na
2SO
4).Except that after desolvating, obtain title compound into water white oil, be cured by placing this oil, it does not need purifying promptly to can be used in the next step.
1H NMR (400MHz, CDCl
3) δ: 5.23 (1H, br.s), 4.13 (1H, br.s), 2.21 (2H, t, J=7.4Hz), 1.75-1.90 (1H, m), 1.70-1.50 (3H, m), 1.45 (9H, s), 1.44 (9H, s), 1.50-1.25 (4H, m) MS (ES) C
17H
31NO
6Desired value: 345, discovery value: 346 (M+H)
+.
Step 4:(7S)-and the 7-[(tertbutyloxycarbonyl) amino]-7-[5-(2-naphthyl)-1H-imidazoles-2-yl] heptan
Tert-butyl acrylate (I4)
At room temperature, with I3 and Cs
2CO
3The EtOH solution of (0.5 equivalent) (0.47M solution) stirred 30 minutes, under reduced pressure it was concentrated then.2-bromo-1-(2-naphthyl) ethyl ketone (1 equivalent) is joined in the DMF solution (0.27M solution) of gained salt, and at N
2In, at room temperature the gained mixture was stirred 1.5 hours.Under reduced pressure, by DMF being removed with methylbenzene azeotropic.EtOAc is added wherein, the gained mixture is filtered, and the gained resistates is washed with EtOAc.The filtrate that under reduced pressure is combined concentrates.With gained oil and NH
4The xylene solution reflux of OAc (20 equivalent) (bathing temperature for 150 ℃) 2 hours.Utilize the Dean-Stark trap with excessive N H
4OAc and H
2O removes.Said mixture is cooled to room temperature, with EtOAc dilution and water (* 2), saturated NaHCO
3The aqueous solution, water (* 2) and salt water washing.Above-mentioned solution is carried out drying (Na
2SO
4), under reduced pressure concentrate and on silica gel, the gained brown oil carried out purifying by chromatography, with EtOAc/ sherwood oil (9: 1～1: 1) wash-out, thereby obtain title compound into water white oil.
1H NMR (300MHz, CDCl
3) δ: 11.83 (1H, s), 8.24 (1H, s), 8.00-7.75 (4H, m), 7.62 (1H, s), 7.53-7.35 (2H, m), 7.08 (1H, d, J=7.5Hz), 4.55-4.70 (1H, m), 2.16 (2H, t, J=7.0Hz), 1.95-1.65 (2H, m), 1.60-1.15 (6H, m), 1.40 (9H, s), 1.38 (9H, s) .MS (ES) C
29H
39N
3O
4Desired value: 493, discovery value: 494 (M+H)
+.
Step 5:2-[(1S)-the 1-amido (ammonio)-6-carboxyl hexyl]-5-(2-naphthyl)-1H-miaow
Azoles-1-two (trifluoroacetate) (I5)
Under 0 ℃, above-claimed cpd I4 is dissolved in (0.2M solution) among the TFA/DCM (1: 1).Cooling bath is removed and at room temperature the gained mixture was stirred 60 minutes.Under reduced pressure solvent is removed and under reduced pressure by the gained resistates being concentrated with methylbenzene azeotropic.The thick amino acid salts of gained does not need to be further purified and can use.MS (ES) C
20H
23N
3O
2, desired value: 337, discovery value: 338 (M+H)
+
Step 6:2-((1S)-6-carboxyl-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) acetyl
Base] amino } hexyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate (I6)
At room temperature, with the DMF solution pre-mixing of EDC.HCl (1 equivalent), HOBt (1 equivalent) and (5-methoxyl group-2-Methyl-1H-indole-3-yl) acetate (1 equivalent) 1 hour, then this solution is joined I5 and iPrNEt
2In the DMF solution of (3 equivalent).At room temperature said mixture was stirred 3 hours, after this, use H
2O (0.1%TFA) and MeCN (+0.1%TFA) (post: C18), RP-HPLC directly carries out purifying to the thick product of gained by preparation as elutriant.Desired components is carried out lyophilize, thereby obtain title compound into white bulky powder.
1H NMR (400MHz, DMSO-d6) δ: 14.56 (1H, br.s), 12.00 (1H, br.s), 10.62 (1H, s), 8.65 (1H, s), 8.33 (1H, s), 8.20-7.80 (6H, m), 7.59 (2H, s), 7.10 (1H, d, J=7.68Hz), 6.97 (1H, s), 6.60 (1H, s), 5.10-5.00 (1H, m), 3.67 (3H, s), 3.65-3.40 (2H, m), 2.31 (3H, s), 2.16 (2H, br.s), 2.05-1.95 (2H, m), 1.50-1.20 (6H, m) .MS (ES) C
32H
34N
4O
4Desired value: 538, discovery value: 539 (M+H)
+.
Embodiment 108
2-((1S)-7-(hydroxyl amino)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl]
Amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate (J1)
2-((1S)-6-carboxyl-1-{[(5-methoxyl group-2 Methyl-1H-indoles-3-yl) ethanoyl] amino } hexyl)-5-(2-naphthyl)-1H-imidazoles is prepared as described in embodiment 107 steps 6.In case coupling is finished, in linked reaction solution, add EDCHCl (1.5 equivalent) and HOBt (1.5 equivalent), and after at room temperature 1 hour, hydroxylamine hydrochloride (1.5 equivalent) and DIPEA (1.5 equivalent) are added wherein.The said mixture stirring is spent the night, use H then
2O (0.1%TFA) and MeCN (+0.1%TFA) (post: C18), RP-HPLC directly carries out purifying to the gained crude product by preparation as elutriant.Desired components is carried out lyophilize, thereby obtain title compound into white powder.
1H NMR (400MHz, DMSO-d6) δ: 14.44 (1H, br.s), 10.62 (1H, br.s), 10.31 (1H, s), 8.61 (1H, d, J=7.5Hz), 8.33 (1H, s), 8.16 (1H, s), 8.06 (1H, d, J=8.6Hz), 8.01-7.86 (3H, m), 7.61 (2H, m), 7.10 (1H, d, J=8.6Hz), 6.96 (1H, d, J=2.2Hz), 6.59 (1H, dd, J=8.5,2.2Hz), 5.03 (1H, m), 3.67 (3H, s), and 3.65-3.40 (2H, m), 2.31 (3H, s), and 2.03-1.85 (2H, m), 1.91 (2H, t, J=7.4Hz), 1.50-1.20 (6H, m) .MS (ES) C
32H
35N
5O
4Desired value: 553, discovery value: 554 (M+H)
+.
| Embodiment | Title | (M+H) + | Method according to embodiment No |
| 109 | 2-{ (1S)-1-[(3-fluoro-4-nitro benzoyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-1-trifluoroacetate | 453 | 1 |
| 110 | 2-cyano group-5-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) octyl group] amino } carbonyl) pyridine two (trifluoroacetate); | 416 | 1 |
| 111 | 2-((1S)-1-{[(4-cyano-phenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 501 | 2 |
| 112 | 5-(2-naphthyl)-2-((1S)-1-{[(3-nitrophenyl) alkylsulfonyl] amino }-7-oxo octyl group)-1H-imidazoles-1-trifluoroacetate; | 522 | 2 |
| 113 | 2-[(1S)-1-([[2-(dimethyl amido (ammonio)) ethyl] (methyl) amino] alkylsulfonyl } amino)-7-oxo octyl group]-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate); | 500 | 3 |
| 114 | 5-(2-naphthyl)-2-{ (1S)-7-oxo-1-[(1,3-thiazoles-5-base carbonyl) amino] octyl group }-1H-imidazoles-1-trifluoroacetate; | 447 | 1 |
| 115 | 5-(3-chloro-phenyl-)-2-((1S)-1-{[(4-cyano-phenyl) alkylsulfonyl] amino }-7-oxo octyl group)-1H-imidazoles-1-trifluoroacetate; | 485 | 2 |
| 116 | 5-(3-chloro-phenyl-)-2-((1S)-1-{[(3-nitrophenyl) alkylsulfonyl] amino }-7-oxo octyl group)-1H-imidazoles-1-trifluoroacetate; | 507 | 2 |
| 117 | 2-((1S)-1-{[(4-cyano-phenyl) alkylsulfonyl] amino }-7-oxo octyl group)-5-(3-p-methoxy-phenyl)-1H-imidazoles-1-trifluoroacetate; | 481 | 2 |
| 118 | 5-(3-p-methoxy-phenyl)-2-((1S)-1-{ [(3-nitrophenyl) alkylsulfonyl] amino }-7-oxo octyl group)-1H-imidazoles-1-trifluoroacetate; | 501 | 2 |
| 119 | 5-(3-p-methoxy-phenyl)-2-{ (1S)-7-oxo-1-[(1,3-thiazole-5-base carbonyl) amino] octyl group }-1H-imidazoles-1-trifluoroacetate; | 427 | 1 |
| 120 | 2-((1S)-7-[(2-aminophenyl) amino]-1-{ [(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 630 | 108 |
| 121 | 5-(3-p-methoxy-phenyl)-2-[(1S)-1-([(3S)-and 1-methylpyrrolidin-3-yl] carbonyl } amino)-7-oxo octyl group]-1H-imidazoles-1-two (trifluoroacetate); | 427 | 1 |
| 122 | (3S)-3-[({ (1S)-1-[5-(3-p-methoxy-phenyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 441 | 1 |
| 123 | (3S)-1-sec.-propyl-3-[({ (1S)-1-[5-(3-p-methoxy-phenyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl] piperidines two (trifluoroacetate); | 469 | 1 |
| 124 | 5-(3-chloro-phenyl-)-2-[(1S)-1-([(3R)-and 1-methylpyrrolidin-3-yl] carbonyl } amino)-7-oxo octyl group]-1H-imidazoles-1-two (trifluoroacetate); | 431 | 1 |
| 125 | 2-[(1S)-1-([(3R)-and 1-methylpyrrolidin-3-yl] carbonyl } amino)-7-oxo octyl group]-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate); | 447 | 1 |
| 126 | 4-methyl-2-[({ (1S)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl] morpholine-4-two (trifluoroacetate); | 463 | 1 |
| 127 | 4-[({ (1S)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-azonia two ring [2.2.2] octanes two (trifluoroacetate); | 473 | 1 |
| 128 | 4-[2-((1S)-1-[5-(3-chloro-phenyl-)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino)-1-methyl-2-oxoethyl] morpholine-4-two (trifluoroacetate); | 461 | 1 |
| 129 | 2-[(1S)-and 1-{[(5-methoxyl group-2-methyl-1H-indol-3-yl) ethanoyl] amino }-7-(methylamino)-7-oxo heptyl]-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 552 | 108 |
| 130 | 5-(the 3-p-methoxy-phenyl-2-[(1S)-1-([(3R)-and 1-methylpyrrolidin-3-yl] carbonyl } amino)-7-oxo octyl group]-1H-imidazoles-1-two (trifluoroacetate); | 427 | 1 |
| 131 | (3R)-3-[({ (1S)-1-[5-(3-p-methoxy-phenyl)-1H-imidazoles-1--2-yl]-7-oxo octyl group } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 441 | 1 |
| 132 | 5-(3-chloro-phenyl-)-2-[(1S)-1-([(3S)-and 1-methylpyrrolidin-3-yl] carbonyl } amino)-7-oxo octyl group]-1H-imidazoles-1-two (trifluoroacetate); | 431 | 1 |
| 133 | 2-[(1S)-1-([(3S)-and 1-methylpyrrolidin-3-yl] carbonyl } amino)-7-oxo octyl group]-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate); | 447 | 1 |
| 134 | 2-((1S)-1-{[(5-methoxyl group-2-methyl-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 501 | 1 |
| 135 | 1-methyl-4-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } carbonyl) piperidines two (trifluoroacetate); | 425 | 1 |
Embodiment 136
2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-{ (1S)-1-[5-(2-naphthyl)-1,3,4-Evil
Diazole-2-yl]-7-oxo nonyl } ethanamide (K5)
Step 1:N '-(2S)-the 2-[(tertbutyloxycarbonyl) amino]-8-hydroxy decanoyl-2-naphthoyl hydrazine
(K1)
In DCM, naphthyl-2-formic acid, HOBt (1 equivalent) and EDC.HCl (1 equivalent) were stirred 3 hours, then with (2S)-2-[(tertbutyloxycarbonyl) amino]-8-hydroxyl caprinoyl hydrazine (G2, embodiment 88, step 2) adds wherein and at room temperature the gained mixture stirred 16 hours.Said mixture is distributed between DCM and the 0.1M HCl.Organic phase is separated, use saturated NaHCO
3Solution washing, carry out drying (Na
2SO
4) and under reduced pressure it is concentrated.Thus obtained thick product does not need to be further purified promptly to can be used in the next step.MS (ES) C
26H
37N
3O
5, desired value: 471, discovery value: 472 (M+H)
+
Step 2:N '-(2S)-the 2-[(tertbutyloxycarbonyl) amino]-8-oxo decanoyl-2-naphthoyl hydrazine
(K2)
The thick hydrazides of above-mentioned gained (K1) is dissolved among the anhydrous DCM, Dess-Martin is crossed iodine alkane (1.5 equivalent) adding wherein and at room temperature the gained mixture was stirred 2 hours.With saturated NaHCO
3The aqueous solution and 1M Na
2S
2O
3The aqueous solution (6 equivalent) adds wherein and with gained mixture vigorous stirring 15 minutes.To respectively be separated, the gained water extracts with DCM.The DCM that is combined carries out drying (Na mutually
2SO
4) and under reduced pressure it is concentrated.Utilize (SiO
2, EtOAc/ sherwood oil (2: 1) is as elutriant), TLC carries out purifying to products obtained therefrom by preparation, thereby obtains the product into water white oil.MS (ES) C
26H
35N
3O
5, desired value: 469, discovery value: 470 (M+H)
+
Step 3:{ (1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl }-amino
T-butyl formate (K3)
With hydrazides (K2), be combined in the 2-tertbutylimido-2-diethylamino-1 on the polystyrene, 3-dimethyl-perhydro-1,3, the mixture of 2-diaza phosphorine (2.3mmol/g, 5 equivalents) and TsCl (1.2 equivalent) is suspended among the anhydrous THF.Above-mentioned suspension is leniently stirred and be heated 4 hours under 65 ℃.Said mixture is filtered, and use the THF washing resin.The filtrate that under reduced pressure is combined concentrates, and the thick product of gained does not need to be further purified promptly to can be used in the next step.MS (ES) C
26H
33N
3O
4, desired value: 451, discovery value: 452 (M+H)
+
Step 4:(9S)-and 9-amino-9-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl] ninth of the ten Heavenly Stems-3-ketone (K4)
The TFA that in the DCM solution of 0 ℃ De oxadiazole (K3), adds equal volume.Cooling bath is removed and at room temperature the gained mixture was stirred 30 minutes.Under reduced pressure solvent is removed, and the gained resistates is distributed in DCM and saturated NaHCO
3Between the aqueous solution.Organic phase is carried out drying (Na
2SO
4) and under reduced pressure it is concentrated, the thick product that obtains thus is used for next step like this.MS (ES) C
21H
25N
3O
2, desired value: 351, discovery value: 352 (M+H)
+
Step 5:2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-{ (1S)-1-[5-(2-naphthyl)-
1,3,4-oxadiazole-2-yl]-7-oxo nonyl } ethanamide (K5)
The DMF solution (pre-mixing 3 minutes) that adds (5-methoxyl group-2-Methyl-1H-indole-3-yl) acetate (1.3 equivalent), HOBt (1.3 equivalent) and EDC.HCl (1.3 equivalent) in the thick amine of above-mentioned gained (K4) is subsequently to wherein adding DIPEA (1.3 equivalent).At room temperature said mixture was stirred 3 hours.Use H
2O (+0.1%TFA) and MeCN (+0.1%TFA) as elutriant (post: C18), by the preparation RP-HPLC the said products is separated.To expect that under reduced pressure the acetonitrile in the component removes, and will remain water and be distributed in saturated NaHCO
3Between the aqueous solution and the DCM.The DCM that is combined carries out drying (Na mutually
2SO
4) and under reduced pressure it is concentrated.At MeCN/H
2Among the O gained resistates is carried out lyophilize, thereby obtain expected product into white solid.
1H NMR (300MHz, DMSO-d6) δ: 10.60 (1H, s), 8.71 (1H, d, J=8.2Hz), 8.47 (1H, s), 8.12-7.85 (4H, m), 7.65-7.45 (2H, m), and 7.12-6.96 (2H, m), 6.62-6.50 (1H, m), 5.22-5.07 (1H, m), 3.65 (3H, s), 3.52 (2H, s), and 2.42-2.23 (7H, m), 2.05-1.75 (2H, m), 1.47-1.15 (6H, m), 0.90 (3H, t, J=7.3Hz) .MS (ES) C
33H
36N
4O
4Desired value: 552, discovery value: 553 (M+H)
+.[α]
D=-13 °, c=0.163 (EtOH)
Embodiment 137
2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-{ (1S)-1-[5-(2-naphthyl)-1, the 3-oxazole-
The 2-yl]-7-oxo nonyl } ethanamide (L5)
Step 1:2-azido--1-(2-naphthyl) ethyl ketone (L1)
In the acetone soln of 2-bromo-1-(2-naphthyl) ethyl ketone, add NaN
3(1 equivalent), and at room temperature said mixture was stirred 24 hours.EtOAc is added (10 volume) wherein and to the gained mixture to be filtered.Under reduced pressure gained filtrate is concentrated, on silicon-dioxide, the gained resistates is carried out purifying, carry out wash-out, thereby obtain product into white solid with the 10%EtOAc/ sherwood oil by flash chromatography.
1H NMR (300MHz, CDCl
3) δ: 8.39 (1H, s), 8.02-7.82 (4H, m), 7.69-7.50 (2H, m), 4.68 (2H, s) .MS (ES) C
12H
9N
3The O desired value: 211, discovery value: 212 (M+H)
+.
Step 2:2-amino-1-(2-naphthyl) ethyl ketone .HCl (L2)
In the methanol solution of trinitride (L1), add 1M HCl (1 equivalent) and Pd/ carbon (10%wt), and at H
2Under the atmosphere, at room temperature said mixture was stirred 3.5 hours.Catalyzer is leached and wash with methyl alcohol.The filtrate that under reduced pressure is combined concentrates, and the thick product of gained does not need to be further purified promptly to can be used in the next step.MS (ES) C
12H
11NO, desired value: 185, discovery value: 186 (M+H)
+
Step 3:[(1S)-1-({ [2-oxo-(2-naphthyl) ethyl] amino } carbonyl)-7-oxo nonyl]-
T-butyl carbamate (L3)
With (2S)-2-[(tertbutyloxycarbonyl) amino]-the DMF solution jolting of 8-oxo capric acid, EDCHCl (1.3 equivalent) and HOBt (1.3 equivalent) 5 minutes.The DMF solution that in said mixture, adds thick amine (L2) (1 equivalent) and DIPEA (1 equivalent).The gained mixture was stirred 1 hour.It is distributed between DMF and the 1M NaOH.Gained DCM phase sequence with 1M NaOH, 1M HCl and salt water washing, carry out drying (Na
2SO
4) and under reduced pressure it is concentrated.Use the 50%EtOAc/ sherwood oil as elutriant, on silicon-dioxide, the gained resistates is carried out purifying, thereby obtain product into water white oil by chromatography.MS (ES) C
27H
36N
2O
5, desired value: 468, discovery value: 469 (M+H)
+
Step 4:{ (1S)-1-[5-(2-naphthyl)-1,3-oxazole-2-yl]-7-oxo nonyl }-carboxylamine
Uncle's fourth
Ester (L4)
At room temperature with PPh
3And C
2Cl
6(1 equivalent) is dissolved among the DCM and with Et
3N (2 equivalent) adds wherein, after stirring 5 minutes, by dripping the DCM solution that adds acid amides (L3) (0.5 equivalent).At room temperature said mixture was stirred 4 hours, be poured in the water then.Drying (Na is separated, carried out to organic phase
2SO
4) and under reduced pressure it is concentrated.Use the 30%EtOAc/ sherwood oil as elutriant, on silicon-dioxide, the thick product of gained is carried out purifying, thereby obtain product into white solid by flash chromatography.MS (ES) C
27H
34N
2O
4, desired value: 450, discovery value: 451 (M+H)
+
Step 5:2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-{ (1S)-1-[5-(2-naphthyl)-
1,3-oxazole-2-yl]-7-oxo nonyl } ethanamide (L5)
Oxazole (L4) (1 equivalent) is dissolved in DCM and TFA (1: the 1) mixture and at room temperature it was stirred 30 minutes, under reduced pressure solvent is removed after this and the gained resistates is distributed in DCM and saturated NaHCO
3Between the aqueous solution.DCM is separated, carries out drying (Na
2SO
4) and under reduced pressure it is concentrated.The DMF solution (pre-mixing 3 minutes) that adds (5-methoxyl group-2-Methyl-1H-indole-3-yl) acetate (1.3 equivalent), HOBt (1.3 equivalent) and EDC.HCl (1.3 equivalent) in above-mentioned gained resistates is subsequently to wherein adding DIPEA (1.3 equivalent).At room temperature said mixture was stirred 2 hours, use H then
2O (+0.1%TFA) and MeCN (+0.1%TFA) as elutriant (post: C18), by the preparation RP-HPLC to the expectation product separate.Under reduced pressure the product component of collecting is concentrated, obtain product into white solid.
1H NMR (300MHz, DMSO-d6) δ: 10.58 (1H, s), 8.58 (1H, d, J=8.2Hz), 8.12 (1H, s), 8.05-7.85 (3H, m), 7.85-7.72 (1H, m), 7.71 (1H, s), 7.60-7.44 (2H, m), 7.13-7.01 (2H, m), 6.62-6.54 (1H, m), 5.10-4.93 (1H, m), 3.67 (3H, s), 3.51 (2H, s), 2.42-2.20 (7H, m), 2.05-1.77 (2H, m), 1.47-1.15 (6H, m), 0.89 (3H, t, J=7.3Hz) .MS (ES) C
34H
37N
3O
4Desired value: 551, discovery value: 552 (M+H)
+.
Embodiment 138
5-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-
2-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate (M7)
Step 1:2,5-two bromo-1-{[2-(dimetylsilyl) oxyethyl groups] methyl }-the 1H-imidazoles
(M1)
In Ar, 0 ℃ will stir down 2, add NaH (1.2 equivalent) in the DMF solution of 5-two bromo-1H-imidazoles (1 equivalent), and under 0 ℃ with said mixture stirring 30 minutes.Then SEM-Cl (1.1eq) is dripped adding wherein, the gained mixture was stirred 16 hours, be warming up to room temperature.By slow adding H
2O is above-mentioned reaction quencher, and with EtOAc the product of expectation extracted.The gained organic layer with the salt water washing, carry out drying (Na
2SO
4) and under reduced pressure concentrate.Use the 10%EtOAc/ sherwood oil to carry out wash-out, the thick product of gained is carried out purifying by column chromatography, thus the product that obtains expecting.
1H NMR (300MHz, CD
3CN) δ: 7.10 (1H, s), 5.21 (2H, s), 3.53 (2H, t, J=7.3Hz), 0.90 (2H, t, J=7.3Hz), 0.10 (9H, s) .MS (ES) C
9H
16Br
2N
2OSi desired value: 354: 356: 358[1: 2: 1], discovery value: 355: 357: 359[1: 2: 1] (M+H)
+.
Step 2:5-bromo-2-(2-naphthyl)-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-
Imidazoles (M2)
Under Ar, to toluene solution, the 2M Na of the imidazoles (M1) (1 equivalent) that stirs
2CO
3Add Pd (PPh in the mixture of the aqueous solution (2 equivalent) and 2-naphthyl boric acid (1 equivalent)
3)
4(5mol%), and with said mixture reflux 16 hours.Be cooled to after the room temperature, EtOAc is added wherein, the gained mixture washs with 2M NaOH.The gained organic layer with the salt water washing, carry out drying (Na
2SO
4) and under reduced pressure concentrate.Use the 10%EtOAc/ sherwood oil to carry out wash-out, by column chromatography the gained resistates is carried out purifying, thereby obtain the bromine imidazoles.
1H NMR (300MHz, CD
3CN) δ: 8.28 (1H, s), 7.95-7.80 (4H, m), 7.58-7.48 (2H, m), 7.10 (1H, s), 5.20 (2H, s), 3.58-3.48 (2H, t, J=7.3Hz), 0.95-0.85 (2H, t, J=7.3Hz), 0.10 (9H, s) .MS (ES) C
19H
23BrN
2OSi desired value: 402: 404[1: 1], discovery value: 403: 405[1: 1] (M+H)
+.
Step 3:5-(2-ethyl-1,3-dioxolane-2-yl) hexanal (M3)
In 5 fens clock times; to the 5-of-78 ℃ stirrings (2-ethyl-1; 3-dioxolane-2-yl)-N-methoxyl group-N-methyl-valeramide (1 equivalent) is [by making 7-oxo n-nonanoic acid and N; the coupling of O-dimethyl hydroxylamine is carried out ketal protection subsequently and is obtained preparation] anhydrous THF mixture in slowly add 1M LiAlH
4THF solution (1.6 equivalent).After 45 minutes, by adding Et
2O will react quencher and subsequently to wherein adding Rochelle ' s salt brine solution (10%w/v).In vigorous stirring, said mixture is warming up to room temperature.With organic phase separate, with the salt water washing, carry out drying (Na
2SO
4) and under reduced pressure concentrate.Use the 5%EtOAc/ sherwood oil to carry out wash-out, the gained resistates is carried out purifying by column chromatography, thus the aldehyde that obtains expecting.
1H?NMR(300MHz，CD
3CN)δ：9.77(1H，s)，4.00(4H，s)，2.44(2H，t，J＝7.0Hz)，1.75-1.48(6H，m)，1.46-1.25(4H，m)，1.00-0.80(3H，t，J＝7.0Hz).
Step 4:6-(2-ethyl-1,3-dioxolane-2-yl)-1-(2-(2-naphthyl)-1-{[2-(trimethylammonium
Silyl) oxyethyl group] methyl }-1H-imidazoles-5-yl) oneself-1-alcohol (M4)
Under Ar, in the THF mixture of the bromine imidazoles (M2) (1 equivalent) of-78 ℃ stirrings, drip and add n-BuLi (1.2 equivalents, 1.6M pentane solution).After 15 minutes, the THF solution of pre-cooled aldehyde (M3) (1.6 equivalent) is added wherein, and under-78 ℃, again mixture was stirred 60 minutes.By the saturated NH of slow adding
4The Cl aqueous solution extracts with EtOAc above-mentioned reaction quencher then to the product of expectation.The gained organic layer with the salt water washing, carry out drying (Na
2SO
4) and under reduced pressure concentrate.Use the 5%EtOAc/ sherwood oil to carry out wash-out, the thick product of gained is carried out purifying by column chromatography, thus the alcohol that obtains expecting.
1H NMR (300MHz, CD
3CN) δ: 8.30 (1H, s), 7.95-7.80 (4H, m), 7.58-7.48 (2H, m), 7.10 (1H, s), 5.30 (2H, s), 4.80-4.65 (1H, m), 3.91 (4H, s), 2.52-2.35 (2H, m), 1.75-1.48 (6H, m), 1.46-1.25 (4H, m), 1.10-0.80 (5H, m), 0.20-0.00 (9H, m) .MS (ES) C
30H
44N
2O
4The Si desired value: 524, discovery value: 525 (M+H)
+.
Step 5:5-[1-azido--6-(2-ethyl-1,3-dioxolane-2-yl) hexyl]-2-(2-naphthalene
Base)-and 1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-imidazoles (M5)
Alcohol (M4) (1 equivalent) is dissolved among toluene and the DPPA (1.2 equivalent), then DBU (1.2 equivalent) is added wherein, and when stirring under 50 ℃ with the said mixture heated overnight.Be cooled to after the room temperature, EtOAc added wherein gained mixture H
2The 5%HCl solution washing is used in the O washing then.The gained organic layer with the salt water washing, carry out drying (Na
2SO
4) and under reduced pressure concentrate.Use the 50%EtOAc/ sherwood oil to carry out wash-out, the gained resistates is carried out purifying by column chromatography, thus the trinitride that obtains expecting.
1H NMR (300MHz, CDCl
3) δ: 8.30 (1H, s), 7.95-7.80 (4H, m), 7.58-7.48 (2H, m), 7.10 (1H, s), 5.32 (2H, s), 4.70-4.58 (1H, m), 3.90 (4H, s), 3.69-3.59 (2H, m), 2.52-2.35 (2H, m), 1.75-1.48 (6H, m), 1.46-1.25 (4H, m), 1.00-0.80 (5H, m), 0.10 (9H, s) .MS (ES) C
30H
43N
5O
3The Si desired value: 549, discovery value: 550 (M+H)
+.
Step 6:[6-(2-ethyl-1,3-dioxolane-2-yl)-1-(2-(2-naphthyl)-1-{[2-(front three
The base silyl) oxyethyl group] methyl }-1H-imidazoles-5-yl) hexyl] amine (M6)
Trinitride (M5) (1 equivalent) is dissolved among the EtOAc, and at H
2Under the atmosphere, in the presence of 10%Pd/C, said mixture was stirred 1 hour.With H
2Atmosphere is removed and with N
2Introduce wherein.Above-mentioned reaction mixture is filtered, with the methanol wash catalyzer and under reduced pressure gained filtrate is concentrated.Use the 70%EtOAc/ sherwood oil to carry out wash-out, by column chromatography the gained resistates is carried out purifying, thereby obtain amine.
1H NMR (300MHz, CDCl
3) δ: δ: 8.42-8.35 (1H, s), 7.97-7.87 (2H, m), 7.85-7.70 (2H, m), 7.58-7.45 (2H, m), 7.10 (1H, s), 5.37-5.25 (2H, s), 4.70-4.58 (1H, m), 3.94-3.89 (4H, s), and 3.69-3.59 (2H, m), 2.52-2.35 (2H, m), 1.75-1.48 (6H, m), 1.46-1.25 (4H, m), 1.00-0.80 (5H, m), 0.10 (9H, s) .MS (ES) C
30H
45N
3O
3The Si desired value: 523, discovery value: 524 (M+H)
+.
Step 7:5-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxygen
For nonyl)-2-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate (M7)
In the DCM solution of (5-methoxyl group-2-methyl isophthalic acid-indol-3-yl) acetate (1.2 equivalent), HOBt (1.2 equivalent) and the EDCI (1.2 equivalent) that stir, add amine (M6).At room temperature said mixture was stirred 16 hours.The gained reaction mixture in proper order with 0.25M HCl solution, 0.25M NaOH solution and salt water washing, carry out drying (Na
2SO
4) and under reduced pressure it is concentrated.The gained acid amides is absorbed among the THF, the THF solution of 1M TBAF (2 equivalent) is added wherein and the gained mixture heating up was refluxed 6 hours.Be cooled to after the room temperature, EtOAc added wherein gained mixture H
2O and salt water washing, carry out drying (Na
2SO
4) and under reduced pressure concentrate.Then, de-protected imidazoles is absorbed among the THF, 1M HCl solution (4 equivalent) adding wherein and is at room temperature stirred the gained mixture 4 hours.With with said mixture and with EtOAc gained ketone being extracted among the 1M NaOH.The gained organism is with the salt water washing and under reduced pressure concentrate.Use H
2O (+0.1%TFA) and MeCN (+0.1%TFA) as elutriant (post: C18), by the preparation RP-HPLC gained mixture is carried out purifying.Desired components is carried out lyophilize, thereby obtain title compound into water white oil.
1H NMR (300MHz, d6-DMSO) δ: 10.70-10.60 (1H, s) 8.65-8.53 (1H, s), 8.45-8.33 (1H, d, J=8Hz), 8.25-8.12 (1H, d, J=8Hz), 8.10-7.90 (3H, br, s), and 7.75-7.65 (2H, m), 7.55 (1H, s), and 7.23-7.13 (2H, d, J=8Hz), 7.06 (1H, s), 6.65 (1H, s), 5.05-4.95 (1H, m), 3.76 (3H, s), 3.53 (2H, s), 2.45-2.30 (7H, m), and 1.90-1.20 (8H, m), 0.93 (3H, t, J=7.3Hz) .MS (ES) C
31H
36N
2O
3The S desired value: 550, discovery value: 551.
Embodiment 139
2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-[7-oxo-1-(2-phenyl-1,3-thiazoles-
The 5-yl) nonyl] ethanamide (N4)
Step 1:6-(2-ethyl-1,3-dioxolane-2-yl)-1-(2-phenyl-1,3-thiazoles-5-yl) oneself-
1-ketone (N1)
In Ar, under-78 ℃,, drip the pentane solution that adds 1.6M t-BuLi (3.2 equivalent) in the anhydrous THF mixture of 3-dioxolane (1.6 equivalent) to 2-(5-bromine the amyl group)-2-ethyl-1 that stirs.After 30 minutes, the THF solution of pre-cooled N-methoxyl group-N-methyl-2-phenyl-1,3-thiazoles-5-carboxylic acid amides (1 equivalent, WO 2001052846) is added wherein, under-78 ℃, said mixture was stirred 60 minutes, then by slowly adding saturated NH
4The Cl aqueous solution will react quencher, and with EtOAc the product of expectation be extracted.The gained organic layer with the salt water washing, carry out drying (Na
2SO
4) and under reduced pressure concentrate.Use the 10%EtOAc/ sherwood oil to carry out wash-out, the thick product of gained is carried out purifying by column chromatography, thus the alcohol that obtains expecting.
1H NMR (300MHz, CD
3CN) δ: 8.76 (1H, s), 8.15-8.05 (2H, m), 7.70-7.52 (3H, m), 3.94-3.89 (4H, m), and 3.02-2.91 (2H, t, J=8.0Hz), 1.75-1.65 (4H, m), 1.60-1.50 (4H, m), 1.45-1.30 (2H, m), 1.00-0.80 (3H, m) .MS (ES) C
20H
25NO
3The S desired value: 359, discovery value: 360 (M+H)
+.
Step 2:6-(2-ethyl-1,3-dioxolane-2-yl)-1-(2-phenyl-1,3-thiazoles-5-yl) oneself-
1-alcohol (N2)
In the anhydrous EtOH solution of the ketone (N1) of the stirring of room temperature, add NaBH
4(1 equivalent), and with gained mixture stirring 30 minutes.By the saturated NH of slow adding
4The Cl aqueous solution extracts with EtOAc above-mentioned reaction quencher then to the product of expectation.The gained organic layer with the salt water washing, carry out drying (Na
2SO
4) and under reduced pressure concentrate.Use the 10%EtOAc/ sherwood oil to carry out wash-out, the thick product of gained is carried out purifying by column chromatography, thus the alcohol that obtains expecting.
1H NMR (300MHz, CD
3CN) δ: 7.95 (2H, d, J=7.5Hz), 7.65-7.45 (1H, s), 7.45-7.35 (3H, m), 5.05-4.95 (1H, m), 3.94-3.89 (4H, m), 1.75-1.55 (6H, m), 1.45-1.25 (6H, m), 1.00-0.80 (3H, m) .MS (ES) C
20H
27NO
3The S desired value: 361, discovery value: 362 (M+H)
+.
Step 3:[6-(2-ethyl-1,3-dioxolane-2-yl)-1-(2-phenyl-1,3-thiazoles-5-yl) is own
Base] amine (N3)
5-[1-azido--6-(2-ethyl-1,3-dioxolane-2-yl) hexyl]-2-phenyl-1,3-thiazoles is prepared according to the method for using in embodiment 89 steps 2 by alcohol (N2).
1H NMR (300MHz, CDCl
3) δ: 8.00-7.90 (2H, d, J=7.5Hz), 7.57 (1H, s), 7.45-7.35 (3H, m), 5.10 (1H, t, J=7.3Hz), 3.95 (4H, s), 1.89-1.78 (2H, m), 1.65-1.55 (4H, m), 1.45-1.25 (6H, m), 0.90-0.80 (3H, m) .MS (ES) C
20H
26N
4O
2The S desired value: 386, discovery value: 387 (M+H)
+.
Then, reduce according to embodiment 89 steps 3 pair above-mentioned trinitride, thus the amine that obtains expecting (N3).
1H NMR (300MHz, CDCl
3) δ: 7.95 (2H, d, J=7.5Hz), 7.57 (1H, s), 7.45-7.35 (3H, m), 4.95 (1H, t, J=7.3Hz), 3.95 (4H, s), 1.89-1.78 (2H, m), 1.65-1.55 (4H, m), 1.45-1.25 (6H, m), 0.90-0.80 (3H, m) .MS (ES) C
20H
28N
2O
2The S desired value: 360, discovery value: 361 (M+H)
+.
Step 4:2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-[7-oxo-1-(the 2-phenyl-
1,3-thiazoles-5-yl) nonyl] ethanamide (N4)
This compound is prepared according to embodiment 89 steps 4 by amine (N3).
1H NMR (300MHz, (CD
3) SO) δ: 10.65 (1H, s), 8.60-8.40 (1H, d, J=5Hz), 7.92-7.82 (2H, m) 7.66 (1H, s), 7.55-7.44 (3H, m), 7.10 (1H, d, J=8.6Hz), 7.05 (1H, s), 6.60 (1H, d, J=8.6Hz), 5.17 (1H, app.q, J=6.0Hz), 3.76 (3H, s), and 3.56-3.50 (2H, br.s), 2.45-2.30 (7H, m), 1.90-1.20 (8H, m), 0.93 (3H, t, J=7.3Hz) .MS (ES) C
30H
35N
3O
3The S desired value: 517, discovery value: 518.
Embodiment 140
2-((1S)-1-{[(1-methyl piperidine-4-yl) carbonyl] amino }-7-oxo nonyl)-the 4-phenyl pyrazoline
Pyridine two (trifluoroacetate) (O4)
Step 1:N-[(1E)-6-(2-ethyl-1,3-dioxolane-2-yl) hexylidene]-the 2-methylpropane
-2-sulfinyl amine (O1)
At room temperature, with the DCM solution stirring of 6-(2-ethyl-1,3-dioxolane-2-yl) hexanal (M3) (1.1 equivalent), (R)-(+)-uncle's butane sulfinyl amine (1.0 equivalent) and anhydrous cupric sulfate (2.2 equivalent) 70 hours.Make the reaction mixture filtration over celite.Under reduced pressure solvent is removed.Use the hexane/ethyl acetate mixture as elutriant, by flash chromatography the thick product of gained is carried out purifying, thereby obtain expected product into oil.
1H NMR (300MHz, CDCl
3) δ: 8.05 (1H, t, J=4.6Hz), 3.91 (4H, s), 2.60-2.40 (2H, m), 1.70-1.50 (6H, m), 1.47-1.28 (4H, m), 1.18 (9H, s), 0.88 (3H, t, J=7.5Hz).
13C NMR (75MHz, CDCl
3) δ: 169.6,111.9,65.0,56.5,36.5,36.0,29.8,29.5,25.5,23.5,22.3,8.1.MS (ES) C
15H
29NO
3The S desired value: 303, discovery value: 304 (M+H)
+.
Step 2:N-[(1S)-6-(2-ethyl-1,3-dioxolane-2-yl)-1-(4-phenylpyridine-2-yl)
Hexyl]-the 2-methylpropane-2-sulfinyl amine (sulfinamide) is (O2)
The THF solution of 2-bromo-4-phenylpyridine (1 equivalent) is cooled to-78 ℃, it is handled by dripping n-BuLi (1.1 equivalent).After 30 minutes, the THF solution of imines (O1) (1.2 equivalent) is added wherein.Under-78 ℃, above-mentioned reaction mixture was stirred 2 hours, make it slowly be warming up to room temperature then.Use H
2O will react quencher, and the gained water extracts with EtOAc.The organic phase that is combined is carried out drying (MgSO
4) and under reduced pressure solvent is removed.The thick amine of gained need not be further purified and can use; Two kinds of diastereomers of LC-MS analysis revealed 4.3: 1.MS (ES) C
26H
38N
2O
3S, desired value: 459, discovery value: 460 (M+H)
+
Step 3:(1S)-7-oxo-1-(4-phenylpyridine-2-yl) nonane-1-ammonium trifluoroacetate
(O3)
Disubstituted pyridines (O2) (1 equivalent) is dissolved in the methanol solution of 1.25N HCl, and at room temperature it was stirred 30 minutes.To react quencher with 1N NaOH solution, the gained water extracts with EtOAc.Organic phase is carried out drying (MgSO
4), and under reduced pressure solvent is removed.The thick amine of gained does not need to be further purified and can use.Get an aliquot and carry out purifying, show by RP-HPLC:
1H NMR (300MHz, d6-DMSO) δ: 8.68 (1H, d, J=5.1Hz), 8.41 (3H, br.s), 7.87-7.74 (5H, m), 7.57-7.49 (2H, m), 4.43 (1H, m), 2.39-2.31 (4H, m), 1.95-1.80 (2H, m), and 1.45-1.13 (6H, m), 0.86 (3H, t, J=4.6Hz) .MS (ES) C
20H
26N
2The O desired value: 310, discovery value: 311 (M+H)
+.
Step 4:2-((1S)-1-{[(1-methyl piperidine-4-yl) carbonyl] amino }-7-oxo nonyl)-4-
Phenylpyridine two (trifluoroacetate) (O4)
The DMF solution that in the DMF solution of amine (O3) (1 equivalent) and DIPEA (2.2 equivalent), adds EDCHCl (1.3 equivalent), HOBt (1.3 equivalent) and 1-methyl piperidine-4-carboxylic acid (1.2 equivalent).At room temperature said mixture was stirred 3 hours, use H then
2O (+0.1%TFA) and MeCN (+0.1%TFA) as elutriant (post: C18), by the preparation RP-HPLC to the expectation product separate.Desired components is carried out lyophilize, thereby obtain imidazoles into water white oil.
1H NMR (300MHz, CDCl
3) δ: 9.22 (1H, bs), 8.65 (1H, s), 8.05 (1H, s), and 7.93-7.71 (4H, m), 7.66-7.53 (3H, m), 5.17 (1H, m), 3.60 (1H, m), 3.44-3.13 (1H, m), and 2.85-2.63 (5H, m), 2.60-2.46 (1H, m), 2.43-2.33 (4H, m), 2.24-1.82 (6H, m), 1.61-1.25 (6H, m), 1.03 (3H, t, J=7.3Hz) .MS (ES) C
27H
37N
3O
2Desired value: 436, discovery value: 437 (M+H)
+.
Embodiment 141
(7S)-and 7-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-[5-(2-naphthalene
Base)-1,3,4-oxadiazole-2-yl] enanthic acid (P4)
Step 1:N '-(2S)-8-tert.-butoxy-2-[(tertbutyloxycarbonyl) amino]-8-oxo octyl group-2-
Naphthoyl hydrazine (P1)
At room temperature, with EDCHCl (1.5 equivalent), HOBt (1.5 equivalent) and (2S)-and 8-tert.-butoxy-2-[(tertbutyloxycarbonyl) amino]-sad (I3 of 8-oxo, DMF (0.1M) the solution pre-mixing of embodiment 107 step 3) (1 equivalent) 1 hour adds 2-naphthoyl hydrazine wherein then.At room temperature said mixture was stirred 16 hours, under reduced pressure it is concentrated into drying then.The gained resistates is dissolved among the DCM, washs with 1M HCl solution and salt solution.Above-mentioned solution is carried out drying (Na
2SO
4), under reduced pressure concentrate and on silica gel, the gained brown oil carried out purifying by chromatography, with 30%EtOAc/ sherwood oil wash-out, thereby obtain hydrazides into white solid.
1H NMR (400MHz, CDCl
3, 300K)
(9.36 1H, broad s), 9.12 (1H, broad s), 8.36 (1H, s), and 7.90-7.80 (4H, m), 7.61-7.49 (2H, m), 5.15 (1H, d, J=8Hz), 4.38-4.24 (1H, m), 2.20 (2H, t, J=7Hz), 1.98-1.85 (1H, m), 1.76-1.64 (1H, m), 1.64-1.52 (2H, m), 1.50-1.30 (22H, m) .MS (ES) C
28H
39N
3O
6Desired value: 513, discovery value: 514 (M+H
+).
Step 2:(7S)-and the 7-[(tertbutyloxycarbonyl) amino]-7-[5-(2-naphthyl)-1,3,4-oxadiazole-2-
Base] the enanthic acid tert-butyl ester (P2)
Desired compounds is prepared as described in embodiment 136 steps 3 by hydrazides (P1), is yellow solid.
1H NMR (500MHz, d6-DMSO, 325K)
8.57 (1H, s), 8.19-8.11 (2H, m), 8.09-8.00 (2H, m), 7.72-7.60 (2H, m), 7.58 (1H, broad s), 4.92-4.80 (1H, m), 2.18 (2H, t, J=7Hz), 2.00-1.80 (2H, m), 1.55-1.25 (24H, m) .MS (ES) C
28H
37N
3O
5Desired value: 495, discovery value: 496 (M+H
+).
Step 3:(1S)-and 6-carboxyl-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl] oneself-1-ammonium trifluoro
Acetate (P3)
The expectation compound is prepared as described in embodiment 136 steps 4 by carbamate (P2), but does not need base conditioning, is yellow solid.
1H NMR (300MHz, d6-DMSO, 300K)
(12.0 1H, broad s), 8.84 (3H, broad s), 8.65 (1H, s), 8.25-8.00 (4H, m), and 7.76-7.62 (2H, m), 4.94-4.84 (1H, m), 2.21 (2H, t, J=7Hz), 2.15-1.95 (2H, m), 1.60-1.25 (6H, m) .MS (ES) C
19H
21N
3O
3Desired value: 339, discovery value: 340 (M+H
+).
Step 4:(7S)-and 7-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-
[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl] enanthic acid (P4)
Title compound (P4) obtains preparation by amine (P3) as described in embodiment 136 steps 5, be white powder.
1H NMR (300MHz, d6-DMSO, 300K) δ 11.95 (1H, broad s), 10.59 (1H, broads), 8.71 (1H, d, J=8Hz), 8.46 (1H, s), 8.14-7.90 (4H, m), and 7.72-7.62 (2H, m), 7.10 (1H, d, J=8Hz), 7.04 (1H, d, J=2Hz), 6.58 (1H, dd, J=8Hz, J=2Hz), and 5.22-5.10 (1H, m), 3.64 (3H, s), 3.52 (2H, s), 2.33 (3H, s), 2.17 (2H, t, J=7Hz), 2.05-1.85 (2H, m), 1.50-1.20 (6H, m) .MS (ES) C
31H
32N
4O
5Desired value: 540, discovery value: 541 (M+H
+).
Embodiment 142
(7S)-and 7-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-[5-(2-naphthalene
Base)-1,3,4-oxadiazole-2-yl] heptamide (Q1)
(7S)-and 7-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl] enanthic acid is as acquisition as described in embodiment 141 steps 4.In case coupling is finished, in reaction mixture, add HATU (1.3 equivalent) and after 30 minutes, with NH
31,4-dioxane (10 equivalent) solution adds wherein.The said mixture stirring is spent the night, use H then
2O (+0.1%TFA) and MeCN (+0.1%TFA) as elutriant (post: C18), by the preparation RP-HPLC directly the gained crude product is carried out purifying.Desired components is carried out lyophilize, thereby obtain Q1 into white powder.
1H NMR (300MHz, d6-DMSO, 300K) δ 10.59 (1H, broads), 8.71 (1H, d, J=8Hz), 8.46 (1H, s), 8.15-7.90 (4H, m), and 7.72-7.60 (2H, m), 7.18 (1H, broad s), 7.09 (1H, d, J=8Hz), 7.03 (1H, d, J=2Hz), 6.65 (1H, broad s), 6.58 (1H, dd, J=8Hz, J=2Hz), and 5.20-5.10 (1H, m), 3.64 (3H, s), 3.52 (2H, s), 2.33 (3H, s), 2.00 (2H, t, J=7Hz), 2.10-1.85 (2H, m), 1.50-1.20 (6H, m) .MS (ES) C
31H
33N
5O
4Desired value: 539, discovery value: 540 (M+H
+).
Embodiment 143
(7S)-and 7-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-[5-(2-naphthalene
Base)-1,2,4-triazole-3-yl] enanthic acid (R4)
Step 1:(2S)-and 8-tert.-butoxy-2-[(tertbutyloxycarbonyl) amino]-8-oxo decoyl hydrazine (R
1
)
Hydrazides (R
1) by (2S)-2-[(tertbutyloxycarbonyl) amino] sad 8-tertiary butyl 1-methyl diester (I2, embodiment 107 steps 2) prepares as described in embodiment 88 steps 2, is light yellow oil.MS (ES) C
17H
33N
3O
5, desired value: 359, discovery value: 360 (M+H)
+
Step 2:(7S)-and the 7-[(tertbutyloxycarbonyl) amino]-7-[5-(2-naphthyl)-4H-1,2,4-triazole-3-
Base] the enanthic acid tert-butyl ester (R2)
The triazole of expectation is by hydrazides (R
1) and the 2-naphthyl cyanide as described in embodiment 88 steps 3, be prepared, obtain light yellow oil.
1H NMR (300MHz, d6-DMSO, 340K)
15.5 (1H, broads), 8.82 (1H, s), 8.82 (1H, d, J=8Hz), 8.05-7.84 (4H, m), and 7.58-7.48 (2H, m), 5.55-5.40 (1H, m), 2.50-2.32 (1H, m), 2.28 (2H, t, J=7Hz), 2.32-2.12 (1H, m), 1.80-1.30 (24H, m) .MS (ES) C
28H
38N
4O
4Desired value: 494, discovery value: 495 (M+H)
+.
Step 3:(1S)-and 6-carboxyl-1-[5-(2-naphthyl)-4H-1,2,4-triazole-3-yl] oneself-1-ammonium three
Fluoroacetate (R3)
This expectation compound is prepared as described in embodiment 136 steps 4 by carbamate (R2), but does not need base conditioning, is brown oil.
1H NMR (300MHz, d6-DMSO, 300K)
(14.78 1H, broad s), 11.98 (1H, broad s), 8.58 (1H, s), 8.48 (3H, broad s), 8.18-7.95 (4H, m), 7.68-7.55 (2H, m), 4.55-4.40 (1H, m), 2.20 (2H, t, J=7Hz), 2.06-1.86 (2H, m), 1.60-1.20 (6H, m) .MS (ES) C
19H
22N
4O
2Desired value: 338, discovery value: 339 (M+H
+).
Step 4:(7S)-and 7-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-
[5-(2-naphthyl)-4H-1,2,4-triazole-3-yl] enanthic acid (R4)
Title compound (R4) obtains preparation by amine (R3) as described in embodiment 88 steps 5, be white powder.
1H NMR (300MHz, d6-DMSO, 300K) δ 10.57 (1H, broad s), 8.52 (1H, s), 8.39 (1H, d, J=8Hz), 8.15-7.90 (4H, m), 7.62-7.52 (2H, m), 7.09 (1H, d, J=9Hz), 7.03 (1H, d, J=2Hz), 6.59 (1H, dd, J=9Hz, J=2Hz), 5.07-4.95 (1H, m), 3.67 (3H, s), 3.60-3.40 (2H, m), 2.32 (3H, s), 2.14 (2H, t, J=7Hz), 1.97-1.77 (2H, m), 1.50-1.20 (6H, m) .MS (ES) C
31H
33N
5O
4Requires:539, discovery value: 540 (M+H
+).
Embodiment 144
(7S)-and 7-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-[5-(2-naphthalene
Base)-and 4H-1,2,4-triazole-3-yl] heptamide (S1)
Title compound (S1) obtains preparation by amine (R3) as described in embodiment 142 steps 1, be white powder.
1H NMR (300MHz, d6-DMSO, 300K) δ 10.57 (1H, broad s), 8.52 (1H, s), 8.39 (1H, d, J=8Hz), 8.14-7.91 (4H, m), and 7.61-7.53 (2H, m), 7.17 (1H, broad s), 7.09 (1H, d, J=8Hz), 7.02 (1H, d, J=2Hz), 6.65 (1H, broad s), 6.59 (1H, dd, J=8Hz, J=2Hz), and 5.07-4.95 (1H, m), 3.67 (3H, s), and 3.60-3.40 (2H, m), 2.32 (3H, s), 1.98 (2H, t, J=7Hz), 1.94-1.78 (2H, m), 1.50-1.20 (6H, m) .MS (ES) C
31H
34N
6O
3Desired value: 538, discovery value: 539 (M+H
+).
Embodiment 145
2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-{ (1S)-1-[5-(2-naphthyl)-1,2,4-Evil
Diazole-3-yl]-7-oxo nonyl } ethanamide (T7)
Step 1:[(1S)-and 1-(aminocarboxyl)-7-oxo nonyl] t-butyl carbamate (T1)
To (2S)-2-[(tertbutyloxycarbonyl) amino]-add Py (1 equivalent), Boc in the dioxane solution of 8-oxo capric acid
2O (1.3 equivalent) and bicarbonate of ammonia (1.26 equivalent).At room temperature above-mentioned reaction mixture was stirred 72 hours, then under reduced pressure with solvent evaporation.The thick product of gained dilutes with EtOAc, and uses H
2O, HCl (1N) and salt solution wash.Organic phase is carried out drying (Na
2SO
4) and under reduced pressure it is concentrated, thereby obtaining white powder, it can be used for next step like this.MS (ES) C
15H
28N
2O
4, desired value: 300, discovery value: 301 (M+H+).
Step 2:[(1S)-and 1-cyano group-7-oxo nonyl] t-butyl carbamate (T2)
To 0 ℃ acid amides (A1) (1 equivalent) and Et
3Drip in the DCM solution of N (2.2 equivalent) and add TFAA (2 equivalent).Above-mentioned reaction mixture was at room temperature stirred 1 hour, use saturated NaHCO then
3The aqueous solution, H
2O and salt solution wash it.Organic phase is carried out drying (Na
2SO
4) and under reduced pressure it is concentrated, obtain the yellow oil compound thus, be used for next step like this.MS (ES) C
15H
26N
2O
3, desired value: 282, discovery value: 305 (M+Na
+).
Step 3:[(1S)-and 1-cyano group-7-hydroxyl nonyl] t-butyl carbamate (T3)
The MeOH solution of nitrile (T2) (1 equivalent) is cooled to 0 ℃, and with NaBH
4(4 equivalent) portioning adds wherein.Under 0 ℃, above-mentioned reaction mixture was further stirred 15 minutes, at room temperature stirred then 1 hour.Water will react quencher then, methyl alcohol be steamed gained resistates Et
2O (3 *) extracts.Collect organic phase, with the salt water washing, carry out drying (Na
2SO
4) and under reduced pressure evaporate.Thus obtained thick product is directly used in the next step like this.MS (ES) C
15H
28N
2O
3, desired value: 284, discovery value: 307 (M+Na
+).
Step 4:{ (1S)-7-hydroxyl-1-[(hydroxylamino) (imino-) methyl] nonyl } the carboxylamine uncle
Butyl ester (T4)
With NH
2The MeOH solution of OH.HCl (1.5 equivalent) joins in the MeOH solution of KOH (1.5 equivalent).Said mixture was stirred 20 minutes, then solid is leached, and gained solution is joined in the nitrile (T3) (1 equivalent).Then above-mentioned gained mixture heating up is refluxed, under reduced pressure solvent is removed after 16 hours, the thick product of gained is used for next step like this.MS (ES) C
15H
31N
3O
4, desired value: 317, discovery value: 318 (M+H+).
Step 5:{ (1S)-7-hydroxyl-1-[5-(2-naphthyl)-1,2,4-oxadiazole-3-yl] nonyl } amino
T-butyl formate (T5)
At room temperature, the DMF mixture with 2-naphthoic acid (0.9 equivalent), TBTU (1 equivalent), HOBt (0.2 equivalent) and DIPEA (5 equivalent) stirred 5 minutes; Then to wherein adding aldoxime (T4) and at room temperature the gained mixture being stirred hour.Then, said mixture is warming up to 110 ℃ 4 hours.Under reduced pressure solvent is removed, the thick product of gained is used for next step like this.MS (ES) C
26H
35N
3O
4, desired value: 453, discovery value: 454 (M+H+).
Step 6:{ (1S)-1-[5-(2-naphthyl)-1,2,4-oxadiazole-3-yl]-7-oxo nonyl }-amino
T-butyl formate (T6)
In the DCM solution of oxadiazole (1 equivalent), add Dess-Martin and cross iodine alkane (1.1 equivalent).At room temperature said mixture was stirred 2 hours, then with saturated NaHCO
3The aqueous solution (contains Na
2S
2O
3(6 equivalent)) add wherein and the gained mixture was stirred 15 minutes.To respectively be separated, the gained water extracts with DCM.The organic phase that is combined is carried out drying (Na
2SO
4) and under reduced pressure it is concentrated.Thus obtained product does not need to be further purified promptly to can be used in the next step.MS (ES) C
26H
33N
3O
4, desired value: 451, discovery value: 452 (M+H+).
Step 7:2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-{ (1S)-1-[5-(2-naphthyl)-
1,2,4-oxadiazole-3-yl]-7-oxo nonyl } ethanamide (T7)
Ketone (T6) (1 equivalent) is dissolved in DCM and TFA (1: the 1) mixture, and at room temperature it is stirred.After 20 minutes, under reduced pressure solvent is removed, and the gained resistates is distributed in saturated NaHCO
3Between the aqueous solution and the DCM.Drying (Na is separated, carried out to organic phase
2SO
4) and under reduced pressure it is concentrated.
The DCM solution (pre-mixing 3 minutes) that adds (5-methoxyl group-2-Methyl-1H-indole-3-yl) acetate (1.05 equivalent), HOBt (1.05 equivalent) and EDC.HCl (1.05 equivalent) in above-mentioned gained resistates is subsequently to wherein adding DIPEA (1.05 equivalent).At room temperature said mixture was stirred 4 hours.Use H
2(post: C18), RP-HPLC separates products obtained therefrom by preparation, desired components is carried out lyophilize, thereby obtain the finished product into the fluffy compound of white as elutriant for O (0.1%TFA) and MeCN (0.1%TFA).
1H NMR (300MHz, d6-DMSO) δ: 10.57 (1H, s), 8.75 (1H, s), 8.60 (1H, d, J=8.2Hz), 8.18-7.18 (4H, m), 7.65-7.49 (2H, m), and 7.16-6.98 (2H, m), 6.63-6.54 (1H, m), 5.11-4.98 (1H, m), 3.68 (3H, s), 3.58-3.42 (2H, m), and 2.42-2.22 (7H, m), 1.97-1.75 (2H, m), 1.50-1.12 (6H, m), 0.89 (3H, t, J=7.2Hz) .MS (ES) C
33H
36N
4O
4Desired value: 552, discovery value: 553 (M+H
+).
Embodiment 146
2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-{ (1S)-1-[3-(2-naphthyl)-1,2,4-Evil
Diazole-5-yl]-7-oxo nonyl } ethanamide (U2)
Step 1:{ (1S)-1-[3-(2-naphthyl)-1,2,4-oxadiazole-5-yl]-7-oxo nonyl }-amino
T-butyl formate (U1)
At room temperature with (2S)-2-[(tertbutyloxycarbonyl) amino]-the DMF mixture of 8-oxo capric acid (1 equivalent), TBTU (1.2 equivalent), HOBt (0.2 equivalent) and DIPEA (5 equivalent) stirred 5 minutes; Then to wherein adding N-hydroxyl naphthalene-2-imines acid amides (carboximidamide), and at room temperature the gained mixture was stirred 20 minutes, wait at this moment with mixture be warming up to 110 ℃ 2 hours.Under reduced pressure solvent is removed, the thick product of gained is used for next step like this.MS (ES) C
26H
33N
3O
4, desired value: 451, discovery value: 452 (M+H+).
Step 2:2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-{ (1S)-1-[3-(2-naphthyl)-
1,2,4-oxadiazole-5-yl]-7-oxo nonyl } ethanamide (U2)
As described in embodiment 145 steps 7, oxadiazole is converted into title compound by deprotection and coupling.
1H NMR (400MHz, d6-DMSO) δ: 10.60 (1H, s), 8.80 (1H, d, J=7.8Hz), 8.58 (1H, s), and 8.16-7.98 (4H, m), 7.68-7.60 (2H, m), 7.10 (1H, d, J=8.6Hz), 7.05 (1H, d, J=2.5Hz), 6.60 (1H, dd, J
1=8.6Hz, J
2=2.5Hz), 5.18-5.10 (1H, m), 3.71 (3H, s), 3.58-3.47 (2H, m), 2.41-2.30 (7H, m), 2.02-1.86 (2H, m), 1.46-1.17 (6H, m), 0.90 (3H, t, J=7.3Hz) .MS (ES) C
33H
36N
4O
4Desired value: 552, discovery value: 553 (M+H
+).
Embodiment 147
2-{ (1S)-1-[(methoxycarbonyl) amino]-7-oxo nonyl }-5-(2-naphthyl)-1H-imidazoles-1-
Trifluoroacetate (V3)
Step 1:[(1S)-and 7-oxo-1-(5-(2-naphthyl)-1H-imidazoles-2-yl) nonyl] carboxylamine
The tert-butyl ester (V1)
According to embodiment 1 step 2 for [(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-2-yl) octyl group] the described method of t-butyl carbamate, the title product is by (2S)-2-[(tertbutyloxycarbonyl) amino]-8-oxo capric acid and 2-bromo-1-(2-naphthyl) ethyl ketone prepare, and is light yellow solid.
1H NMR (300MHz, d6-DMSO) δ: 12.30-11.70 (1H, m), 8.30-8.07 (1H, m), and 7.95-7.72 (4H, m), 7.62 (1H, s), and 7.50-7.31 (2H, m), 7.12-6.90 (1H, m), and 4.70-4.50 (1H, m), 2.245-2.30 (4H, m), and 1.92-1.65 (2H, m), 1.55-1.15 (15H, m), 0.89 (3H, t, J=7.1Hz) .MS (ES) C
27H
35N
3O
3Desired value: 449, discovery value: 450 (M+H)
+.
Step 2:(9S)-9-amino-9-[5-(2-naphthyl)-1H-imidazoles-2-yl] ninth of the ten Heavenly Stems-3-ketone (V2)
Under 0 ℃, carbamate (V1) (1 equivalent) is dissolved among the TFA/DCM (1: 1).Cooling bath is removed and at room temperature the gained mixture was stirred 60 minutes.Under reduced pressure solvent is removed, and the gained irreducible oil is distributed in DCM and saturated NaHCO
3Between the aqueous solution.The gained organic phase is carried out drying (Na
2SO
4) and under reduced pressure it is concentrated into drying.Thus obtained thick product does not need to be further purified promptly to can be used in the next step.MS (ES) C
22H
27N
3O, desired value: 349, discovery value: 350 (M+H)
+
Step 3:2-{ (1S)-1-[(methoxycarbonyl) amino]-7-oxo nonyl }-5-(2-naphthyl)-1H-
Imidazoles-1-trifluoroacetate (V3)
To amine (V2) and Et
3Add chlorocarbonic acid methyl esters (2.2 equivalent) in the DCM solution of N (2.2 equivalent).At room temperature above-mentioned reaction mixture is stirred, till raw material all consumes.Use H
2O (+0.1%TFA) and MeCN (+0.1%TFA) as elutriant (post: C18), by the preparation RP-HPLC the said products is separated.Desired components is carried out lyophilize, thereby obtain title compound into water white oil.
1HNMR (400MHz, CD
3CN) δ: 8.37 (1H, s), 8.03 (1H, d, J=8.7Hz), 8.00-7.95 (2H, m), 7.81 (1H, dd, J
1=8.7Hz, J
2=1.8Hz), 7.72-7.65 (2H, m), 7.64-7.58 (2H, m), 5.14-5.05 (1H, m), 3.66 (3H, s), 2.46-2.38 (4H, m), 2.07-1.99 (2H, m), 1.59-1.28 (6H, m), 0.98 (3H, t, J=7.2Hz) .MS (ES) C
24H
29N
3O
3Desired value: 407, discovery value: 408 (M+H
+).
Embodiment 148
2-((1S)-1-{[(dimethylamino) carbonyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-
Imidazoles-1-trifluoroacetate (W1)
To amine (V2) and Et
3Add dimethylcarbamyl chloride (2.2 equivalent) in the DCM solution of N (2.2 equivalent).At room temperature above-mentioned reaction mixture is stirred, till raw material all consumes.Use H
2O (+0.1%TFA) and MeCN (+0.1%TFA) as elutriant (post: C18), by the preparation RP-HPLC the said products is separated.Desired components is carried out lyophilize, thereby obtain title compound into water white oil.
1HNMR (300MHz, CD
3CN) δ: 7.80-7.65 (5H, m), 7.56-7.44 (2H, m), 7.42-7.35 (2H, m), 7.33 (1H, s), 5.37-5.24 (1H, m), 3.01 (6H, s), 2.46-2.32 (4H, m), 2.24-2.01 (2H, m), 1.61-1.24 (6H, m), 0.97 (3H, t, J=7.4Hz) .MS (ES) C
25H
32N
4O
2Desired value: 407, discovery value: 421 (M+H
+).
Embodiment 149
3-nitro-N-[7-oxo-1-(4-phenyl-2-furyl) octyl group] benzsulfamide (X5)
Step 1:1-(4-phenyl-2-furyl) suffering-7-alkene-1-alcohol (X1)
Under Ar, in the anhydrous THF mixture of the Mg (2.5 equivalent) that stirs, add I
2(＞5mol%), and with the said mixture reflux, until solution become colourless till.Then, 7-bromine heptan-1-alkene (2.2 equivalent) dripped add wherein, and after adding fully, the gained mixture heating up was refluxed 2.5 hours.The gained Grignard reagent is used for next step immediately.
Under 0 ℃ and Ar, the gained Grignard reagent is joined in the THF solution of 4-phenyl-2 furan carboxyaldehyde (1 equivalent), and the gained mixture was stirred 30 minutes.By the saturated NH of slow adding
4The Cl aqueous solution extracts with EtOAc above-mentioned reaction quencher then to the product of expectation.The gained organic layer with the salt water washing, carry out drying (Na
2SO
4) and under reduced pressure concentrate.Use the 5%EtOAc/ sherwood oil to carry out wash-out, the thick product of gained is carried out purifying by column chromatography, thus the alcohol that obtains expecting.
1H NMR (300MHz, CD
3Cl3) δ: 7.65 (2H, d, J=7.3Hz), 7.42 (2H, t, J=7.2Hz), and 7.25-7.15 (1H, m), 6.60 (1H, d, J=5.3Hz), 6.30 (1H, d, J=5.3Hz), 5.87-5.75 (1H, m), 5.05-4.89 (2H, m), 4.75-4.65 (1H, m), 2.15-2.05 (2H, m), 1.87-1.75 (2H, m), 1.45-1.35 (6H, m) .MS (ES) C
18H
22O
2Desired value: 270 discovery values: 271 (M+H)
+.
Step 2:1-(4-phenyl-2-furyl) suffering-7-alkene-1-base trinitride (X2)
Alcohol (X1) (1 equivalent) is dissolved in the toluene, thereby obtains 0.5M solution, then DPPA (1.2 equivalent) and DBU (1.2 equivalent) are added wherein, and when stirring under 50 ℃ with the said mixture heated overnight.Be cooled to after the room temperature, EtOAc added wherein gained mixture H
2The 5%HCl solution washing is used in the O washing then.The gained organic layer with the salt water washing, carry out drying (Na
2SO
4) and under reduced pressure concentrate.Use the 10%EtOAc/ sherwood oil to carry out wash-out, by column chromatography the gained resistates is carried out purifying, thereby obtain trinitride.
1H NMR (300MHz, CD
3Cl3) δ: 7.65 (2H, d, J=7.3Hz), 7.42 (2H, t, J=7.2Hz), and 7.25-7.15 (1H, m), 6.60 (1H, d, J=5.3Hz), 6.30 (1H, d, J=5.3Hz), 5.87-5.75 (1H, m), 5.05-4.89 (2H, m), 4.45-4.35 (1H, m), 2.15-2.05 (2H, m), 1.87-1.75 (2H, m), 1.45-1.35 (6H, m) .MS (ES) C
18H
21N
3O desired value: 295 discovery values: 296 (M+H)
+.
Step 3:[1-(4-phenyl-2-furyl) suffering-7-alkene-1-yl] amine (X3)
Under Ar, (X2) is dissolved among the THF with trinitride, with PPh
3(1.2 equivalent) adds wherein, and at room temperature above-mentioned solution stirring spent the night.Water added wherein and with gained mixture restir 24 hours, under reduced pressure gained solution is concentrated then, the thick product of gained is carried out purifying, at first use methanol wash by the SCX cylinder, with the amine of methanol ammonia eluant solution expectation, under reduced pressure desired components is concentrated then.
1H NMR (300MHz, CD
3Cl3) δ: 7.65 (2H, d, J=7.3Hz), 7.42 (2H, t, J=7.2Hz), and 7.25-7.15 (1H, m), 6.60 (1H, d, J=5.3Hz), 6.30 (1H, d, J=5.3Hz), 5.87-5.75 (1H, m), 5.05-4.89 (2H, m), 3.95-3.85 (1H, m), 2.15-2.05 (2H, m), 1.87-1.75 (2H, m), 1.45-1.35 (6H, m) .MS (ES) C
18H
23NO desired value: 269 discovery values: 270 (M+H)
+.
Step 4:3-nitro-N-[1-(4-phenyl-2-furyl) suffering-7-alkene-1-yl] benzsulfamide
(X4)
Add 3-nitrobenzene sulfonyl chloride (1.2 equivalent) in the DCM solution with the amine (X3) (1 equivalent) that stirs, and at room temperature said mixture was stirred 2 hours.The gained reaction mixture in proper order with 0.25M HCl solution, 0.25M NaOH solution and salt water washing, carry out drying (Na
2SO
4) and under reduced pressure it is concentrated.Use the 50%EtOAc/ sherwood oil to carry out wash-out, by column chromatography the gained mixture is carried out purifying, thereby obtain sulphonamide.
1H NMR (300MHz, d6-DMSO) δ: 8.70 (1H, d, J=7.3Hz), 8.40 (1H, s) 8.15-8.05 (2H, m), 7.60 (1H, t, J=7.2Hz), 7.45-7.25 (4H, m), 6.60 (1H, d, J=5.3Hz), 6.30 (1H, d, J=5.3Hz), and 5.87-5.75 (1H, br, m), 5.05-4.89 (2H, t, J=8.3Hz), 4.45-4.35 (1H, m), 2.15-2.05 (2H, m), and 1.87-1.75 (2H, m), 1.45-1.35 (6H, m) .MS (ES) C
24H
26N
2O
5S desired value: 454 discovery values: 455 (M+H)
+.
Step 5:3-nitro-N-[7-oxo-1-(4-phenyl-2-furyl) octyl group] benzsulfamide
(X5)
To the DMF-H that stirs
2Add CuCl (1 equivalent) and PdCl in O (5: the 1) mixture
2(0.1 equivalent) is at O
2Under the atmosphere gained mixture was stirred 1 hour, then sulphonamide (X3) (1 equivalent) is added wherein.At room temperature, at O
2In the atmosphere final solution was stirred 18 hours.Then, under reduced pressure above-mentioned solution is concentrated, and the gained resistates is absorbed among the DCM, uses saturated NH
4The Cl aqueous solution and salt solution wash.The gained organism is carried out drying (Na
2SO
4), and under reduced pressure it is concentrated.Use H
2O (+0.1%TFA) and MeCN (+0.1%TFA) as elutriant (post: C18), by the preparation RP-HPLC gained mixture is carried out purifying.Desired components is carried out lyophilize, thereby obtain title compound.
1H NMR (300MHz, 6-DMSO) δ: 8.70 (1H, d, J=7.3Hz), 8.40 (1H, s) 8.15-8.05 (2H, m), 7.65-7.55 (1H, t, J=7.2Hz), 7.45-7.25 (4H, m), 6.60 (1H, d, J=5.3Hz), 6.30 (1H, d, J=5.3Hz), 4.45-4.35 (1H, m), 2.40 (2H, t, J=7.2Hz), 2.15-2.05 (3H, s), 1.87-1.75 (2H, m), 1.45-1.45 (6H, m) .MS (ES) C
24H
26N
2O
6S desired value: 470 discovery values: 471 (M+H)
+.
Embodiment 150
2-(1S)-7-[(ethylsulfonyl) amino]-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) second
Acyl group] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate (Y1)
To (7S)-7-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-[5-(2-naphthyl)-1H-imidazoles-2-yl] add EDCI (1.5 equivalent), DMAP (1.5 equivalent) in DCM (0.2M solution) solution of enanthic acid (free alkali of embodiment 107) (1 equivalent); after at room temperature stirring one hour, ethyl sulfonamide (1.5 equivalent) is added wherein.The said mixture stirring is spent the night, under reduced pressure solvent is removed then, use H
2O (0.1%TFA) and MeCN (+0.1%TFA) (post: C18), RP-HPLC carries out purifying to the gained crude product by preparation as elutriant.Desired components is carried out lyophilize, thereby obtain title compound into white powder.
1H NMR (400MHz, DMSO) δ: 14.44 (1H, br.s), 11.51 (1H, s), 10.62 (1H, s), 8.60 (1H, d, J=6.6Hz), 8.32 (1H, s), 8.16 (1H, s), 8.06 (1H, d, J=8.7Hz), 8.00-7.92 (2H, m), 7.88 (1H, d, J=8.7Hz) 7.66-7.54 (2H, m), 7.09 (1H, d, J=8.7Hz), 6.96 (1H, s), 6.59 (1H, d, J=8.7Hz), 5.08-5.00 (1H, m), 3.67 (3H, s), 3.54 (2H, app.quart.), 3.33 (2H, q, J=7.4Hz), 2.31 (3H, s), 2.24 (2H, t, J=7.5Hz), and 2.03-1.83 (2H, m), 1.53-1.12 (6H, m), 1.18 (3H, t, J=7.4Hz) .MS (ES) C
34H
39N
5O
5The S desired value: 629, discovery value: 630 (M+H)
+.
Embodiment 151
5-(2-naphthyl)-2-((1S)-8,8,8-three fluoro-1-{[(5-methoxyl groups-2-Methyl-1H-indole-3-yl)
Ethanoyl] amino }-7-oxo octyl group)-1H-imidazoles-1-trifluoroacetate (Z1)
To (7S)-7-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-[5-(2-naphthyl)-1H-imidazoles-2-yl] add Na in EtOH (0.5M solution) solution of enanthic acid (free alkali of embodiment 107) (1 equivalent)
2CO
3(1 equivalent).At room temperature above-mentioned multiphase mixture was stirred 40 minutes, under reduced pressure solvent is removed then.DCM is added wherein (0.14M solution), the gained mixture is cooled to 0 ℃, then TFAA (6 equivalent) is added wherein, subsequently pyridine (8 equivalent) is added wherein with ice bath.After under uniform temp, keeping 40 minutes, some water addings wherein and with DCM are extracted product.The organic phase of collecting is handled with salt solution and is carried out drying (Na
2SO
4), under reduced pressure, use H except that after desolvating
2O (0.1%TFA) and MeCN (+0.1%TFA) (post: C18), RP-HPLC carries out purifying to the gained crude product by preparation as elutriant.Desired components is carried out lyophilize, thereby obtain title compound, be the mixture of ketone and hydrated form into white powder.
1H NMR (500MHz, pyridine) δ: 11.65-11.55 (0.5H, m), 11.50-11.38 (0.5H, m), and 9.21-9.12 (0.5H, m), 8.71-8.63 (2H, m), and 8.30-8.10 (1.5H, m), 8.00-7.79 (4.5H, m), and 7.56-7.30 (4H, m), 7.09-6.97 (1H, m), and 5.76-5.62 (1H, m), 4.11-3.96 (1.5, m), 3.85-3.71 (2.5H, m) 2.71-2.58 (1H, m), 2.55-2.41 (3.5H, m), and 2.40-2.23 (2H, m), 2.21-2.03 (2H, m), 2.10-1.79 (1.5H, m), 1.70-1.00 (6H, m) .MS (ES) C
33H
33F
3N
4O
3Desired value: 590, discovery value: 609 (M+H
2O+H)
+.
Embodiment 152-298 is prepared according to the reaction scheme and the method that provide among embodiment 1-4,32,33, the 87-89,107,108 and 136～151.
| Embodiment | Title | (M+H) + | Method according to embodiment No |
| 152 | 3-nitro-N-[7-oxo-1-(4-phenyl-1,3-thiazol-2-yl) octyl group] benzsulfamide; | 488 | 149 |
| 153 | 2-((1S)-7-amino-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 538 | 325 |
| 154 | 2-((1S)-7-(dimethylamino)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 566 | 108 |
| 155 | 2-((1S)-7-(sec.-propyl amino)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 580 | 108 |
| 156 | 2-((1S)-7-anilino-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 614 | 108 |
| 157 | 2-((1S)-7-(benzylamino)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 628 | 108 |
| 158 | 2-{ (1S)-1-{[(5-methoxyl group-2-methyl isophthalic acid H-indol-3-yl) ethanoyl] amino }-the 7-[(methyl sulphonyl) amino]-7-oxo heptyl }-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 616 | 108 |
| 159 | 1-methyl-4-[({ (1S)-1-[5-(2-naphthyl)-4H-1,2,4-triazole-3-yl]-7-oxo nonyl } amino) carbonyl] the piperidines trifluoroacetate; | 476 | 88 |
| 160 | (3S)-and 1-methyl-3-[({ (1S)-1-[5-(2-naphthyl)-4H-1,2,4-triazole-3-yl]-7-oxo nonyl } amino) carbonyl] the tetramethyleneimine trifluoroacetate; | 462 | 88 |
| 161 | (3S)-and 1-methyl-3-[({ (1S)-1-[5-(2-naphthyl)-4H-1,2,4-triazole-3-yl]-7-oxo nonyl } amino) carbonyl] the piperidines trifluoroacetate; | 476 | 88 |
| 162 | N-{ (1S)-1-[5-(2-naphthyl)-4H-1,2,4-triazole-3-yl]-7-oxo nonyl }-1,3-thiazoles-5-carboxylic acid amides; | 462 | 88 |
| 163 | 4-cyano group-N-{ (1S)-1-[3-(2-naphthyl)-1H-1,2,4-triazole-5-yl]-7-oxo nonyl } benzsulfamide; | 516 | 88 |
| 164 | 2-((1S)-7-[methoxyl group (methyl) amino]-1-{ [(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 582 | 108 |
| 165 | 1-methyl-4-[({ (1S)-7-(methylamino)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo heptyl } amino) carbonyl] piperidines two (trifluoroacetate); | 476 | 108 |
| 166 | 4-[({ (1S)-7-(hydroxyl amino)-1-[5-(2-naphthyl)-1H-imidazoles-1--2 yl]-7-oxo heptyl } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 478 | 108 |
| 167 | 2-{ (1S)-6-carboxyl-1-[(1,3-thiazole-5-base carbonyl) amino] hexyl }-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 449 | 107 |
| 168 | 4-[({ (1S)-7-[(2-aminophenyl) amino]-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo heptyl } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 553 | 108 |
| 169 | 2-[(1S)-6-carboxyl-1-([(3R)-and 1-methylpyrrolidin-3-yl] carbonyl } amino) hexyl]-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate); | 449 | 107 |
| 170 | 2-[(1S)-6-carboxyl-1-([(3S)-and 1-methylpyrrolidin-3-yl] carbonyl } amino) hexyl]-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate); | 449 | 107 |
| 171 | 2-((1S)-6-carboxyl-1-{[(dimethylamino) alkylsulfonyl] amino } hexyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 445 | 326 |
| 172 | 4-[({ (1S)-7-[methoxyl group (methyl) amino]-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo heptyl } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 506 | 108 |
| 173 | 2-((1S)-1-{[(5-methoxyl group-2-methyl isophthalic acid H-indol-3-yl) ethanoyl] amino }-7-oxo-7-{[(trifluoromethyl) alkylsulfonyl] amino } heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 670 | 150 |
| 174 | 2-((1S)-7-(ethylamino)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 566 | 108 |
| 175 | (3S)-and 3-[({ (1S)-1-[3-(3, the 5-dichlorophenyl)-1H-1,2,4-triazole-5-yl]-7-oxo nonyl } amino) carbonyl]-1-crassitude trifluoroacetate; | 480 | 88 |
| 176 | 4-[({ (1S)-1-[3-(3, the 5-dichlorophenyl)-1H-1,2,4-triazole-5-yl]-7-oxo nonyl } amino) carbonyl]-1-azonia two ring [2.2.2] octane trifluoroacetates; | 506 | 88 |
| 177 | N-{ (1S)-1-[3-(3, the 5-dichlorophenyl)-1H-1,2,4-triazole-5-yl]-7-oxo nonyl }-2-(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanamide; | 570 | 88 |
| 178 | 2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-{ (1S)-1-[3-(3-p-methoxy-phenyl)-1H-1,2,4-triazole-5-yl]-7-oxo nonyl } ethanamide; | 532 | 88 |
| 179 | 2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-[7-oxo-1-(4-phenyl-1,3-thiazoles-2-yl) octyl group] ethanamide; | 504 | 149 |
| 180 | 2-((1S)-1-{[(5-methoxyl group-2-methyl isophthalic acid H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate; | 551 | 1 |
| 181 | 2-{ (1S)-1-[(1H-indol-3-yl ethanoyl) amino]-7-oxo nonyl }-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate; | 507 | 1 |
| 182 | 2-((1S)-1-{[(2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate; | 521 | 1 |
| 183 | 2-((1S)-1-{[(5-methoxyl group-1H-indoles-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate; | 537 | 1 |
| 184 | 2-((1S)-1-{[(5-bromo-IH-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate; | 587 | 1 |
| 185 | 2-((1S)-1-{[(5-fluoro-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate; | 525 | 1 |
| 186 | 1-[2-((1S)-1-[5-(2-naphthyl)-1H-imidazoles-3--2-yl]-7-oxo nonyl } amino)-the 2-oxoethyl]-1H-benzoglyoxaline-3-two (trifluoroacetate); | 508 | 1 |
| 187 | 2-((1S)-1-{[(7-methoxyl group-1-cumarone-2-yl) carbonyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate; | 524 | 1 |
| 188 | 2-((1S)-1-{[(5-methoxyl group-1H-indoles-2-yl) carbonyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate; | 523 | 1 |
| 189 | 2-((1S)-1-{[(5-fluoro-1H-indoles-2-yl) carbonyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate; | 511 | 1 |
| 190 | 6-[2-((1S)-1-[5-(2-naphthyl)-1H-imidazoles-3--2-yl]-7-oxo nonyl } amino)-the 2-oxoethyl] [1,2,4] triazolo [1,5-a] pyrimidine-4-two (trifluoroacetate); | 510 | 1 |
| 191 | 5-(2-naphthyl)-2-((1S)-7-oxo-1-{[(4-phenyl-1,3-thiazoles-2-yl) ethanoyl] amino } nonyl)-1H-imidazoles-3-trifluoroacetate; | 551 | 1 |
| 192 | 2-((1S)-1-{[(5-chloro-1-thionaphthene-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate; | 558 | 1 |
| 193 | 2-((1S)-1-{[(4-chloro-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate; | 541 | 1 |
| 194 | 5-(2-naphthyl)-2-((1S)-7-oxo-1-{[(2-oxo-1,3-benzoxazole-3 (2H)-yl) ethanoyl] amino } nonyl)-1H-imidazoles-3-trifluoroacetate; | 525 | 1 |
| 195 | 2-((1S)-1-{[(5-methoxyl group-2-oxo-2,3-dihydro-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate; | 553 | 1 |
| 196 | 2-((1S)-1-{[(6-methoxyl group-2-oxo-2,3-dihydro-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate; | 553 | 1 |
| 197 | 2-ethyl-1-[3-((1S)-1-[5-(2-naphthyl)-1H-imidazoles-3--2-yl]-7-oxo nonyl } amino)-the 3-oxopropyl]-IH-benzoglyoxaline-3-two (trifluoroacetate); | 550 | 1 |
| 198 | 5-(2-naphthyl)-2-{ (1S)-1-[(1-naphthyl ethanoyl) amino]-7-oxo nonyl }-1H-imidazoles-3-trifluoroacetate; | 518 | 1 |
| 199 | 5-(2-naphthyl)-2-{ (1S)-1-[(2-naphthyl ethanoyl) amino]-7-oxo nonyl }-1H-imidazoles-3-trifluoroacetate; | 518 | 1 |
| 200 | 5-(2-naphthyl)-2-((1S)-7-oxo-1-{[(2-oxo quinazoline-1 (2H)-yl) ethanoyl] amino } nonyl)-1H-imidazoles-3-trifluoroacetate; | 536 | 1 |
| 201 | 2-((1S)-1-{[(4-methyl isophthalic acid-oxo naphthyridine (phthalazin)-2 (1H)-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate; | 550 | 1 |
| 202 | 5-(2-naphthyl)-2-{ (1S)-7-oxo-1-[(phenyl acetyl) amino] nonyl }-1H-imidazoles-3-trifluoroacetate; | 468 | 1 |
| 203 | 2-((1S)-1-{[(2,6-dichlorophenyl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate; | 536 | 1 |
| 204 | 2-((1S)-1-{[(2,4-dichlorophenyl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate; | 536 | 1 |
| 205 | 2-[(1S)-1-({ [2-fluoro-6-(trifluoromethyl) phenyl] ethanoyl } amino)-7-oxo nonyl]-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate; | 554 | 1 |
| 206 | 2-[(1S)-1-({ [2-fluoro-3-(trifluoromethyl) phenyl] ethanoyl } amino)-7-oxo nonyl]-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate; | 554 | 1 |
| 207 | 2-[(1S)-and 1-{[(5-methoxyl group-2-methyl isophthalic acid H-indol-3-yl) ethanoyl] amino }-7-oxo-7-(1,3-thiazoles-2-base is amino) heptyl]-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate; | 621 | 150 |
| 208 | 2-[(1S)-1-([(5-methoxyl group-2-methyl isophthalic acid H-indol-3-yl) ethanoyl] amino }-7-oxo-7-(1,3,4-thiadiazoles-2-base is amino) heptyl]-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate; | 622 | 150 |
| 209 | The 2-methyl isophthalic acid-[2-((1S)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo nonyl } amino)-the 2-oxoethyl]-IH-benzoglyoxaline-3-two (trifluoroacetate); | 522 | 1 |
| 210 | 1-[2-((1S)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo nonyl } amino)-the 2-oxoethyl]-2-(trifluoromethyl)-1H-benzoglyoxaline-3-two (trifluoroacetate); | 576 | 1 |
| 211 | 2-{ (1S)-1-[(1H-indazolyl-1-base ethanoyl) amino]-7-oxo nonyl }-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 508 | 1 |
| 212 | 3-[2-((1S)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo nonyl } amino)-the 2-oxoethyl] quinoline two (trifluoroacetate); | 519 | 1 |
| 213 | 2-((1S)-1-{[(dimethylamino) (oxo) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 449 | 1 |
| 214 | 2-{ (1S)-1-[(1,2-benzoisoxazole-3-base ethanoyl) amino]-7-oxo nonyl }-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 509 | 1 |
| 215 | 2-((1S)-1-{[(2-Methyl-1H-indole-1-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 521 | 1 |
| 216 | 2-{ (1S)-1-[(1H-1,2,3-benzotriazole-1-base ethanoyl) amino]-7-oxo nonyl }-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 509 | 1 |
| 217 | 2-((1S)-1-{[(5-cyano-1 H-indol--1-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 532 | 1 |
| 218 | 2-((1S)-1-{[(dimethyl amido (ammonio)) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate); | 436 | 1 |
| 219 | 1-methyl-4-[({ (1S)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo nonyl } amino) carbonyl] piperidines two (trifluoroacetate); | 475 | 1 |
| 220 | 4-[({ (1S)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo nonyl } amino) carbonyl]-1-azonia two ring [2.2.2] octanes two (trifluoroacetate); | 487 | 1 |
| 221 | (7S)-and 7-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-N-methyl-7-[5-(2-naphthyl)-4H-1,2,4-triazole-3-yl] heptamide; | 553 | 144 |
| 222 | 4-[({ (1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl } amino) carbonyl]-1-azonia two ring [2.2.2] octane trifluoroacetates; | 489 | 136 |
| 223 | 2-ethyl-1-[3-((1S)-and 1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl } amino)-the 3-oxopropyl]-1H-benzoglyoxaline-3-trifluoroacetate; | 552 | 136 |
| 224 | 6-[2-((1S)-and 1-[5-(2-naphthyl)-1,3,4-Evil diazole-2-yl]-7-oxo nonyl } amino)-the 2-oxoethyl] [1,2,4] triazolo [1,5-a] pyrimidine-3-trifluoroacetate; | 512 | 136 |
| 225 | 1-methyl-4-[({ (1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl } amino) carbonyl] the piperidines trifluoroacetate; | 477 | 136 |
| 226 | (3R)-and 1-methyl-3-[({ (1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl } amino) carbonyl] the tetramethyleneimine trifluoroacetate; | 463 | 136 |
| 227 | (4R)-4-[({ (1S)-1-[5-(2-naphthyl)-1H-imidazoles-3--2-yl]-7-oxo nonyl } amino) carbonyl]-2,3,4,9-tetrahydrochysene-1H-β-Ka Lin-2-two (trifluoroacetate); | 548 | 1 |
| 228 | (7S)-and 7-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-N-methyl-7-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl] heptamide; | 554 | 142 |
| 229 | 4-[({ (1S)-6-carboxyl-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl] hexyl } amino) carbonyl]-1-methyl piperidine trifluoroacetate; | 465 | 141 |
| 230 | (7S)-and 7-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-7-[(1,3-thiazole-4-base carbonyl) amino] enanthic acid; | 451 | 141 |
| 231 | 4-[({ (1S)-1-[5-(2,3-dihydro-1,4-Ben Bing Er Evil star-6-yl)-1H-imidazoles-3--2-yl]-7-oxo nonyl } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 483 | 1 |
| 232 | 2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-{ (1S)-1-[4-(2-naphthyl)-1,3-Evil azoles-2-yl]-7-oxo nonyl } ethanamide; | 552 | 33 |
| 233 | 2-((1S)-7-(methylamino)-7-oxo-1-{ [(1-pyridine-2-phenylpiperidines-3-yl) carbonyl] amino } heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 539 | 327 |
| 234 | 2-[2-((1S)-7-(methylamino)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo heptyl } amino)-the 2-oxoethyl]-2,3-dihydro-1H-isoindole two (trifluoroacetate); | 510 | 327 |
| 235 | 2-{ (1S)-7-(methylamino)-7-oxo-1-[(piperidines-1-base ethanoyl) amino] heptyl }-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 476 | 327 |
| 236 | 4-[({ (1S)-7-(methylamino)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo heptyl } amino) carbonyl]-1-azonia two ring [2.2.2] octanes two (trifluoroacetate); | 488 | 327 |
| 237 | 5-[({ (1S)-7-(methylamino)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo heptyl } amino) carbonyl]-1,2,3,4-tetrahydrochysene-1,8-naphthyridines-1-two (trifluoroacetate); | 511 | 327 |
| 238 | 2-((1S)-7-(methylamino)-7-oxo-1-{ [(5-tetramethyleneimine-1-base-2H-tetrazolium-2-yl) ethanoyl] amino } heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 530 | 327 |
| 239 | 2-{ (1S)-7-(methylamino)-7-oxo-1-[(1,3-thiazoles-5-base carbonyl) amino] heptyl }-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 462 | 327 |
| 240 | 2-((1S)-7-(methylamino)-1-{[(4-methyl-1,2,3-thiadiazoles-5-yl) carbonyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 477 | 327 |
| 241 | 2-{ (1S)-7-(methylamino)-7-oxo-1-[(pyridin-3-yl carbonyl) amino] heptyl }-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 456 | 327 |
| 242 | 2-{ (1S)-7-(methylamino)-7-oxo-1-[(phenyl acetyl) amino] heptyl }-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 469 | 327 |
| 243 | (7S)-7-([(3S)-and 1-methylpyrrolidin-3-yl] carbonyl } amino)-7-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl] enanthic acid; | 451 | 141 |
| 244 | (3S)-and 3-[({ (1S)-6-carboxyl-1-[5-(2-naphthyl)-4H-1,2,4-triazole-3-yl] hexyl } amino) carbonyl]-1-crassitude trifluoroacetate; | 450 | 143 |
| 245 | (3S)-and 3-[({ (1S)-7-amino-1-[5-(2-naphthyl)-4H-1,2,4-triazole-3-yl]-7-oxo heptyl } amino) carbonyl]-1-crassitude trifluoroacetate; | 449 | 144 |
| 246 | 4-[({ (1S)-1-[5-(2,3-dihydro-1,4-Ben Bing Er Evil star-5-yl)-1H-imidazoles-3--2-yl]-7-oxo nonyl } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 483 | 304 |
| 247 | 4-[({ (1S)-1-[5-(1,3-benzothiazole-2-yl)-1H-imidazoles-3--2-yl]-7-oxo nonyl } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 482 | 304 |
| 248 | 4-[({ (1S)-1-[5-(1-thionaphthene-2-yl)-1H-imidazoles-3--2-yl]-7-oxo nonyl } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 481 | 304 |
| 249 | 2-[(1S)-and the 1-{[(benzylamino) carbonyl] amino }-7-(methylamino)-7-oxo heptyl]-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 484 | 328 |
| 250 | 2-[(1S)-1-({ [(4-p-methoxy-phenyl) amino] carbonyl } amino)-7-(methylamino)-7-oxo heptyl]-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 500 | 328 |
| 251 | 2-[(1S)-and 1-{[(cyclopentyl amino) carbonyl] amino }-7-(methylamino)-7-oxo heptyl]-5-(2-naphthyl)-IH-imidazoles-1-trifluoroacetate; | 462 | 328 |
| 252 | 2-((1S)-7-(methylamino)-1-{[(3-nitrophenyl) alkylsulfonyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 536 | 328 |
| 253 | 2-[(1S)-and the 1-{[(4-cyano-phenyl) alkylsulfonyl] amino }-7-(methylamino)-7-oxo heptyl]-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 516 | 328 |
| 254 | 2-[(1S)-7-(methylamino)-1-([(3S)-and 1-methylpyrrolidin-3-yl] carbonyl } amino)-7-oxo heptyl]-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate); | 462 | 328 |
| 255 | 2-[(1S)-7-(methylamino)-1-([(3R)-and 1-methylpyrrolidin-3-yl] carbonyl } amino)-7-oxo heptyl]-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate); | 462 | 328 |
| 256 | 2-[(1S)-and the 1-{[(benzyloxy) carbonyl] amino }-7-(methylamino)-7-oxo heptyl]-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 485 | 328 |
| 257 | 1-methyl-4-[({ (1R)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo nonyl } amino) carbonyl] piperidines two (trifluoroacetate); | 475 | 1 |
| 258 | (3R)-and 3-[({ (1S)-6-carboxyl-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl] hexyl } amino) carbonyl]-1-crassitude trifluoroacetate; | 451 | 141 |
| 259 | 5-methoxyl group-N-{ (1S)-7-(methylamino)-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-7-oxo heptyl }-1H-indoles-2-carboxylic acid amides; | 526 | 142 |
| 260 | (7S)-and the 7-{[(benzylamino) carbonyl] amino }-N-methyl-7-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl] heptamide; | 486 | 142 |
| 261 | 2-((1R)-1-{[(5-methoxyl group-2-methyl isophthalic acid H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 551 | 1 |
| 262 | 4-[({ (1S)-1-[5-(4-methoxy quinoline-2-yl)-1H-imidazoles-3--2-yl]-7-oxo nonyl } amino) carbonyl]-1-methyl piperidine two (trifluoroacetate); | 506 | 1 |
| 263 | 3-[2-((1S)-1-{[(1-methyl piperidine-4-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] quinoline three (trifluoroacetate); | 476 | 1 |
| 264 | 6-[2-((1S)-1-{[(1-methyl piperidine-4-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] quinoline three (trifluoroacetate); | 476 | 1 |
| 265 | 1-methyl-4-([(1S)-and 7-oxo-1-(5-quinoline-2-base-1H-imidazoles-1--2-yl) nonyl] amino } carbonyl) piperidines two (trifluoroacetate); | 476 | 1 |
| 266 | 4-([(1S)-and 1-(5-isoquinoline 99.9-3-base-1H-imidazoles-1--2-yl)-7-oxo nonyl] amino } carbonyl)-1-methyl piperidine two (trifluoroacetate); | 476 | 1 |
| 267 | 1-methyl-N-{1-[2-(2-naphthyl)-1H-imidazoles-5-yl]-7-oxo nonyl } piperidines-4-carboxylic acid amides; | 475 | 138 |
| 268 | 1-methyl-N-[7-oxo-1-(3-phenyl-1H-pyrazoles-5-yl) nonyl] piperidines-4-carboxylic acid amides; | 425 | 89 |
| 269 | 2-[(1S)-1-(kharophen)-7-oxo nonyl]-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 392 | 1 |
| 270 | 2-((1S)-1-{[(1,3-dimethyl pyrrolidine-3-yl) carbonyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate); | 475 | 1 |
| 271 | 4-[3-((1S)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo nonyl } amino)-the 3-oxopropyl] thiomorpholine-4-1,1-dioxide two (trifluoroacetate); | 539 | 1 |
| 272 | 5-(2-naphthyl)-2-{ (1S)-7-oxo-1-[(trifluoroacetyl group) amino] nonyl }-1H-imidazoles-1-trifluoroacetate; | 446 | 302 |
| 273 | 2-((1S)-1-{[2-(dimethyl amido (ammonio))-2-methylpropionyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate); | 463 | 1 |
| 274 | 2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate); | 447 | 1 |
| 275 | 2-[(1S)-and 1-{[3-(2-ethyl-1H-benzoglyoxaline-1-yl) propionyl] amino }-7-(methylamino)-7-oxo heptyl]-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 551 | 327 |
| 276 | 6-[2-((1S)-7-(methylamino)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo heptyl } amino)-the 2-oxoethyl] [1,2,4] triazolo [1,5-a] pyrimidine-3-two (trifluoroacetate); | 511 | 327 |
| 277 | 2-((1S)-7-(methylamino)-7-oxo-1-[(2-oxo quinazoline-1 (2H)-yl) ethanoyl] amino } heptyl)-5-(2-naphthyl)-IH-imidazoles-1-trifluoroacetate; | 537 | 327 |
| 278 | 2-((1S)-7-(methylamino)-7-oxo-1-[(2-oxo-1,3-benzoxazole-3 (2H)-yl) ethanoyl] amino } heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 526 | 327 |
| 279 | 1-ethyl-3-[({ (1S)-7-(methylamino)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo heptyl } amino) carbonyl] piperidines two (trifluoroacetate); | 490 | 327 |
| 280 | 2-((1S)-1-{[methoxyl group (oxo) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 436 | 147 |
| 281 | 2-((1S)-1-{[2-methyl-2-(methyl amido (ammonio)) propionyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate); | 449 | 1 |
| 282 | 2-(5-methoxyl group-2-Methyl-1H-indole-3-yl)-N-[7-oxo-1-(3-phenyl-1H-pyrazoles-5-yl) nonyl] ethanamide; | 501 | 89 |
| 283 | 1-methyl-4-([(1S)-and 7-oxo-1-(5-quinoline-2-base-1H-imidazoles-1--2-yl) nonyl] amino } carbonyl) the piperidines dichloride; | 476 | 1 |
| 284 | 1-methyl-4-[({ (1S)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo nonyl } amino) (oxo) ethanoyl] piperazine-1-two (trifluoroacetate); | 504 | 1 |
| 285 | 2-((1S)-1-{[morpholine-4-base (oxo) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-IH-imidazoles-1-trifluoroacetate; | 491 | 301 |
| 286 | 2-((1S)-1-{[amino (oxo) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 421 | 1 |
| 287 | 2-((1S)-1-{[3-(diethyl amido (ammonio)) propionyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate); | 477 | 1 |
| 288 | 2-((1S)-1-{[3-(dimethyl amido (ammonio)) propionyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate); | 449 | 1 |
| 289 | 2-((1S)-1-{[(5-cyano-1 H-indol--3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 468 | 1 |
| 290 | 2-{ (1S)-1-[(carboxyl carbonyl) amino]-7-oxo nonyl }-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 422 | 300 |
| 291 | 2-{ (1S)-1-[(methyl sulphonyl) amino]-7-oxo nonyl }-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 428 | 2 |
| 292 | 2-((1S)-1-{[(dimethylamino) alkylsulfonyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 457 | 3 |
| 293 | 5-methoxyl group-2-methyl-3-(2-oxo-2-[(1S)-and 7-oxo-1-(4-phenylpyridine-2-yl) nonyl] amino } ethyl)-IH-indoles two (trifluoroacetate); | 512 | 140 |
| 294 | 2-ethyl-1-(the 3-oxo-3-{[(1S)-7-oxo-1-(4-phenylpyridine-2-yl) nonyl] amino } propyl group)-1H-3,1-benzoglyoxaline-1-two (trifluoroacetate); | 511 | 140 |
| 295 | 1-methyl-N-{ (1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl } piperidines-4-carboxylic acid amides; | 477 | 308 |
| 296 | 6-[2-((1S)-1-{[(1-methyl piperidine-4-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] the quinoline trichloride; | 476 | 1 |
| 297 | N-{ (1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl } quinine-4-carboxylic acid amides; | 489 | 308 |
| 298 | 4-methoxyl group-2-[2-((1S)-1-{[(1-methyl piperidine-4-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-3--5-yl] the quinoline trichloride; | 506 | 1 |
Concrete intermediate of the present invention provides in embodiment 299.
Embodiment 299
| Intermediate 1 | 2-[(1-S)-the 1-amido (ammonio)-6-carboxyl hexyl]-5-(2-naphthyl)-1H-imidazoles-1-two (trifluoroacetate); | ?338(M+H) + |
| Intermediate 2 | (1S)-and 1-[3-(2-naphthyl)-1H-1,2,4-triazole-5-yl]-7-oxo nonane-1-ammonium trifluoroacetate; | ?351(M+H) + |
| Intermediate 3 | (1S)-1-[5-(2-naphthyl)-1H-imidazoles-2-yl]-7-oxo nonyl } t-butyl carbamate; | ?448(M+H) + |
| Intermediate 4 | (1S)-7-oxo-1-(4-phenylpyridine-2-yl) ninth of the ten Heavenly Stems-1-ammonium trifluoroacetate; | ?311(M+H) + |
| Intermediate 5 | 2-[(1S)-the 1-amido (ammonio)-7-oxo octyl group]-5-(2-naphthyl)-1H-imidazoles-3-two (trifluoroacetate); | ?336(M+H) + |
| Intermediate 6 | 2-[(1S)-the 1-amido (ammonio)-7-oxo octyl group]-5-phenyl-1H-imidazoles-3-two (trifluoroacetate); | ?286(M+H) + |
Embodiment 300
2-{ (1S)-1-[(carboxyl carbonyl) amino]-7-oxo nonyl }-5-(2-naphthyl)-1H-imidazoles-1-
Trifluoroacetate (AA1)
Will ((1S)-1-[5-(2-naphthyl)-1H-imidazoles-2-yl]-7-oxo nonyl } amino) (oxo) methyl acetate (being prepared as described in embodiment 147) is dissolved among the THF and with LiOHH
2The H of O (1.05 equivalent)
2O solution adds wherein, at room temperature the gained mixture is stirred 1 hour then.To react quencher with 1M HCl, reach till 5, under reduced pressure THF be removed then until the pH value.The gained water extracts with DCM (3 *); Drying (Na is carried out in the organic phase salt water washing that merges then
2SO
4) and under reduced pressure it is concentrated.Use H
2O (0.1%TFA) and MeCN (+0.1%TFA) (post: C18), RP-HPLC carries out purifying to the thick product of gained by preparation as elutriant.Desired components is carried out lyophilize, thereby obtain title compound into water white oil.
1H NMR (300MHz, DMSO-d6) δ: 9.39 (1H, d, J=8.2Hz), 8.30 (1H, s), and 8.11-7.85 (6H, m), 7.58-7.47 (2H, m), and 6.88-6.18 (1H, bs), 5.15-5.02 (1H, m), and 2.45-2.36 (4H, m), 2.13-1.87 (2H, m), and 1.55-1.41 (2H, m), 1.40-1.20 (4H, m), 0.90 (3H, t, J=7.3Hz) .MS (ES) C
24H
27N
3O
4Desired value: 421, discovery value: 422 (M+H)
+.
Embodiment 301
2-((1S)-1-{[morpholine-4-base (oxo) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-
1H-imidazoles-1-trifluoroacetate (BB1)
At room temperature, with EDCHCl (1.1 equivalent), HOBt (1.1 equivalent) and embodiment 300, the DMF solution pre-mixing of AA1 (1 equivalent) 1 hour joins this solution morpholine (1 equivalent) and iPrNEt then
2In the DMF solution of (1 equivalent).At room temperature said mixture is stirred, use H then
2O (0.1%TFA) and MeCN (+0.1%TFA) (post: C18), RP-HPLC directly carries out purifying to the thick product of gained by preparation as elutriant.Desired components is carried out lyophilize, thereby obtain title compound into water white oil.
1H?NMR(400MHz，DMSO-d6)δ：9.40(1H，bs)，8.31(1H，s)，8.06-7.88(2H，m)，7.97-7.88(3H，m)，7.61-7.50(2H，m)，6.89-6.01(1H，bs)，5.13-5.04(1H，m)，3.65-3.58(4H，m)，3.54-3.48(4H，m)，2.44-2.36(4H，m)，2.05-1.89(2H，m)，1.52-1.41(2H，m)，1.40-1.21(4H，m)，0.89(3H，t，J＝7.3Hz).
MS (ES) C
28H
34N
4O
4Desired value: 490, discovery value: 491 (M+H)
+.
Embodiment 302
5-(2-naphthyl)-2-{ (1S)-7-oxo-1-[(trifluoroacetyl group) amino] nonyl }-1H-imidazoles-1-
Trifluoroacetate (CC1)
To 0 ℃ embodiment 147, V2 and Et
3Add TFAA (1 equivalent) in the DCM solution of N (1 equivalent).At room temperature this reaction mixture was stirred 1 hour.After under reduced pressure solvent being removed, use H
2O (0.1%TFA) and MeCN (+0.1%TFA) (post: C18), RP-HPLC carries out purifying to the thick product of gained by preparation as elutriant.Desired components is carried out lyophilize, thereby obtain title compound into water white oil.
1H NMR (400MHz, CD3CN) δ: 10.67 (1H, d, J=8.0Hz), 8.42 (1H, s), and 8.07-8.01 (1H, m), 8.00-7.93 (2H, m), 7.88-7.81 (1H, m), 7.74 (1H, s), 7.67-7.58 (2H, m), and 5.49-5.39 (1H, m), 2.48-2.37 (4H, m), 2.26-2.18 (2H, m), 1.61-1.42 (3H, m), 1.41-1.29 (3H, m), 0.99 (3H, t, J=7.3Hz) .MS (ES) C
24H
26F
3N
3O
2Desired value: 445, discovery value: 446 (M+H)
+.
Embodiment 303
2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-5-
(2-naphthyl)-1H-imidazoles-3-dichloride (DD3)
Step 1:3-[({ (1S)-1-[5-(2-naphthyl)-1H-imidazoles-2-yl]-7-oxo nonyl } amino)-
Carbonyl
Base] azetidine-1-t-butyl formate (DD1)
In DMF, 1-(tertbutyloxycarbonyl) azetidine-3-carboxylic acid (1.2 equivalent), EDC.HCl (1.45 equivalent) and HOBt (1.4 equivalent) were stirred 5 minutes.The gained clear solution is joined embodiment 147, among the V2 and at room temperature it was stirred 1 hour.The gained mixture dilutes with DCM and uses saturated NaHCO
3The aqueous solution washs.Drying (Na is separated, carried out to organic phase
2SO
4) and under reduced pressure it is concentrated.On silica gel, the gained resistates is carried out purifying, use 1: 1 sherwood oil/EtOAc to carry out wash-out by flash chromatography.The product component that under reduced pressure is combined concentrates, thereby obtains to be the title compound of water white oil.MS (ES) C
31H
40N
4O
4, desired value: 532, discovery value: 533 (M+H)
+
Step 2:N-{ (1S)-1-[5-(2-naphthyl)-1H-imidazoles-2-yl]-7-oxo nonyl } nitrogen heterocyclic
Butane-3-carboxylic acid amides (DD2)
DD1 is dissolved in 1: 1 mixture of DCM and TFA.At room temperature said mixture was stirred 20 minutes, with DCM it is diluted then.With 1M NaOH solution said mixture is neutralized, organic phase is separated, with salt water washing, drying (Na
2SO
4).Filter and under reduced pressure it is concentrated into drying.Thereby obtain to be the thick title compound of water white oil.MS (ES) C
26H
32N
4O
2, desired value: 432, discovery value: 433 (M+H)
+
Step 3:2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-the 7-oxo
Nonyl)-5-(2-naphthyl)-1H-imidazoles-3-dichloride (DD3)
DD2 is dissolved in the methyl alcohol, formaldehyde (15 equivalents, 37% aqueous solution) adding wherein and with the gained mixture was stirred 4 minutes.With NaOAc (3.2 equivalent) and NaBH
3(CN) (3.2 equivalent) adds wherein and at room temperature the gained mixture stirred 25 minutes.The gained mixture dilutes with DCM, and uses saturated NaHCO
3The aqueous solution (5 *) and salt water washing.The gained organic phase is carried out drying (Na
2SO
4), and under reduced pressure it is concentrated.Use H
2(post: C18), RP-HPLC carries out purifying to the gained resistates by preparation as elutriant for O (0.1%TFA) and MeCN (0.1%TFA).Under reduced pressure desired components is concentrated, thereby remove MeCN, with saturated NaHCO
3The aqueous solution adds wherein.Gained solution extracts with DCM (2 *), and the organic phase that under reduced pressure is combined concentrates.In the 0.1M HCl aqueous solution/MeCN, the gained resistates is carried out lyophilize, thereby obtain title compound into light yellow oil.
1H NMR (400MHz, DMSO-d6) δ: 15.50-14.20 (2H, br, m), 10.61 (0.6H, br.s), 10.09 (0.4H, br.s), 9.21-9.00 (1H, m), 8.59-8.44 (1H, m), 8.17 (1H, s), 8.10-7.86 (4H, m), 7.68-7.50 (2H, m), 5.40-5.20 (1H, m), 4.40-4.16 (2H, m), 4.15-4.03 (1H, m), 4.01-3.84 (1H, m), 3.78-3.65 (1H, m), 2.86-2.71 (3H, m), 2.45-2.34 (4H, m), 2.11-1.83 (2H, m), 1.56-1.18 (6H, m), 0.90 (3H, t, J=7.3Hz) .MS (ES) C
27H
34N
4O
2Desired value: 446, discovery value: 447 (M+H)
+.
Embodiment 304
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-the 7-oxo
Nonyl)-5-[4-(1H-pyrazol-1-yl) phenyl]-1H-imidazoles-3-trifluoroacetate (EE7)
Step 1:2,4-two bromo-1-{[2-(trimethyl silyl) oxyethyl groups] methyl }-the 1H-imidazoles
(EE1)
Under 0 ℃, NaH (60%, 1.2 equivalent) portioning is joined 2, in the THF solution of 4-dibromo imidazoles (1 equivalent).After 1 hour, SEM-Cl (1.2 equivalent) is added wherein, and at room temperature the gained mixture was stirred 12 hours.Use H
2O will react quencher carefully, and the gained water extracts with EtOAc (3 *).The organic phase that is combined is carried out drying (MgSO
4) and under reduced pressure it is concentrated.On silica gel, it is carried out purifying, use 5-33%EtOAc/ pentane wash-out, thereby obtain title compound into oil by flash chromatography.
1HNMR (300MHz, CDCl
3) δ: 7.09 (1H, s), 5.22 (2H, s), 3.54 (2H, t, J=8.1Hz), 0.92 (2H, t, J=8.1Hz), 0.00 (9H, s) .MS (ES) C
9H
16Br
2N
2The OSi desired value: 354/356/358, discovery value: 355/357/359 (M+H)
+.
Step 2:(-)-(R)-N-[(1S)-and 1-(4-bromo-1-{[2-(trimethyl silyl) oxyethyl group] first
Base }-1H-imidazoles-2-yl)-6-(2-ethyl-1,3-dioxolane-2-yl) hexyl]-2-methylpropane-2-Asia
Sulphonamide (EE2)
Under Ar atmosphere, in the anhydrous THF solution of-78 ℃ EE1 (1 equivalent), slowly add n-BuLi (1.1 equivalent) solution.After 30 minutes, the THF solution of the O1 of embodiment 140 is added wherein, and under-78 ℃, above-mentioned reaction mixture was stirred 3 hours, in 2 hour time, made it slowly be warming up to room temperature then.Water (25mL) will react quencher carefully, and the gained water extracts with EtOAc (* 3).The organic phase that is combined is carried out drying (MgSO
4) and under reduced pressure with its evaporate to dryness.By LC-MS the thick product of gained is separated, show diastereomeric excess 77%.On silica gel, it is carried out purifying by flash chromatography, use the 1-25%EtOAc/ pentane to carry out wash-out, thereby obtain two kinds of components, first kind of component is non-enantiomer mixture (37%de), second kind of component be expectation (R, S)-diastereomer (＞95%de).
[α]
D 25 ℃=-19.0 (c=2.05 in DCM).
1H NMR (300MHz, CDCl
3) δ: 6.88 (1H, s), 5.39 (1H, d, J=11.0Hz), 5.12 (1H, d, J=11.0Hz), 4.49 (1H, m), 3.91 (4H, s), 3.74 (1H, d, J=7.5Hz), 3.50 (2H, t, J=8.3Hz), 2.06 (2H, m), 1.65-1.51 (6H, m), 1.36-1.19 (4H, m), 1.15 (9H, s), 0.90 (5H, m), 0.00 (9H, s); MS (ES) C
24H
45BrN
3O
4The SSi desired value: 579/581, discovery value: 580/582 (M+H)
+.
Step 3:(9S)-and 9-amino-9-(4-bromo-1-{[2-(trimethyl silyl) oxyethyl group] first
Base }-1H-imidazoles-2-yl) ninth of the ten Heavenly Stems-3-ketone (EE3)
EE2 is dissolved in methyl alcohol (the about 12 equivalents) solution of 1.2M HCl and at room temperature the gained mixture was stirred 30 minutes, use saturated NaHCO then
3The aqueous solution is with its quencher.With DCM (2 *) mixture is extracted, the organic extraction of merging carries out drying (Na
2SO
4), filter and under reduced pressure it be concentrated into drying, thereby obtain thick product into water white oil.MS (ES) C
18H
34BrN
3O
2Si, desired value: 433, discovery value: 434 (M+H)
+
Step 4:5-methoxyl group-3-(2-methoxyl group-2-oxoethyl)-2-Methyl-1H-indole-1-first
Tert-butyl acrylate (EE4)
(5-methoxyl group-2-Methyl-1H-indole-3-yl) acetate is dissolved among the anhydrous MeOH, amberlyst 15 resins (2.8 weight part) adding wherein and is at room temperature stirred the gained mixture spend the night.Said mixture is carried out centrifugal, supernatant liquor is separated and under reduced pressure it is concentrated into drying.The gained resistates is dissolved among the DCM, uses saturated NaHCO
3Solution washing, carry out drying (Na
2SO
4) and under reduced pressure it is concentrated into drying.Gained oil is dissolved among MeCN and the DMAP (0.2 equivalent) and with Boc
2O (1.2 equivalent) adds wherein, at room temperature the gained mixture is stirred 2 hours then.Under reduced pressure solvent is removed, the gained resistates does not need to be further purified promptly to can be used in the next step.MS (ES) C
18H
23NO
5, desired value: 333, discovery value: 334 (M+H)
+
Step 5:[1-(tertbutyloxycarbonyl)-5-methoxyl group-2-Methyl-1H-indole-3-yl] acetate
(EE5)
EE4 is dissolved in the THF/ water mixture (1: 1) and LiOH (3 equivalent) is added wherein, said mixture was stirred 2 hours.The gained mixture carries out acidifying with 0.1M HCl and extracts with DCM.The salt water washing of gained organic phase, drying (Na
2SO
4), filter and under reduced pressure it be concentrated into drying, thereby obtain white solid.
1H NMR (300MHz, DMSO-d6) δ: 12.29 (1H, s), 7.90 (1H, d, J=9.1Hz), 6.99 (1H, d, J=2.4Hz), 6.84 (1H, dd, J
1=2.4Hz, J
2=9.1Hz), 3.77 (3H, s), 3.62 (2H, s), 2.46 (3H, s), 1.62 (9H, s) .MS (ES) C
17H
21NO
5Desired value: 319, discovery value: 320 (M+H)
+.
Step 6:3-(2-{[(1S)-1-(4-bromo-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-
1H-imidazoles-2-yl)-and 7-oxo nonyl] amino }-the 2-oxoethyl)-5-methoxyl group-2-methyl isophthalic acid H-Yin
Diindyl-1-t-butyl formate (EE6)
With the DMF mixture jolting of EE5 (1.2 equivalent), EDC.HCl (1.3 equivalent) and HOBt (1.3 equivalent) 5 minutes, then this mixture and DIPEA (1 equivalent) are joined among the EE3.The said mixture stirring is spent the night, then it is distributed in DCM and saturated NaHCO
3Between the aqueous solution.The gained organic phase is carried out drying (Na
2SO
4), under reduced pressure be concentrated into drying and on silica gel, the gained resistates is carried out purifying by flash chromatography, carry out wash-out at 3: 1 with sherwood oil/EtOAc.The product component that under reduced pressure is combined concentrates, thereby obtains to be the title compound of colorless solid.
1H NMR (300MHz, CDCl
3) δ: 7.97 (1H, d, J=9.1Hz), 6.89-6.80 (2H, m), 6.73 (1H, m), 5.99 (1H, d, J=8.85Hz), 5.58 (1H, d, J=10.8Hz), 5.17-4.98 (2H, m), 3.78 (3H, s), 3.58-3.42 (4H, m), 2.46 (3H, s), and 2.41-2.21 (4H, m), 1.85-1.69 (2H, m), 1.67 (9H, s), and 1.50-1.34 (2H, m), 1.25-1.06 (4H, m), 1.01 (3H, t, J=7.5Hz), 0.94-0.81 (2H, m) ,-0.02 (9H, s) .MS (ES) C
35H
53BrN
4O
6The Si desired value: 734, discovery value: 735 (M+H)
+.
Step 7:2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] ammonia
Base }-7-oxo nonyl)-5-[4-(1H-pyrazol-1-yl) phenyl]-1H-imidazoles-3-trifluoroacetate
(EE7)
With EE6, [4-(1H-pyrazol-1-yl) phenyl] boric acid (1.5 equivalent), dicyclohexyl-(2 ', 6 '-dimethoxy-biphenyl-2-yl) phosphine (0.25 equivalent), Pd (OAc)
2(0.1 equivalent) and K
3PO
4(3 equivalent) places the chromacoll pipe, and it is suspended among the n-BuOH of the degassing.Replace air with Ar atmosphere, heated 16 hours down with the pipe stirring of sealing with at 90 ℃.The gained mixture dilutes, uses H with DCM
2O and 1M NaOH wash, carry out then drying (Na
2SO
4) and under reduced pressure it is concentrated into drying.THF solution (3 equivalent) with 0.33M TBAF is handled the gained resistates, and under 70 ℃ said mixture is heated 5 hours.It is diluted and use H with DCM
2O (3 *) washs.Under 3000rpm, after centrifugal 3 minutes, water is removed, under reduced pressure the gained organic phase is concentrated and the gained resistates is dissolved among the DCM/TFA (1: 1), at room temperature it was stirred 45 minutes.Under reduced pressure solvent is removed, and the gained resistates is distributed in DCM and saturated NaHCO
3Between the aqueous solution.Under 3000rpm, after centrifugal 3 minutes water is removed, and under reduced pressure the gained resistates is concentrated into drying.Use H
2(post: C18), RP-HPLC slightly goes to protect product to carry out purifying to gained by preparation as elutriant for O (0.1%TFA) and MeCN (0.1%TFA).The product component of collecting is carried out lyophilize, thereby obtain to be the title compound of white solid.
1H NMR (300MHz, CDCl
3) δ: 14.23 (1H, br.s), 10.62 (1H, s), 8.59 (1H, d, J=2.2Hz), 8.54 (1H, d, J=6.6Hz), 8.06-7.94 (3H, m), 7.93-7.84 (2H, m), 7.79 (1H, s), 7.10 (1H, d, J=11.5Hz), and 7.00-6.95 (1H, m), 6.64-6.56 (2H, m), and 5.05-4.94 (1H, m), 3.69 (3H, s), 3.57 (1H, d, J=15.0Hz), 3.48 (1H, d, J=15.0Hz), 2.42-2.28 (7H, m), and 2.01-1.79 (2H, m), 1.47-1.12 (6H, m), 0.90 (3H, t, J=7.3Hz) .MS (ES) C
33H
38N
6O
3Desired value: 566, discovery value: 567 (M+H)
+.
Embodiment 305
5-(2 methoxy quinoline-3-yl)-2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl]
Amino }-7-oxo nonyl)-1H-imidazoles-3-two (trifluoroacetate) is (FF5)
Step 1:3-([(1S)-1-(4-bromo-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-
Imidazoles-2-yl)-and 7-oxo nonyl] amino } carbonyl) azetidine-1-t-butyl formate (FF1)
In DMF, 1-(tertbutyloxycarbonyl) azetidine-3-carboxylic acid (1.2 equivalent), EDC.HCl (1.45 equivalent) and HOBt (1.4 equivalent) were stirred 5 minutes.The gained clear solution is joined embodiment 304, among the EE3 and at room temperature it was stirred 1 hour.The gained reaction mixture dilutes with DCM and uses saturated NaHCO
3The aqueous solution washs.Drying (Na is separated, carried out to organic phase
2SO
4) and under reduced pressure it is concentrated.On silica gel, the gained resistates is carried out purifying, carry out wash-out, thereby obtain title compound into water white oil with the 55%EtOAc/ sherwood oil by flash chromatography.
1H NMR (300MHz, CDCl
3) δ: 6.87 (1H, s), 6.43 (1H, d, J=7.3Hz), 5.54 (1H, d, J=10.6Hz), 5.19-5.01 (2H, m), 4.06-3.85 (4H, m), 3.57-3.42 (2H, m), 3.15-3.02 (1H, m), 2.44-2.28 (4H, m), 1.97-1.76 (2H, m), 1.58-1.45 (2H, m), 1.40 (9H, s), and 1.33-1.14 (4H, m), 1.01 (3H, t, J=7.3Hz), and 0.96-0.81 (2H, m) ,-0.02 (9H, s) .MS (ES) C
27H
47BrN
4O
5The Si desired value: 616, discovery value: 617 (M+H)
+.
Step 2:N-[(1S)-1-(4-bromo-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-
Imidazoles-2-yl)-and 7-oxo nonyl] azetidine-3-carboxylic acid amides (FF2)
(FF1) is dissolved among the 20%TFA/DCM with carbamate, after 20 minutes the toluene adding wherein and under reduced pressure concentrated said mixture.The gained resistates dilutes with DCM and uses saturated NaHCO
3The aqueous solution washs.With DCM water is extracted, the organic extraction that is combined carries out drying (Na
2SO
4) and under reduced pressure it is concentrated into drying, thereby obtain amine into water white oil.MS (ES) C
22H
39BrN
4O
3Si, desired value: 516, discovery value: 517 (M+H)
+
Step 3:N-[(1S)-1-(4-bromo-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-
Imidazoles-2-yl)-7-oxo nonyl]-1-methyl azetidine-3-carboxylic acid amides (FF3)
Title compound is prepared according to the method for embodiment 303 steps 3, thereby obtains thick product, and it does not need to carry out purifying by preparation RP-HPLC and can use.MS (ES) C
23H
41BrN
4O
3Si, desired value: 530, discovery value: 531 (M+H)
+
Step 4:(2-methoxy quinoline-3-yl) boric acid (FF4)
(2-fluorine quinoline-3-yl) boric acid is dissolved in the MeOH solution of 1.25M HCl and at room temperature it was stirred 1 hour.Use saturated NaHCO
3The aqueous solution extracts (3 *) with the said mixture quencher and with DCM to mixture.The gained organism is carried out drying (Na
2SO
4) and under reduced pressure it is concentrated, thereby obtaining thick product into light yellow solid, it does not need to be further purified promptly to can be used in the next step.MS (ES) C
10H
10BNO
3, desired value: 203, discovery value: 204 (M+H)
+
Step 5:5-(2 methoxy quinoline-3-yl)-2-((1S)-1-{[(1-methyl azetidine-3-
Base) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-3-two (trifluoroacetate) is (FF5)
In the chromacoll pipe, to bromide (FF
3) and boric acid (FF4) (1.5 equivalent), dicyclohexyl-(2 ', 6 '-dimethoxy-biphenyl-2-yl) phosphine (0.25 equivalent), Pd (OAc)
2(0.1 equivalent) and K
3PO
4The n-BuOH mixture of (3 equivalent) outgases.Replace air with Ar atmosphere, and when stirring, under 90 ℃, sealed tube was heated 2 hours.The gained mixture dilutes, uses saturated NaHCO with DCM
3Solution washing, carry out drying (Na
2SO
4) and under reduced pressure it is concentrated into drying.Be dissolved in the gained resistates among the DCM/TFA (1: 1) and at room temperature the gained mixture stirred 5 hours.Toluene added wherein and under reduced pressure the gained mixture is concentrated, the gained resistates dilutes with DCM and uses saturated NaHCO
3The aqueous solution washs.With DCM water is extracted, organism is carried out drying (Na
2SO
4), filter and under reduced pressure it be concentrated into drying.Use H
2(post: C18), RP-HPLC carries out purifying to the gained resistates by preparation, and desired components is carried out lyophilize, thereby obtains the title compound into water white oil as elutriant for O (0.1%TFA) and MeCN (0.1%TFA).
1H NMR (400MHz, DMSO-d6) δ: 9.78 (1H, br.s), 8.80 (1H, br.s), 8.70 (1H, s), 7.93 (1H, d, J=7.6Hz), 7.81 (2H, d, J=8.1Hz), 7.72-7.64 (1H, m), 7.51-7.44 (1H, m), 5.08-4.98 (1H, m), 4.41-4.27 (1H, m), and 4.26-4.17 (1H, m), 4.14 (3H, s), and 4.13-4.04 (1H, m), 3.97-3.87 (1H, m), and 3.67-3.55 (1H, m), 2.81 (3H, s), and 2.43-2.35 (4H, m), 2.03-1.77 (2H, m), and 1.52-1.41 (2H, m), 1.40-1.19 (4H, m), 0.89 (3H, t, J=7.2Hz) .MS (ES) C
27H
35N
5O
3Desired value: 477, discovery value: 478 (M+H)
+.
Embodiment 306
2-((1S)-{ [3-(dimethyl amido (ammonio)) propionyl] amino }-7-oxo ninth of the ten Heavenly Stems
Base)-5-(2-naphthyl)-1H-imidazoles-3-dichloride (GG1)
With N, the DCM solution of N-dimethyl-Beta-alanine hydrochloride (1.25 equivalent), TBTU (1.25 equivalent) and DIPEA (2.5 equivalent) joins embodiment 147, among the V2, and at room temperature said mixture is stirred 1 hour.The gained mixture dilutes with DCM and uses saturated NaHCO
3Solution washing carries out drying (Na to the gained organic phase
2SO
4) and under reduced pressure it is concentrated into drying.The gained resistates is dissolved among the THF, polymkeric substance-bonded tetraalkyl volatile salt (2.5mmol/g, 10 equivalents) is added wherein and gained mixture jolting 12 hours.Polymkeric substance is leached and under reduced pressure with solvent evaporation after, use H
2O (+0.1%TFA) and MeCN (+0.1%TFA) as elutriant (post: C18), by the preparation RP-HPLC to the expectation product separate.Under reduced pressure desired components is concentrated, thereby remove MeCN, with saturated NaHCO
3The aqueous solution adds wherein.The gained water extracts with DCM (2 *), and the organic phase that under reduced pressure is combined concentrates.From the 0.1M HCl aqueous solution/MeCN, the gained resistates is carried out lyophilize, thereby obtain to be the expectation compound of light yellow hygroscopic solid.
1H NMR (400MHz, DMSO-d6) δ: 15.70-14.60 (1H, br.m), 10.53 (1H, br.s), 9.09 (1H, d, J=6.4Hz), 8.58 (1H, s), 8.19 (1H, s), 8.07-7.90 (4H, m), 7.63-7.54 (2H, m), 5.19-5.10 (1H, m), 3.37-3.26 (2H, m), 2.94-2.73 (3H, m), 2.74 (6H, s), and 2.44-2.36 (4H, m), 2.09-1.88 (2H, m), 1.51-1.21 (6H, m), 0.89 (3H, t, J=7.3Hz).
13C NMR (100MHz, DMSO-d6) δ: 211.3,170.3,149.5,133.1,133.0,129.2,128.4,128.2,127.5,127.3,124.9,124.7,123.6,115.6,52.8,46.8,42.5,41.7,35.3,33.2,30.1,28.4,25.4,23.4,8.1.MS (ES) C
27H
36N
4O
2Desired value: 448, discovery value: 449 (M+H)
+.
Embodiment 307
4-methoxyl group-2-[2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-
The oxo nonyl)-and 1H-imidazoles-1--5-yl] quinoline trichloride (HH7)
Step 1:2-chloro-1-(4-methoxy quinoline-2-yl) ethyl ketone (HH1)
In the DCM solution of 0 ℃ 4-methoxy quinoline-2-carboxylic acid and DMF (50 μ L), drip and add oxalyl chloride (1.2 equivalent).Cooling bath is removed and at room temperature said mixture was stirred 2 hours, under reduced pressure solvent is removed then.The gained resistates is dissolved among the THF/MeCN (1: 1) and with it is cooled to 0 ℃, with pre-cooled (0 ℃) TMSCHN
2(1.2 equivalent) and Et
3N (1.2 equivalent) drips adding and wherein and under 0 ℃ the gained mixture was stirred 2 hours.Et with excessive 2M HCl
2O solution add wherein and under 0 ℃ with above-mentioned reaction restir 1 hour, then it is distributed in saturated NaHCO
3Between the aqueous solution and the DCM.Drying (Na is separated, carried out to organic phase
2SO
4) and under reduced pressure it is concentrated, thereby obtaining the dun solid, it is used for next step like this.
1H NMR (300MHz, CDCl
3) δ: 8.47 (1H, d, J=8.0Hz), 8.09 (1H, d, J=8.4Hz), 7.81-7.73 (1H, m), 7.66-7.58 (1H, m), 7.51 (1H, s), 5.31 (2H, s), 4.13 (3H, s) .MS (ES) C
12H
10ClNO
2Desired value: 235, discovery value: 236 (M+H)
+.
Step 2:(2S)-and the 2-[(tertbutyloxycarbonyl) amino]-8-oxo capric acid 2-(4-methoxy quinoline-2-
Base)-2-oxoethyl ester (HH2)
At room temperature with (2S)-2-[(tertbutyloxycarbonyl) amino]-8-oxo capric acid (1 equivalent) and Cs
2CO
3The EtOH solution stirring of (0.5 equivalent) 30 minutes under reduced pressure concentrates it then.The gained resistates is diluted among the DMF and at 15 minutes in the clock time HH1 (1 equivalent) slowly added wherein.At room temperature above-mentioned reaction mixture was stirred 1 hour, then under reduced pressure with solvent evaporation.On silica gel, the thick product of gained is carried out purifying, use the 80%EtOAc/ sherwood oil to carry out wash-out, thereby obtain product into orange oil by column chromatography.MS (ES) C
27H
36N
2O
7, desired value: 500, discovery value: 501 (M+H)
+
Step 3:{ (1S)-1-[5-(4-methoxy quinoline-2-yl)-1H-imidazoles-2-yl]-7-oxo ninth of the ten Heavenly Stems
Base } t-butyl carbamate (HH3)
With ester (HH2) and NH
4The mixture of OAc (20 equivalent) is suspended in the dimethylbenzene, and is heated for 180 seconds in microwave oven under 160 ℃.The gained reaction mixture dilutes with DCM and uses saturated NaHCO
3The aqueous solution washs.Organic phase is carried out drying (Na
2SO
4), filter and under reduced pressure concentrate, on silica gel, the gained brown oil is carried out purifying by chromatography, use the 2.5%MeOH/DCM wash-out, thereby obtain imidazoles into orange oil.MS (ES) C
27H
36N
4O
4, desired value: 480, discovery value: 481 (M+H)
+
Step 4:(9S)-and 9-amino-9-[5-(4-methoxy quinoline-2-yl)-1H-imidazoles-2-yl] ninth of the ten Heavenly Stems-3-
Ketone (HH4)
Be dissolved in imidazoles (HH3) among the TFA/DCM (1: 1) and at room temperature the gained mixture stirred one hour.Under reduced pressure solvent is removed, and the gained resistates is distributed in saturated NaHCO
3Between the aqueous solution and the DCM.Drying (Na is separated, carried out to organic phase
2SO
4) and under reduced pressure it is concentrated, thereby obtaining amine, it does not need to be further purified and can use.MS (ES) C
22H
28N
4O
2, desired value: 380, discovery value: 381 (M+H)
+
Step 5:3-[({ (1S)-1-[5-(4-methoxy quinoline-2-yl)-1H-imidazoles-2-yl]-the 7-oxo
Nonyl } amino) carbonyl] azetidine-1-t-butyl formate (HH5)
Amine (HH4) (1 equivalent) is joined in the DMF clear solution of EDC-HCl (1.45 equivalent), HOBt (1.41 equivalent) and 1-(tertbutyloxycarbonyl) azetidine-3-carboxylic acid (1.24 equivalent).At room temperature said mixture was stirred 30 minutes, dilute and wash with 1N NaOH solution (2 *) with DCM.Organic phase is carried out drying (Na
2SO
4), filter and under reduced pressure it concentrated, thereby obtain thick product, it does not need to be further purified and can use.MS (ES) C
31H
41N
5O
5, desired value: 563, discovery value: 564 (M+H)
+
Step 6:N-{ (1S)-1-[5-(4-methoxy quinoline-2-yl)-1H-imidazoles-2-yl]-the 7-oxo
Nonyl } azetidine-3-carboxylic acid amides (HH6)
Be dissolved in acid amides (HH5) in DCM/TFA (1: the 1) mixture and at room temperature said mixture stirred 1 hour, dilute with DCM then and under reduced pressure solvent is removed.The gained resistates is distributed in saturated NaHCO
3Between the aqueous solution and the DCM, then it is separated, the gained organic phase is carried out drying (Na
2SO
4), filter and under reduced pressure concentrate, thereby obtain thick amine, it does not need to be further purified and can use.MS (ES) C
20H
33N
5O
3, desired value: 463, discovery value: 464 (M+H)
+
Step 7:4-methoxyl group-2-[2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl]
Amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] quinoline trichloride (HH7)
(HH6) is dissolved in the methyl alcohol with amine, and formaldehyde (15 equivalents, 37% aqueous solution) adding wherein and with the gained mixture was stirred 4 minutes.With NaOAc (3.2 equivalent) and NaBH
3(CN) (3.2 equivalent) adds wherein and at room temperature said mixture stirred 25 minutes.The gained mixture dilutes with DCM, and uses saturated NaHCO
3The aqueous solution (5 *) and salt water washing.The gained organic phase is carried out drying (Na
2SO
4), and under reduced pressure it is concentrated.Use H
2(post: C18), RP-HPLC carries out purifying to the gained resistates by preparation as elutriant for O (0.1%TFA) and MeCN (0.1%TFA).After the product component that freeze-drying is collected, the gained tfa salt is dissolved in several the dripping and with it is distributed in saturated NaHCO
3Between the aqueous solution and the DCM; The gained water extracts with DCM (2 *), and the organic extraction that is combined carries out drying (Na
2SO
4) and under reduced pressure it is concentrated.From the 0.1N HCl aqueous solution/MeCN, the gained resistates is carried out lyophilize, thereby obtain to be the title compound of light yellow hygroscopic solid.
1H NMR (400MHz, D
2O) δ: 8.39 (1H, d, J=8.3Hz), 8.28 (1H, s), and 8.12-8.01 (2H, m), 7.84-7.77 (1H, m), 7.59 (1H, s), 5.14-5.08 (1H, m), and 4.68-4.55 (1H, m), 4.54-4.46 (1H, m), 4.37 (3H, s), 4.32-4.20 (1H, m), and 4.18-4.09 (1H, m), 3.88-3.78 (1H, m), and 3.02-2.98 (3H, m), 2.59-2.50 (4H, m), and 2.11-1.97 (2H, m), 1.63-1.53 (2H, m), and 1.50-1.28 (4H, m), 0.97 (3H, t, J=7.3Hz) .MS (ES) C
27H
35N
5O
3Desired value: 477, discovery value: 478 (M+H)
+.
Embodiment 308
N-{ (1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-5-oxo heptyl } quinine-4-carboxylic acyl
Amine (II2)
Step 1:((1S)-and 1-{[2-(2-steams acyl group) diazanyl] carbonyl }-7-oxo nonyl) the carboxylamine uncle
Butyl ester (II1)
At room temperature, with EDCHCl (1.4 equivalent), HOBt (1.4 equivalent) and (2S)-the 2-[(tertbutyloxycarbonyl) amino]-DMF (0.5M) the solution pre-mixing of 8-oxo capric acid 10 minutes, DMF (1M) solution with 2-naphthoyl hydrazine (1 equivalent) adds wherein then.At room temperature said mixture was stirred 16 hours, then it is diluted among the DCM, washs with 0.1M HCl solution and salt solution.Above-mentioned solution is carried out drying (Na
2SO
4), and under reduced pressure concentrate, on silica gel, the thick product of gained is carried out purifying by chromatography, use the 1%MeOH/DCM wash-out, thereby obtain hydrazides into expectation.
1H NMR (300MHz, CDCl
3, 300K)
(9.64 1H, broad 8), 9.44 (1H, broad s), 8.36 (1H, s), and 7.86-7.81 (4H, m), 7.57-7.46 (2H, m), 5.36 (1H, d, J=7Hz), 4.39-4.36 (1H, m), and 2.41-2.32 (4H, m), 1.90-1.84 (1H, m), and 1.72-1.66 (1H, m), 1.56-1.28 (15H, m), 1.02 (3H, t, J=7.5Hz) .MS (ES) C
26H
35N
3O
5Desired value: 469, discovery value: 470 (M+H
+).
Step 2:N-{ (1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-5-oxo heptyl } Kui
Rather-4-carboxylic acid amides (II2)
According to embodiment 136 steps 3 and 4 described methods; hydrazides (II1) is converted into Xiang Ying De oxadiazole and the Boc-protecting group is removed; use the DMF solution of quinine-4-carboxylic acid (2.7 equivalent), TBTU (3.2 equivalent) and DIPEA (6.3 equivalent) that gained amine (1 equivalent) is handled then, and at room temperature its stirring is spent the night.Use H
2O (+0.1%TFA) and MeCN (+0.1%TFA) as elutriant (post: C18), by the preparation RP-HPLC products obtained therefrom is separated.Use saturated NaHCO
3The aqueous solution alkalizes to desired components and extracts with EtOAc.EtOAc is carried out drying (Na mutually
2SO
4) and under reduced pressure it is concentrated, thereby obtain expected product into white powder.
1H NMR (400MHz, DMSO-d6,300K) δ: 8.55 (1H, s), 8.16-8.13 (2H, m), and 8.04-8.01 (3H, m), 7.69-6.63 (2H, m), 5.21-5.16 (1H, m), 2.76 (6H, t, J=7.5Hz), 2.43-2.38 (4H, m), 2.05-1.90 (2H, m), 1.63 (6H, t, J=7.5Hz), 1.51-1.23 (6H, m), 0.91 (3H, t, J=7.2Hz) .MS (ES) C
29H
36N
4O
3Desired value: 488, discovery value: 489 (M+H)
+.
Embodiment 309
N-{ (1S)-1-[5-(4-methoxy quinoline-2-yl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl }-
1-methyl chloride heterocycle butane-3-carboxylic acid amides (JJ3)
Step 1:4-methoxy quinoline-2-carbohydrazide (JJ1)
4-methoxy quinoline-2-methyl-formiate (1 equivalent) is dissolved among the i-PrOH (0.75M), then hydrazine monohydrate (10 equivalent) is added wherein.With above-mentioned reaction mixture heated overnight, then under reduced pressure with solvent evaporation, the thick product of gained does not need purifying promptly to can be used in the next step under 80 ℃.MS (ES) C
11H
11N
3O
2, desired value: 217, discovery value: 218 (M+H)
+
Step 2:(9S)-and 9-amino-9-[5-(4-methoxy quinoline-2-yl)-1,3,4-oxadiazole-2-yl]
The ninth of the ten Heavenly Stems-3-ketone (JJ2)
Title compound is prepared as described in embodiment 308 steps 1 and 2, by hydrazides (JJ1) and (2S)-the 2-[(t-butoxycarbonyl) amino]-8-oxo capric acid begins, and obtains the product into brown oil.
1H NMR (300MHz, CDCl3,300K) δ: 8.23 (1H, d, J=8.2Hz), 8.15 (1H, d, J=8.4Hz), 7.77 (1H, t, J=8.4Hz), 7.68 (1H, s), 7.59 (1H, t, J=8.2Hz), 4.36 (1H, t, J=7Hz), 4.15 (3H, s), and 2.43-2.36 (6H, m), 2.16-1.88 (2H, m), 1.65-1.32 (6H, m), 1.03 (3H, t, J=7.3Hz) .MS (ES) C
21H
26N
4O
3Desired value: 382, discovery value: 383 (M+H)
+.
Step 3:N-{ (1S)-1-[5-(4-methoxy quinoline-2-yl)-1,3,4-oxadiazole-2-yl]-7-oxygen
For nonyl }-1-methoxyl group azetidine-3-carboxylic acid amides (JJ3)
Title compound is prepared by thick amine (JJ2) as described in embodiment 303 step 1-3.After preparation HPLC purifying, use saturated NaHCO
3The aqueous solution alkalizes to desired components.The gained water extracts with DCM, and the gained organic phase is carried out drying (Na
2SO
4) and under reduced pressure it is concentrated, thereby obtain expected product into white powder.
1H NMR (400MHz, DMSO-d6,300K) δ: 8.64 (1H, d, J=7.7Hz), 8.21 (1H, d, J=8.1Hz), 8.09 (1H, d, J=8.3Hz), 7.87 (1H, t, J=7.2Hz), 7.70 (2H, m), 5.22-5.20 (1H, m), 4.17 (3H, s), 3.50-3.00 (5H, m), 2.43-2.37 (4H, m), 2.17 (3H, s), 2.00-1.80 (2H, m), 1.50-1-20 (6H, m), 0.89 (3H, t, J=7.2Hz) .MS (ES) C
26H
33N
5O
4Desired value: 479, discovery value: 480 (M+H)
+.
Embodiment 310
5-(hydroxymethyl)-2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] ammonia
Base }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate (KK6)
Step 1:4-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-1-{[2-(trimethylammonium
Silyl) oxyethyl group] methyl }-1H-imidazoles-2-formaldehyde (KK1)
Under-40 ℃, to 4-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-1-{[2-(trimethyl silyl) oxyethyl group that stirs] methyl }-drip the hexane solution that adds BuLi (2 equivalent) in the THF solution of 1H-imidazoles (referring to WO03/022274) (1 equivalent), kept away that and under-40 ℃, again said mixture was stirred 30 minutes.Then, DMF (4 equivalent) added wherein and with cooling bath remove, make above-mentioned reaction mixture be warming up to room temperature and it was stirred 30 minutes, after this by adding saturated NH
4The Cl aqueous solution will react quencher.The gained organism with EtOAc (2 *) extract, with the salt water washing, carry out drying (Na
2SO
4) and under reduced pressure it is concentrated.On silica gel, the gained material is carried out purifying, use the 15%EtOAc/ sherwood oil to carry out wash-out by column chromatography.
1H?NMR(300MHz，CDCl
3)δ：9.81(1H，s)，7.30(1H，s)，5.95(2H，s)，4.87(2H，s)，3.58(2H，t，J＝7.7Hz)，1.05-0.85(20H，m)，0.05(6H，s).
Step 2:1-(4-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-1-{[2-(front three
The base silyl) oxyethyl group] methyl }-1H-imidazoles-2-yl)-6-(2-ethyl-1,3-dioxolane-2-yl)
Oneself-1-alcohol (KK2)
To-78 ℃ the 2-ethyl-2-(5-iodine amyl group)-1 that stirs, the Et of 3-dioxolane (1.5 equivalent)
2Drip the hexane solution that adds uncle-BuLi (3 equivalent) in the O solution, and under-40 ℃, said mixture was further stirred 30 minutes.Et with aldehyde (KK1) (1 equivalent)
2O solution once adds wherein, after 5 minutes, cooling bath is removed then, makes reaction be warming up to room temperature and at room temperature it is stirred 1 hour.By adding saturated NH
4The Cl aqueous solution will react quencher and will respectively be separated.The gained organism extracts with EtOAc (2 *), then with the organic constituent of salt water washing merging, it is carried out drying (Na
2SO
4) and under reduced pressure it is concentrated.On silica gel, the gained material is carried out purifying, use the 50-70%EtOAc/ sherwood oil to carry out wash-out by column chromatography.
1H?NMR(300MHz，CDCl
3)δ：6.85(1H，s)，5.45(1H，d，J＝10.0Hz)，5.38(1H，d，J＝10.0Hz)，4.82-4.65(4H，m)，3.98-3.85(4H，m)，3.55(2H，t，J＝7.7Hz)，2.00-1.88(1H，m)，1.70-1.30(11H，m)，0.97-0.82(14H，m)，0.10-0.00(15H，s).
Step 3:1-(4-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-1-{[2-(front three
The base silyl) oxyethyl group] methyl }-1H-imidazoles-2-yl)-6-(2-ethyl-1,3-dioxolane-2-yl)
Oneself-1-trinitride (KK3)
In the toluene solution of substrate (KK2) (1 equivalent) that stirs and DBU (1.5 equivalent), add DPPA (1.5 equivalent) and at room temperature with said mixture stirring 18 hours.Said mixture Et
2O dilution and use saturated NaHCO
3Drying (Na is carried out in the aqueous solution and salt water washing then
2SO
4) and under reduced pressure it is concentrated.On silica gel, the gained material is carried out purifying, use the 25%EtOAc/ sherwood oil to carry out wash-out by column chromatography.
1H?NMR(300MHz，CDCl
3)δ：6.91(1H，s)，5.45(1H，d，J＝10.0Hz)，5.39(1H，d，J＝10.0Hz)，4.72(2H，s)，4.39(1H，t，J＝5.5Hz)，3.95(4H，app.s)，3.58(2H，t，J＝7.7Hz)，2.22-2.05(2H，m)，1.70-1.30(10H，m)，0.97-0.82(14H，m)，0.10-0.00(15H，s).
Step 4:N-[1-(4-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-1-{[2-(three
The methyl-silicane base) oxyethyl group] methyl }-1H-imidazoles-2-yl)-6-(2-ethyl-1,3-dioxolane-2-
Base) hexyl]-2-(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanamide (KK4)
In the THF solution of trinitride (KK3) (1 equivalent), add PPh
3(1.2 equivalent) and at room temperature the gained mixture was stirred 60 hours is then with H
2O (0.25 volume) add wherein and with reaction be warming up to 45 ℃ 24 hours.Under reduced pressure THF is removed, then the gained organism with EtOAc extract, with the salt water washing and under reduced pressure it is concentrated, thereby obtain 1-(4-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-imidazoles-2-yl)-6-(2-ethyl-1,3-dioxolane-2-yl) own-1-amine, MS (ES) C
27H
55N
3O
4Si
2, desired value: 541, discovery value: 542 (M+H)
+
DMF is joined in the above-mentioned crude mixture, subsequently with (5-methoxyl group-2 Methyl-1H-indoles-3-yl) acetate (1.5 equivalent), EDCI 1.5 equivalents), HOBt (1.5 equivalent) and Et
3N (2.5 equivalent) adds wherein and the gained mixture was stirred 24 hours.Dimethylbenzene joined in the reaction and under reduced pressure said mixture is concentrated.The gained resistates is absorbed among the EtOAc, uses saturated NaHCO
3Drying (Na is carried out in the aqueous solution and salt water washing then
2SO
4) and under reduced pressure it is concentrated.On silicon-dioxide, said mixture is carried out purifying by column chromatography, with 60-75%EtOAc/ sherwood oil wash-out, thus the acid amides that obtains expecting.
1H NMR (400MHz, CDCl
3) δ: 7.88 (1H, s), 7.16 (1H, d, J=8.8Hz), 6.85 (1H, d, J=1.5Hz), 6.80 (2H, m), 5.60 (1H, d, J=10.4Hz), 5.32 (1H, d, J=10.4Hz), 5.24 (1H, q, J=8.8Hz), 4.69 (1H, d, J=12.8Hz), 4.65 (1H, d, J=12.8Hz), 3.98 (4H, app.s), 3.80 (3H, s), and 3.66-3.48 (4H, s), 2.31 (3H, s), and 1.87-1.48 (8H, m), 1.30-1.10 (6H), 0.97-0.82 (12H), 0.08-0.00 (15H, m) .MS (ES) C
39H
66N
4O
6Si
2Desired value: 742, discovery value: 743 (M+H)
+.
Step 5:N-{6-(2-ethyl-1,3-dioxolane-2-yl)-1-[5-(hydroxymethyl)-1H-miaow
Azoles-2-yl] hexyl }-2-(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanamide (KK5)
Acid amides (KK4) is dissolved among the THF and the THF solution (2.5 equivalent) of 1M TBAF is added wherein.Under 65 ℃,, pass through to add H then with the said mixture heated overnight
2O will react quencher and with DCM product be extracted.The gained organic phase with the salt water washing, carry out drying (Na
2SO
4) and under reduced pressure it is concentrated, thereby the intermediate that obtains expecting.MS (ES) C
27H
38N
4O
5, desired value: 498, discovery value: 499 (M+H)
+
Step 6:5-(hydroxymethyl)-2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) acetyl
Base] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate (KK6)
With 1M HCl solution (4 equivalent) the THF solution of alcohol (KK5) is handled and at room temperature it stirred 4 hours.With among the 1M NaOH and said mixture and under reduced pressure it being concentrated.Use H
2O (+0.1%TFA) and MeCN (+0.1%TFA) (post: C18), RP-HPLC carries out purifying to said mixture by preparation, and desired components is carried out lyophilize, thereby obtains title compound as elutriant.
1H NMR (300MHz, CD
3CN) δ: 9.00-8.90 (1H, s), 8.15-8.00 (1H, d, J=7.0Hz), 7.28-7.18 (1H, d, J=7.0Hz), 7.15-7.05 (1H, s), 7.00-6.90 (1H, s), 6.70 (1H, d, J=7.0Hz), 5.16 (1H, q, J=7.0Hz), 4.55 (2H, s), 3.78 (3H, s), 3.67 (1H, d, J=10.0Hz), 3.60 (1H, d, J=10.0Hz), 2.70-2.20 (7H, m), and 1.90-1.20 (8H, m), 1.00-0.75 (3H, t J=7.0Hz) .MS (ES) C
25H
34N
4O
4Desired value: 454, discovery value: 455 (M+H)
+.
Embodiment 311
4-{[2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo ninth of the ten Heavenly Stems
Base)-and 1H-imidazoles-1--5-yl] methyl } morpholine-4-two (trifluoroacetate) is (LL2)
Step 1:N-[6-(2-ethyl-1,3-dioxolane-2-yl)-1-(5-formyl radical-1H-imidazoles-2-
Base)
Hexyl]-2-(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanamide (LL1)
Embodiment 310 with stirring adds MnO in the DCM solution of the alcohol of KK5
2(10 equivalent) and at room temperature said mixture is stirred and spend the night is then with its filtration over celite.Under reduced pressure solvent is removed, thus the aldehyde that obtains expecting.
1H NMR (300MHz, CDCl
3) δ: 9.85-9.70 (1H, s), 8.05-7.90 (1H, s), 7.65-7.55 (1H, s), 7.15-7.05 (1H, d.J=6.8Hz), 7.85-7.68 (2H, m), 4.85-4.75 (1H, m), 3.95-3.85 (4H, s), 3.85-3.75 (3H, s), 3.55-3.40 (2H, m), 2.30 (3H, s), 1.90-1.20 (8H, m), 1.00-0.75 (7H, m) .MS (ES) C
27H
36N
4O
5Desired value: 496, discovery value: 497 (M+H)
+.
Step 2:4-{[2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-
7-oxo nonyl)-and 1H-imidazoles-1--5-yl] methyl } morpholine-4-two (trifluoroacetate) is (LL2)
Aldehyde (LL1) is absorbed in the methyl alcohol and morpholine (2 equivalent) is added wherein, subsequently with AcOH (2 equivalent) and NaBH
3(CN) (1 equivalent) adds wherein, and at room temperature said mixture stirred 4 hours.By adding saturated NH
4The Cl aqueous solution will react quencher and under reduced pressure said mixture be concentrated.With saturated NaHCO
3The aqueous solution adds wherein, and products obtained therefrom extracts, carries out drying (Na with EtOAc
2SO
4) and under reduced pressure concentrate.Use H
2O (+0.1%TFA) and MeCN (+0.1%TFA) as elutriant (post: C18), by the preparation RP-HPLC gained mixture is carried out purifying.Collect desired components, be placed on then in the acidic solution till the ketal protection is removed, subsequently solution is carried out lyophilize, thereby obtain title compound.
1H-NMR (300MHz, CDCl
3) δ: 9.35 (1H, d, J=3Hz), 9.03 (1H, s), 7.18 (1H, d, J=7.3Hz), 7.03 (1H, s), 6.65 (1H, d, J=7.3Hz), 5.65-5.55 (1H, br.s), 5.10 (1H, q, J=6.5Hz), 4.10 (2H, s), 3.95-3.60 (11H, br.m), 2.95-2.60 (2H, m), 2.45-2.30 (7H, m), 2.05-1.90 (1H, m), 1.85-1.65 (1H, m), 1.55-1.15 (6H, m), 1.05 (3H, t, J=7.0Hz) .MS (ES) C
29H
41N
5O
4Desired value: 523, discovery value: 524 (M+H)
+.
Embodiment 312
2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-
5-[(1E)-3-methoxyl group-3-oxo third-1-alkene-1-yl]-1H-imidazoles-1-trifluoroacetate
(MM1)
To the aldehyde embodiment 311 that stirs, portioning adds Ph in the THF solution of LL1
3P=CHCO
2CH
3(6 equivalent), and at room temperature the gained mixture is stirred and spend the night.By adding 0.1M HCl solution with above-mentioned reaction quencher and be extracted among the EtOAc.The gained organism is carried out drying (Na
2SO
4), and under reduced pressure it is concentrated.Use H
2O (+0.1%TFA) and MeCN (+0.1%TFA) as elutriant (post: C18), by the preparation RP-HPLC the thick product of gained is carried out purifying.Collect desired components, be placed in the acidic solution, subsequently solution is carried out lyophilize, thereby obtain title compound to remove the ketal protection.
1H-NMR (300MHz, CD
3CN) δ: 9.00-8.90 (2H, m), 7.45-7.35 (1H, d, J=8.3Hz), 7.25 (1H, s), 7.12 (1H, d, J=7.3Hz), 6.95 (1H, s), 6.70-6.55 (2H, m), 5.20 (1H, q, J=6.5Hz), 3.95-3.65 (6H, m), 3.55-3.40 (2H, m), and 2.45-2.20 (7H, m), 1.95-1.80 (2H, m), 1.45-1.00 (6H, m), 0.95 (3H, t, J=7.0Hz) .MS (ES) C
28H
36N
4O
5Desired value: 508, discovery value: 509 (M+H)
+.
Embodiment 313
5-(2-carboxy ethyl)-2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] ammonia
Base }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate (NN1)
With embodiment 312, the unsaturated ester of MM1 is dissolved among the anhydrous EtOAc, and at H
2Under the atmosphere, in the presence of 10%Pd/C, said mixture was stirred 1 hour.With H
2Atmosphere is removed and with N
2Introduce wherein.Above-mentioned reaction mixture is filtered, with the EtOAc washing catalyst and under reduced pressure gained filtrate is concentrated.Use H
2O (+0.1%TFA) and MeCN (+0.1%TFA) as elutriant (post: C18), by the preparation RP-HPLC the thick product of gained is carried out purifying.Collect desired components and it is carried out lyophilize, thereby obtain title compound.
1H NMR (300MHz, (CD
3)
2SO) δ: 10.65 (1H, s), 8.65 (1H, d, J=5.0Hz), 7.35 (1H, s), 7.18 (1H, d, J=7.3Hz), 7.02 (1H, s), 6.65 (2H, d, J=7.3Hz), 4.98 (1H, q, J=6.5Hz), 3.78 (3H, s), and 3.70-3.40 (2H, m), 2.90-2.80 (2H, t, J=6.7Hz), 2.70-2.60 (2H, t, J=6.7Hz), 2.45-2.20 (7H, m), 1.90-1.75 (2H, m), and 1.40-1.10 (6H, m), 0.90 (3H, t, J=7.0Hz) .MS (ES) C
27H
36N
4O
5Desired value: 496, discovery value: 497 (M+H)
+.
Embodiment 314
5-ethanoyl-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] ammonia
Base }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate (OO1)
Under Ar, the embodiment 304 to stirring adds tributyl (1-vinyl ethyl ether base) stannic hydride (2 equivalent) and Pd (PPh in the DMF solution of EE6
3)
4(10mol%).Temperature is increased to 110 ℃ and continue heating 48 hours.Under reduced pressure solvent is removed, and on silica gel, the gained resistates is carried out purifying, use the 20%EtOAc/ sherwood oil as elutriant, thereby obtain 5-ethanoyl-(MS (ES) C by flash chromatography
37H
56N
4O
7The Si desired value: 696, discovery value: 697 (M+H)
+) and 5-(1-vinyl ethyl ether base)-imidazoles (MS (ES) C
39H
60N
4O
7The Si desired value: 725, discovery value: 726 (M+H)
+) mixture.
The mixture of purifying is dissolved among the THF, the THF solution (2.5 equivalent) of 1M TBAF is added wherein and under 65 ℃ with the said mixture heated overnight.By adding H
2O is above-mentioned reaction quencher, and product is extracted among the DCM.The organic phase of collecting with the salt water washing, carry out drying (Na
2SO
4) and under reduced pressure concentrate; thereby obtain the similar mixtures of ethanoyl and enol ether: 3-(2-{[(1S)-1-(5-ethanoyl-1H-imidazoles-2-yl)-7-oxo nonyl] amino }-the 2-oxoethyl)-5-methoxyl group-2-Methyl-1H-indole-1-t-butyl formate, MS (ES) C
31H
42N
4O
7Desired value: 566, discovery value: 567 (M+H)
+3-[2-((1S)-1-[5-(1-vinyl ethyl ether base)-1H-imidazoles-2-yl]-7-oxo nonyl } amino)-the 2-oxoethyl]-5-methoxyl group-2-Methyl-1H-indole-1-t-butyl formate, MS (ES) C
33H
46N
4O
6Desired value: 594, discovery value 595 (M+H)
+
Then, this material is dissolved in a small amount of DCM/TFA (1: 1) mixture and it was stirred 1 hour.By adding entry with above-mentioned reaction quencher and under reduced pressure solvent is removed.Use H
2O (+0.1%TFA) and MeCN (+0.1%TFA) (post: C18), RP-HPLC carries out purifying to products obtained therefrom by preparation, and it is carried out lyophilize, thereby obtains title compound as elutriant.
1H-NMR (300MHz, CDCl
3) δ: 8.00 (1H, s), 7.43 (1H, s), 7.08 (1H, d, J=7.3Hz), 6.80-6.65 (2H, m), 6.35 (1H, br.s), 4.88 (1H, q, J=5.5Hz), 3.75 (3H, s), 3.63 (2H, s), and 2.40-2.10 (10H, m), 1.90-1.10 (8H, m), 0.95 (3H, t, J=7.0Hz) .MS (ES) C
26H
34N
4O
4Desired value: 466, discovery value: 467 (M+H)
+.
Embodiment 315
5-cyclohexyl-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] ammonia
Base }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate (PP4)
Step 1:[(1S)-1-(4-hexamethylene-1-alkene-1-base-1-{[2-(trimethyl silyl) oxyethyl group]
Methyl }-1H-imidazoles-2-yl)-7-oxo nonyl] t-butyl carbamate (PP1)
Use hexamethylene-1-alkene-1-ylboronic acid and [(1S)-1-(4-bromo-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-imidazoles-2-yl)-7-oxo nonyl] t-butyl carbamate, carry out the Suzuki coupling according to embodiment 304 steps 7, thereby obtain desired compounds.MS (ES) C
29H
51N
3O
4Si, desired value: 533, discovery value: 534 (M+H)
+
Step 2:[(1S)-1-(5-cyclohexyl-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-
1H-imidazoles-2-yl)-and 7-oxo nonyl] t-butyl carbamate (PP2)
(PP1) is dissolved among the EtOAc with the cyclohexenyl imidazoles, and at H
2Under the atmosphere, in the presence of 10%Pd/C, it was stirred 1 hour.With H
2Atmosphere is removed and with N
2Introduce wherein.Above-mentioned reaction mixture is filtered, with the EtOAc washing catalyst and under reduced pressure gained filtrate is concentrated.Use H
2O (+0.1%TFA) and MeCN (+0.1%TFA) as elutriant (post: C18), by the preparation RP-HPLC the thick product of gained is carried out purifying.Collect desired components and it is carried out lyophilize, thereby obtain expecting compound.MS (ES) C
29H
49N
3O
4Si, desired value: 535, discovery value: 536 (M+H)
+
Step 3:(9S)-9-amino-9-(5-cyclohexyl-1H-imidazoles-2-yl) ninth of the ten Heavenly Stems-3-ketone (PP3)
Be dissolved in carbamate (PP2) among a small amount of DCM/TFA (1: 1) and at room temperature it stirred 1 hour.By adding entry with above-mentioned reaction quencher and under reduced pressure solvent is removed.Products obtained therefrom is distributed in DCM and saturated NaHCO
3Between the aqueous solution.Organic phase is separated, with the salt water washing, carry out drying (Na
2SO
4) and under reduced pressure it is concentrated, thereby the amine that obtains expecting.MS (ES) C
18H
31N
3O, desired value: 305, discovery value: 306 (M+H)
+
Step 4:5-cyclohexyl-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) second
Acyl group] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate (PP4)
(PP3) is absorbed among the DMF with amine, and the DMF solution (pre-mixing 5 minutes) of (5-methoxyl group-2-Methyl-1H-indole-3-yl) acetate (1.3 equivalent), HOBt (1.3 equivalent) and EDC.HCl (1.3 equivalent) is added wherein, then DIPEA (1.3 equivalent) is added wherein.At room temperature said mixture was stirred 3 hours, use H then
2O (0.1%TFA) and MeCN (+0.1%TFA) (post: C18), RP-HPLC carries out purifying to it by preparation as elutriant.Collect desired components and it is carried out lyophilize, thereby obtain title compound.
1H NMR (300MHz, (CD
3)
2SO) δ: 10.65 (1H, s), 8.68 (1H, d, J=3.5Hz), 7.35 (1H, s), 7.18 (1H, d, J=7.3Hz), 7.00 (1H, s), 6.68 (1H, d, J=7.3Hz), 4.98 (1H, q, J=5.0Hz), 3.80 (3H, s), 3.50-3.10 (2H, m), 2.75-2.50 (1H, m), and 2.50-2.30 (7H, m), 2.05-1.70 (6H, m), 1.50-1.10 (12H, m), 0.97 (3H, t, J=7.0Hz) .MS (ES) C
30H
42N
4O
3Desired value: 506, discovery value: 507 (M+H)
+.
Embodiment 316
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-the 7-oxo
Undecyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate (QQ4)
Step 1:(7S)-and the 7-[(tertbutyloxycarbonyl) amino]-7-(4-phenyl-1H-imidazoles-2-yl) enanthic acid
The tert-butyl ester (QQ1)
At room temperature, with embodiment 107, I3 and Cs
2CO
3The EtOH solution stirring of (0.6 equivalent) 30 minutes under reduced pressure concentrates it then.2-bromo-1-phenyl ethyl ketone (1.2 equivalent) is joined in the DMF solution of gained salt, and at N
2In, at room temperature the gained mixture was stirred 1.5 hours.With DMF with the toluene coevaporation.EtOAc is added wherein, the gained mixture is filtered, and the gained resistates is washed with EtOAc.The filtrate that under reduced pressure is combined concentrates.With gained oil and NH
4The toluene solution reflux of OAc (20 equivalent) 2 hours utilizes the Dean-Stark trap with excessive N H simultaneously
4OAc and H
2O removes.Said mixture is cooled to room temperature, with EtOAc dilution and water (* 2), saturated NaHCO
3The aqueous solution, water (* 2) and salt water washing.Above-mentioned solution is carried out drying (Na
2SO
4), under reduced pressure concentrate and on silica gel, the gained brown oil carried out purifying by chromatography, with EtOAc/ sherwood oil (9: 1～3: 2) wash-out, thereby obtain being light brown foamy title compound.
1H NMR (400MHz, DMSO-d6) δ: 11.75 (1H, s), 7.73 (2H, d, J=7.5Hz), 7.76 (1H, s), 7.31, (2H, t, J=7.5Hz), 7.18-7.11 (1H, m), 7.05 (1H, d, J=8.1Hz), 4.63-4.51 (1H, m), 2.15 (2H, t, J=7.2Hz), 1.87-1.75 (1H, m), 1.75-1.64 (1H, m), 1.52-1.43 (2H, m), 1.38 (18H, s), 1.33-1.18 (4H, m) .MS (ES) C
25H
37N
3O
4Desired value: 443, discovery value: 444 (M+H)
+.
Step 2:2-[(1S)-the 1-amido (ammonio)-6-carboxyl hexyl]-5-phenyl-1H-miaow
Azoles-3-two (trifluoroacetate) (QQ2)
Under 0 ℃, imidazoles (QQ1) (1 equivalent) is dissolved among the TFA/DCM (1: 1), cooling bath is removed and at room temperature the gained mixture was stirred 2 hours.Then, under reduced pressure solvent is removed, the thick product of gained does not need to be further purified and can use like this.MS (ES) C
16H
21N
3O
2, desired value: 287, discovery value: 288 (M+H)
+
Step 3:(7S)-and N-methoxyl group-7-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) acetyl
Base] amino }-N-methyl-7-(5-phenyl-1H-imidazoles-2-yl) heptamide (QQ3)
At room temperature, with the DMF solution stirring of EDC.HCl (1.2 equivalent), HOBt (1.2 equivalent) and (5-methoxyl group-2-Methyl-1H-indole-3-yl) acetate (1.2 equivalent) 1 hour, then this solution is joined in the DMF solution of amine (QQ2) (1 equivalent) and DIPEA (2 equivalent).The said mixture stirring is spent the night, and then HATU (2 equivalent) is added wherein, after 1 hour, CH
3ON (CH
3) H.HCl (2 equivalent) adds wherein.After stirring in addition 12 hours again, use H
2O (0.1%TFA) and MeCN (+0.1%TFA) (post: C18), RP-HPLC directly carries out purifying to the gained crude product by preparation as elutriant.Desired components is carried out lyophilize, thereby obtain title compound into white solid.Then, use saturated NaHCO
3The aqueous solution extracts compound, thereby obtains free alkali.
1H NMR (400MHz, DMSO-d6) δ: 10.62 (1H, s), 8.62 (1H, d, J=6.3Hz), 8.03 (1H, s), 7.77 (2H, d, J=7.6Hz), 7.52 (2H, t, J=7.6Hz), 7.48-7.39 (1H, m), 7.10 (1H, d, J=8.6Hz), 6.96 (1H, s), and 6.64-6.56 (2H, m), 5.06-4.96 (1H, m), 3.69 (3H, s), 3.62 (3H, s), and 3.60-3.45 (2H, m), 3.06 (3H, s), and 2.35-2.26 (2H, m), 2.36-2.26 (5H, m), 1.50-1.18 (6H, m) .MS (ES) C
30H
37N
5O
4Desired value: 531, discovery value: 532 (M+H)
+.
Step 4:2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] ammonia
Base }-7-oxo undecyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate (QQ4)
Under-78 ℃, in the THF of QQ3 (2mL) solution, add n-BuLi (5 equivalent).After 1 hour, by adding H carefully
2O is with above-mentioned reaction mixture quencher.Be warming up to after the room temperature, extract water with EtOAc, the organic phase that is combined is carried out drying (MgSO
4) and under reduced pressure solvent is removed.Use H
2O (0.1%TFA) and MeCN (+0.1%TFA) as elutriant (post: C18),, after lyophilize, obtain imidazoles into white solid by the separating substances of preparation RP-HPLC with expectation.
1H NMR (300MHz, CDCl
3) δ: 10.23 (1H, d, J=6.9Hz), 8.25 (1H, s), 7.52-7.32 (6H, m), 7.13 (1H, d, J=8.5Hz), 6.87 (1H, m), 6.73 (1H, d, J=8.5Hz), 5.88 (1H, m), 5.44 (1H, m), 3.73 (2H, s), 3.62 (3H, s), 2.35 (6H, m), 2.27 (3H, s), 1.98 (2H, m), 1.60-0.94 (8H, m), 0.89 (3H, t, J=7.2Hz) .MS (ES) C
32H
40N
4O
3Desired value: 529, discovery value: 530 (M+H)
+.
Embodiment 317
2-((1S)-7-cyclopropyl-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] ammonia
Base }-7-oxo heptyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate (RR1)
This material uses QQ3 and cyclopropyl bromination magnesium to obtain as described in embodiment 316.
1H NMR (300MHz, CDCl
3) δ: 10.32 (1H, d, J=8.0Hz), 8.31 (1H, s), 7.52-7.31 (5H, m), 7.12 (1H, d, J=8.6Hz), 6.89 (1H, d, J=1.5Hz), 6.73 (1H, dd, J=8.6Hz, J=1.5Hz), 5.88 (1H, m), 5.43 (1H, m), 3.73 (2H, s), 3.62 (3H, s), 2.48 (2H, m), 2.27 (3H, s), 2.05-1.86 (4H, m), 1.50 (2H, m), 1.24 (3H, m), 0.98 (3H, m), 0.86 (2H, m) .MS (ES) C
31H
36N
4O
3Desired value: 513, discovery value: 514 (M+H)
+.
Embodiment 318
2-((1S)-{ [(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-9-methyl-7-
The oxo decyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate (SS1)
This material uses QQ3 and isobutyl-bromination magnesium to obtain as described in embodiment 316.
1H NMR (300MHz, CDCl
3) δ: 10.60 (1H, d, J=8.0Hz), 8.19 (1H, s), 7.53-7.32 (5H, m), 7.14 (1H, d, J=8.6Hz), 6.91 (1H, d, J=2.0Hz), 6.75 (1H, dd, J=8.6Hz, J=2.0Hz), 5.75 (1H, br s), 5.46 (1H, m), 3.75 (2H, s), 3.62 (3H, s), 2.37-1.69 (10H, m), 1.46 (2H, m), 1.33-1.00 (5H, m), 0.90 (3H, d, J=6.6Hz), 0.89 (3H, d, J=6.6Hz) .MS (ES) C
32H
40N
4O
3Desired value: 529, discovery value: 530 (M+H)
+.
Embodiment 319
2-((1S)-8-hydroxyl-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-
7-oxo octyl group)-5-phenyl-1H-imidazoles-1-trifluoroacetate (TT1)
The Et that in the THF solution of-78 ℃ chloroiodomethanes (5.3 equivalent), slowly adds MeLi
2O (5.3 equivalent) solution after 5 minutes, is conveyed into solution in the THF solution of QQ3 (1 equivalent) of-78 ℃ embodiment 316 through sleeve pipe.Under-78 ℃, above-mentioned reaction was stirred 2 hours, will react quencher by adding entry carefully then.Be warming up to after the room temperature, the gained water extracts with EtOAc.The organic phase that is combined is carried out drying (MgSO
4), and under reduced pressure solvent is removed.
Under 60 ℃, the thick product of above-mentioned gained is dissolved among the DMF (3mL) and it was handled 2 hours with potassium acetate (1 equivalent).Above-mentioned reaction mixture washs with the EtOAc dilution and with salt solution (2 *).Organic phase is carried out drying (MgSO
4), and under reduced pressure solvent is removed.At room temperature, the thick acetic ester of gained is dissolved in the methyl alcohol (3mL) and handled 30 minutes with yellow soda ash (1 equivalent).Water is added wherein, and the gained water extracts with EtOAc.The organic phase that is combined is carried out drying (MgSO
4) and under reduced pressure it is concentrated.Use H
2O (0.1%TFA) and MeCN (+0.1%TFA) as elutriant (post: C18),, thereby obtain imidazoles into water white oil by the separating substances of preparation RP-HPLC with expectation.
1H NMR (300MHz, CDCl
3) δ: 10.60 (1H, s), 8.56 (1H, br s), 7.99 (1H, s), 7.75 (2H, d, J=7.5Hz), 7.53-7.37 (3H, m), 7.09 (1H, d, J=8.8Hz), 6.95 (1H, d, J=2.0Hz), 6.59 (1H, dd, J=2.0Hz, J=8.8Hz), 4.99 (1H, m), 4.00 (2H, s), 3.67 (3H, s), 3.51 (2H, m), 2.29 (5H, m), 1.88 (2H, m), 1.45-1.12 (8H, m) .MS (ES) C
29H
34N
4O
4Desired value: 502, discovery value: 503 (M+H)
+.
Embodiment 320
2-((1S)-7-(2-furyl)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl]
Amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate (UU1)
The hexane solution (10 equivalent) that in the THF solution of-78 ℃ furans (10 equivalent), slowly adds n-BuLi.Then, above-mentioned solution is warming up to 0 ℃ and under 0 ℃, it was stirred 1.5 hours.Be cooled to after-78 ℃, send it to (7S)-N-methoxyl group-7-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl of-78 ℃ through sleeve pipe) ethanoyl] amino }-N-methyl-7-[5-(2-naphthyl)-1H-imidazoles-2-yl] in the THF solution of heptamide (1 equivalent) (being prepared) according to the mode that is similar to embodiment 316 QQ3.Make above-mentioned reaction mixture be warming up to ambient temperature overnight, water is carefully with its quencher then.The gained water extracts with EtOAc.The organic phase that is combined is carried out drying (MgSO
4), and under reduced pressure solvent is removed.Use H
2O (+0.1%TFA) and MeCN (+0.1%TFA) as elutriant (post: C18),, thereby obtain imidazoles O1 into white solid by the separating substances of preparation RP-HPLC with expectation.
1H NMR (300MHz, DMSO) δ: 10.61 (1H, s), 8.64 (1H, d, J=5.8Hz), 8.33 (1H, s), 8.14 (1H, s), 8.04 (1H, d, J=8.8Hz), 7.99-7.86 (4H, m), 7.58 (2H, m), 7.38 (1H, dd, J=0.7Hz, J=3.6Hz), 7.08 (1H, d, J=8.8Hz), 6.97 (1H, d, J=2.4Hz), 6.67 (1H, dd, J=1.6Hz, J=3.6Hz), 6.57 (1H, dd, J=2.4Hz, J=8.6Hz), 5.04 (1H, m), 3.65 (3H, s), 3.53 (2H, dt, J=14.7Hz, J=14Hz), 2.74 (2H, t, J=7.3Hz), 2.30 (3H, s), 1.94 (2H, m), 1.58-1.17 (6H, m) .MS (ES) C
36H
36N
4O
4Desired value: 589, discovery value: 590 (M+H)
+.
Embodiment 321
2-[(1S)-and 1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-8-(methyl
Sulfinyl)-7-oxo octyl group]-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate (VV1)
Hexane (15 equivalent) solution that in the THF solution of-78 ℃ DMSO (15 equivalent), slowly adds n-BuLi; after 30 minutes, above-mentioned solution is joined (7S)-N-methoxyl group-7-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl of-78 ℃ through sleeve pipe) ethanoyl] amino }-N-methyl-7-[5-(2-naphthyl)-1H-imidazoles-2-yl] in the THF solution of heptamide (1 equivalent) (being prepared) according to the mode that is similar to embodiment 316QQ3.Make above-mentioned reaction mixture be warming up to ambient temperature overnight, then by adding entry carefully with its quencher.The gained water extracts, carries out drying (MgSO with EtOAc
4), under reduced pressure solvent is removed then.Use H
2O (+0.1%TFA) and MeCN (+0.1%TFA) as elutriant (post: C18), the material of expectation is separated, and it is carried out lyophilize, thereby obtain imidazoles into water white oil by preparation RP-HPLC.
1H NMR (300MHz, CDCl
3) δ: 10.10 (1H, br s), 8.25 (1H, s), 8.11 (1H, s), and 7.88-7.73 (3H, m), 7.58-7.46 (2H, m), 7.43-7.34 (1H, m), 7.15 (1H, d, J=8.6Hz), 6.91 (1H, d, J=1.7Hz), 6.74 (1H, dd, J=1.7Hz, J=8.6Hz), 6.11 (1H, d, J=15Hz), 5.48 (1H, m), 3.77 (4H, s), 3.62 (3H, s), 2.69 (3H, s), 2.47 (2H, m), 2.30 (3H, s), 2.15-1.92 (2H, m), 1.53 (2H, m), 1.37-1.04 (4H, m) .MS (ES) C
34H
39N
4O
4The S desired value: 599, discovery value: 600 (M+H)
+.
Embodiment 322
2-[(1S)-and 1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-8-(first sulphur
Acyl group)-7-oxo octyl group]-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate (WW1)
This material uses dimethyl sulfone, obtains as described in embodiment 321.
1H NMR (300MHz, DMSO) δ: 10.83 (1H, s), 8.84 (1H, d, J=6.4Hz), 8.54 (1H, s), 8.37 (1H, s), 8.26 (1H, d, J=8.6Hz), 8.21-8.06 (4H, m), 7.80 (2H, m), 7.31 (1H, d, J=8.6Hz), 7.18 (1H, d, J=2.0Hz), 6.80 (1H, dd, J=2.0Hz, J=8.6Hz), 5.26 (1H, m), 4.64 (2H, s), 3.88 (3H, s), 3.75 (2H, m), 3.26 (3H, s), 2.77 (2H, t, J=7.0Hz), 2.52 (3H, s), 2.15 (2H, m), 1.70-1.36 (6H, m) .MS (ES) C
34H
38N
4O
5The S desired value: 615, discovery value: 616 (M+H)
+.
Embodiment 323
2-((1S)-8-(amino-sulfonyl)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) acetyl
Base] amino }-7-oxo octyl group)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate (XX1)
Hexane (30 equivalent) solution that in the THF solution of (methylsulfonyl) t-butyl carbamates (15 equivalent) of-78 ℃, slowly adds n-BuLi; after 30 minutes; through sleeve pipe above-mentioned solution is joined (7S)-N-methoxyl group-7-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl of-78 ℃) ethanoyl] amino }-N-methyl-7-[5-(2-naphthyl)-1H-imidazoles-2-yl] in the THF solution of heptamide (1 equivalent) (according to being similar to embodiment 316, the mode of QQ3 is prepared).Make said mixture be warming up to ambient temperature overnight, then carefully water with its quencher.The gained water extracts with EtOAc and it is carried out drying (MgSO
4), under reduced pressure solvent is removed.
The thick product of gained is dissolved among the DCM/TFA (3: 1) again and it was stirred 1 hour.Under reduced pressure solvent is removed, used H then
2O (+0.1%TFA) and MeCN (+0.1%TFA) as elutriant (post: C18), by preparation RP-HPLC the product of expectation is separated, thereby obtain imidazoles into white solid.
1H NMR (300MHz, DMSO) δ: 10.61 (1H, s), 8.60 (1H, m), 8.32 (1H, s), 8.13 (1H, s), 8.05 (1H, d, J=8.6Hz), 7.99-7.84 (4H, m), 7.58 (2H, m), 7.09 (3H, m), 6.96 (1H, d, J=2.4Hz), 6.58 (1H, dd, J=2.4Hz, J=8.6Hz), 5.03 (1H, m), 4.15 (2H, s), 3.66 (3H, s), 3.59 (2H, m), 2.60 (2H, t, J=7.0Hz), 2.30 (3H, s), 1.93 (2H, m), 1.48-1.15 (8H, m) .MS (ES) C
33H
37N
5O
5The S desired value: 616, discovery value: 617 (M+H)
+.
Embodiment 324
1-methyl-4-([(1S)-7-oxo-1-(4-phenyl-1H-imidazoles-3--2-yl)-7-pyridine-2-base
Heptyl] amino } carbonyl) piperidines two (trifluoroacetate) is (YY8)
Step 1:(7S)-and the 7-[(tertbutyloxycarbonyl) amino]-7-(5-phenyl-1H-imidazoles-2-yl) enanthic acid
The tert-butyl ester (YY1)
Use Cs
2CO
3(0.5 equivalent) handled [(2S)-8-tert.-butoxy-2-[(tertbutyloxycarbonyl) amino]-sad EtOH solution (0.5M) of 8-oxo.At room temperature above-mentioned reaction mixture was stirred 50 minutes,, gained salt is dissolved among the DMF and subsequently it is handled with 2-bromo-1-phenyl ethyl ketone (1.0 equivalent) then under reduced pressure with solvent evaporation.At room temperature above-mentioned reaction mixture was stirred 1 hour, then DMF and toluene coevaporation are removed.The gained resistates is suspended among the EtOAc and to it filters.Under reduced pressure gained filtrate is concentrated, thereby obtain oil, be dissolved in toluene.Use NH
4OAc (20 equivalent) handles above-mentioned gained solution (0.14M) and is heated backflow 2 hours with the Dean-Stark trap.Above-mentioned reaction mixture is cooled to room temperature, with EtOAc and saturated NaHCO
3The aqueous solution dilutes it.The salt water washing of gained organic layer.Carry out drying and under reduced pressure concentrate, thereby obtain oil, on silica gel, it is carried out purifying,, thereby obtain being the solid title compound with 20%EtOAc/ sherwood oil/EtOAc wash-out by chromatography.
1H NMR (400MHz, DMSO-d
6, 300K) δ 11.77 (1H, s), 7.75 (2H, d, J=7.3Hz), 7.48 (1H, s), 7.33 (2H, t, J=7.6Hz), 7.17 (1H, t, J=7.3Hz), and 7.12-7.02 (1H, m), 4.70-4.50 (1H, m), 2.17 (2H, t, J=7.3Hz), 1.93-1.63 (2H, m), 1.57-1.15 (24H, m); MS (ES) C
25H
37N
3O
4Desired value: 443, discovery value: 444 (M+H)
+.
Step 2:(7S)-and the 7-{1-[(benzyloxy) methyl]-5-phenyl-1H-imidazoles-2-yl }-uncle's 7-[(fourth
The oxygen carbonyl) amino] enanthic acid (YY2)
The MeCN solution of imidazoles (YY1) is handled and under refluxing, it was stirred 3 hours with [(chloro methoxyl group) methyl] benzene (1.2 equivalent).Said mixture is cooled to room temperature, under reduced pressure with solvent evaporation, gained resistates H
2O dilutes and extracts with EtOAc.The organic layer of collecting with the salt water washing, carry out drying and under reduced pressure concentrate, thereby contained (7S)-7-{1-[(benzyloxy) methyl]-5-phenyl-1H-imidazoles-2-yl }-the 7-[(tertbutyloxycarbonyl) amino] the enanthic acid tert-butyl ester and (7S)-7-amino-7-{1-[(benzyloxy) methyl]-5-phenyl-1H-imidazoles-2-yl } Residual oil of mixture of the enanthic acid tert-butyl ester, it does not need to be further purified and can use.MS (ES) C
33H
45N
3O
5, desired value: 563, discovery value: 564 (M+H)
+
DCM/TFA (4: 1) solution to said mixture under 0 ℃ stirs, and then cooling bath is removed and at room temperature reaction mixture is stirred 1 hour.Under reduced pressure solvent is removed and the gained resistates is carried out coevaporation with toluene, thereby obtain desired compounds, it does not need to be further purified and can use.MS (ES) C
24H
29N
3O
3, desired value: 407, discovery value: 408 (M+H)
+
H with above-mentioned intermediate
2O/MeCN solution is cooled to 0 ℃ and use NaHCO
3(3.0 equivalent) and Boc
2O (1.5 equivalent) handles it.At room temperature above-mentioned reaction mixture was stirred 2 hours.Under reduced pressure with CH
3CN removes and the gained water extracts with EtOAc.With 1N HCl its pH value is adjusted to 4-5, and once more it is extracted.The organic phase of collecting with the salt water washing, carry out drying and under reduced pressure concentrate, thereby obtain succinol, on with the silica gel of 50-60%EtOAc/ sherwood oil wash-out, it is carried out purifying, thereby obtain title compound (92%) into light amber oil by chromatography.
1H NMR (400MHz, DMSO-d
6, 300K) δ 8.11 (1H, s), 7.81 (2H, d, J=7.5Hz), 7.50 (2H, t, J=7.7Hz), 7.41-7.28 (7H, m), 5.81 (1H, d, J=10.2Hz), 5.64 (1H, d, J=10.2Hz), 4.96-4.86 (1H, m), 4.69-4.59 (2H, m), 2.17 (2H, t, J=7.3Hz), 1.97-1.85 (2H, m), 1.55-1.43 (15H, m); MS (ES) C
29H
37N
3O
5Desired value: 507, discovery value: 508 (M+H)
+.
Step 3:((1S)-and the 1-{1-[(benzyloxy) methyl]-5-phenyl-1H-imidazoles-2-yl }-the 7-hydroxyl
Heptyl) t-butyl carbamate (YY3)
The THF solution of above-mentioned acid (YY2) is handled and it is cooled to 0 ℃ with 4-methylmorpholine (2.0 equivalent).By dripping chlorocarbonic acid isobutyl ester (2.0 equivalent) gained solution is handled, under 0 ℃ it was stirred 15 minutes then, white precipitate obtains forming during this period.Precipitation is leached, pass through to drip NaBH down at 0 ℃
4The H of (2.5 equivalent)
2O solution (0.6M) is handled gained filtrate.Under uniform temp, above-mentioned reaction mixture was stirred 15 minutes, then it is warming up to room temperature and under reduced pressure THF is removed.Gained resistates H
2O dilutes and extracts with EtOAc.The organic layer of collecting with the salt water washing, carry out drying and under reduced pressure concentrate, thereby obtain yellow oil.On with the silica gel of 30%EtOAc/ sherwood oil wash-out, it is carried out purifying, thereby obtain title compound into light yellow solid by chromatography.
1H?NMR(400MHz，DMSO-d
6，300K)δ8.26(1H，s)，7.83-7.76(3H，m)，7.57-7.50(2H，m)，7.49-7.43(1H，m)，7.38-7.26(5H，m)，5.86(1H，d，J＝10.7Hz)，5.74(1H，d，J＝10.7Hz)，5.04-4.94(1H，m)，4.68(2H，s)，3.36(2H，t，J＝6.6Hz)，2.05-1.81(2H，m)，1.47-1.17(15H，m).
Step 4:((1S)-and the 1-{1-[(benzyloxy) methyl]-5-phenyl-1H-imidazoles-2-yl }-the 7-oxo
Heptyl) t-butyl carbamate (YY4)
Crossing iodine alkane (2.0 equivalent) with pyridine (4.2 equivalent) and Dess-Martin handles the DCM solution of alcohol (YY3).Above-mentioned reaction mixture was stirred 3 hours, use saturated Na then
2CO
3The aqueous solution dilutes above-mentioned reaction mixture and with DCM it is extracted.The organic phase of collecting with the salt water washing, carry out drying and under reduced pressure concentrate, thereby obtain title compound into water white oil.
1H NMR (400MHz, CDCl
3, 300K) δ 9.71 (1H, s), 7.80 (2H, d, J=7.5Hz), 7.43-7.23 (8H, m), 7.20 (1H, s), 5.68 (1H, d, J=10.6Hz), 5.38-5.24 (1H, bs), 5.28 (1H, d, J=10.6Hz), 5.00-4.89 (1H, m), 4.54 (2H, s), 2.36 (2H, t, J=6.6Hz), 2.08-1.89 (2H, m), 1.63-1.53 (2H, m), 1.43 (9H, s), 1.41-1.30 (4H, m); MS (ES) C
29H
37N
3O
4Desired value: 491, discovery value: 492 (M+H)
+.
Step 5:((1S)-and the 1-{1-[(benzyloxy) methyl]-5-phenyl-1H-imidazoles-2-yl }-7-hydroxyl-7-
Pyridine-2-base heptyl) t-butyl carbamate (YY5)
The THF solution of 2-bromopyridine (2.05 equivalent) is cooled to-78 ℃ and with the hexane solution (2.1 equivalent) of the n-BuLi of 1.6M it is handled.Under-78 ℃, the gained orange solution was stirred 30 minutes, use the THF solution of aldehyde (YY4) that it is handled then.Make the gained pale yellow solution be warming up to ambient temperature overnight, it is cooled to 0 ℃ then, use saturated NH
4The Cl aqueous solution extracts it with its quencher and with EtOAc.The organic phase of collecting with the salt water washing, carry out drying and under reduced pressure it evaporated.On silica gel, the gained yellow oil is carried out purifying, use 30-50%EtOAc/ sherwood oil wash-out, thereby obtain title compound into light yellow oil by chromatography.
1H NMR (400MHz, DMSO-d
6, 300K) δ 8.46 (1H, d, J=4.6Hz), 7.82-7.69 (4H, m), 7.45 (1H, d, J=7.9Hz), 7.41-7.26 (8H, m), 7.25-7.16 (2H, m), 5.66 (1H, d, J=10.6Hz), 5.42 (1H, d, J=10.6Hz), 5.25 (1H, d, J=5.0Hz), 4.80-4.68 (1H, m), 4.60-4.46 (2H, m), 3.36-2.28 (2H, m), 1.92-1.77 (2H, m), 1.76-1.64 (1H, m), 1.63-1.49 (1H, m), 1.35 (9H, s), 1.36-1.22 (4H, m); MS (ES) C
3H
42N
4O
4Desired value: 570, discovery value: 571 (M+H)
+.
Step 6:((1S)-and the 1-{1-[(benzyloxy) methyl]-5-phenyl-1H-imidazoles-2-yl }-7-oxo-7-
Pyridine-2-base heptyl) t-butyl carbamate (YY6)
Crossing iodine alkane (2.0 equivalent) with pyridine (4.2 equivalent) and Dess-Martin handles the DCM solution of alcohol (YY5).Above-mentioned reaction mixture was stirred 3 hours, use saturated Na then
2CO
3The aqueous solution dilutes above-mentioned reaction mixture and with DCM it is extracted.The organic phase of collecting with the salt water washing, carry out drying and under reduced pressure concentrate, thereby obtain brown oil, on the silica gel of 20-30%EtOAc/ sherwood oil wash-out, it is carried out purifying, thereby obtains expectation material into light yellow oil by chromatography.
1H NMR (400MHz, CDCl
3, 300K) δ 8.67 (1H, d, J=4.6Hz), 8.02 (1H, d, J=7.9Hz), 7.99-7.89 (2H, m), 7.83 (1H, td, J=1.3Hz, J=7.7Hz), 7.53-7.30 (10H, m), 7.17 (1H, s), 5.96-5.84 (1H, m), 5.49-5.36 (1H, m), and 5.13-5.01 (1H, m), 4.74-4.59 (2H, m), 3.19 (2H, t, J=7.2Hz), 2.54-2.36 (1H, m), 2.23-2.09 (1H, m), 1.79-1.63 (2H, m), 1.50-1.22 (4H, m), 1.42 (9H, s); MS (ES) C
34H
40N
4O
4Desired value: 568, discovery value: 569 (M+H)
+.
Step 7:N-((1S)-1-{1-[(benzyloxy) methyl]-5-phenyl-1H-imidazoles-2-yl }-7-oxygen
Generation-7-pyridine-2-base heptyl)-1-methyl piperidine-4-carboxylic acid amides (YY7)
With TFA/DCM (1: 4) mixture ketone (YY6) is handled down at 0 ℃, then cooling bath is removed and at room temperature above-mentioned reaction mixture was stirred 1 hour.Under reduced pressure solvent is removed and the gained resistates is carried out coevaporation with toluene, thereby obtain thick product, it does not need to be further purified and can use.MS (ES) C
29H
32N
4O
2, desired value: 468, discovery value: 469 (M+H)
+Under 0 ℃, with EDC hydrochloride (1.2 equivalent), HOBt (1.2 equivalent) and Et
3N (4.2 equivalent) handles the DMF solution of 1-methyl piperidine-4-carboxylic acid and under 0 ℃ said mixture was stirred 30 minutes, the DMF solution adding of above-mentioned intermediate wherein and is at room temperature stirred reaction mixture spend the night then.Dilute above-mentioned reaction mixture and extract with 2N NaOH with EtOAc.The organic phase of collecting with the salt water washing, carry out drying and under reduced pressure it evaporated, thereby obtain title compound into light yellow solid, it promptly can be used in the next step without any need for purifying.
1H NMR (400MHz, DMSO-d
6, 300K) δ 8.71 (1H, d, J=4.4Hz), 8.28 (1H, d, J=8.3Hz), 8.01 (1H, dt, J=1.5Hz, J=7.7Hz), 7.95 (1H, d, J=7.7Hz), 7.81-7.72 (3H, m), and 7.69-7.62 (1H, m), 7.41-7.24 (7H, m), 7.21 (1H, t, J=7.3Hz), 5.65 (1H, d, J=10.7Hz), 5.39 (1H, d, J=10.7Hz), 5.12-5.01 (1H, m), 4.56 (1H, d, J=11.6Hz), 4.51 (1H, d, J=11.6Hz), 3.12 (2H, t, J=7.3Hz), 3.04-2.95 (2H, m), 2.76-2.63 (2H, m), 2.22-2.16 (1H, m), 2.14-2.04 (4H, m), 2.00-1.83 (2H, m), 1.82-1.67 (2H, m), 1.67-1.42 (4H, m), 1.41-1.19 (4H, m); MS (ES) C
36H
43N
5O
3Desired value: 593, discovery value: 594 (M+H)
+.
Step 8:1-methyl-4-([(1S)-7-oxo-1-(4-phenyl-1H-imidazoles-3--2-yl)-7-
Pyridine-2-base heptyl] amino } carbonyl) piperidines two (trifluoroacetate) is (YY8)
With BBr3 (3.0 equivalent) toluene solution of acid amides (YY7) is handled down at 0 ℃.At room temperature above-mentioned reaction mixture is stirred and spend the night, water dilutes it and under reduced pressure it is concentrated then.Use H
2O (+0.1%TFA) and MeCN (+0.1%TFA) as elutriant, (Waters X-TERRA MS C18,5 microns, 19 * 150mm) carry out purifying to the gained resistates, thereby obtain the title compound into oil by RP-HPLC.
1HNMR (400MHz, DMSO-d
6, 300K) δ 8.80-8.62 (2H, m), 8.08-7.91 (3H, m), 7.79 (2H, d, J=7.5Hz), 7.72-7.64 (1H, m), 7.59-7.35 (3H, m), 5.07-4.95 (1H, m), 3.53-3.38 (2H, m), and 3.23-3.12 (2H, m), 3.03-2.87 (2H, m), 2.79 (3H, s), 2.53-2.42 (1H, m), 2.09-1.83 (4H, m), and 1.81-1.58 (4H, m), 1.48-1.21 (4H, m); MS (ES) C
28H
35N
2O
2Desired value: 473, discovery value: 474 (M+H)
+.
Embodiment 325
2-((1S)-7-amino-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-
7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate (ZZ7)
Step 1:8-tertiary butyl 1-methyl (2S)-2-{[(benzyloxy) carbonyl] amino } suberate
(ZZ1)
With embodiment 107, I1 (1 equivalent) is dissolved among the THF and with it and is cooled to 0 ℃; 1M HCl (4 equivalent) adding wherein and with the gained mixture was stirred 20 minutes.1MNaOH (4 equivalent) is added wherein, and the gained water extracts with EtOAc, the organic phase of collection with brine treatment, carry out drying (Na
2SO
4) and under reduced pressure solvent is removed.Be dissolved in thus obtained light yellow oil among the DCM and with Et
3N (1.5 equivalent) adds wherein.In this mixture, add the DCM solution of N-(benzyloxycarbonyloxy base) succinimide (1.3 equivalent) and at room temperature it was stirred 1 hour, under reduced pressure solvent is removed.On silica gel, the gained yellow oil is carried out purifying, use 5-50%EtOAc/ sherwood oil wash-out, thereby obtain title compound into water white oil by chromatography.
1H NMR (400MHz, CDCl
3) δ: 7.42-7.28 (5H, m), 5.24 (1H, d, J=7.7Hz), 5.11 (2H, s), 4.41-4.32 (1H, m), 3.74 (3H, s), 2.19 (2H, t, J=7.5Hz), 1.89-1.77 (1H, m), 1.70-1.50 (3H, m), 1.44 (9H, s), 1.38-1.24 (4H, m) .MS (ES) C
21H
31NO
6Desired value: 393, discovery value: 394 (M+H)
+.
Step 2:(2S)-and the 2-{[(benzyloxy) carbonyl] amino }-8-tert.-butoxy-8-oxo is sad
(ZZ2)
Above-mentioned ester (ZZ1) (1 equivalent) is dissolved in THF/H
2Among the O (4: 1), and with LiOH-H
2O (1.1 equivalent) adds wherein, and the gained mixture was stirred 1.5 hours.1MHCl is added wherein, be 4-5 until the pH value, and under reduced pressure THF removed.The gained water extracts with EtOAc (3 *), and the organic phase of collection is with the salt water washing and subsequently it is carried out drying (Na
2SO
4).Under reduced pressure solvent is removed, thereby obtained title compound into water white oil, this compound is cured by placement.MS (ES) C
20H
29NO
6, desired value: 379, discovery value: 380 (M+H)
+
Step 3:(7S)-and the 7-{[(benzyloxy) carbonyl] amino }-7-[5-(2-naphthyl)-1H-imidazoles-2-yl]
The enanthic acid tert-butyl ester (ZZ3)
At room temperature with acid (ZZ2) (1 equivalent) and Cs
2CO
3The EtOH mixture of (0.5 equivalent) stirred 30 minutes, under reduced pressure it was concentrated then.2-2-bromo-1-(2-naphthyl) ethyl ketone (1 equivalent) is joined in the DMF solution of gained salt, and at N
2In, at room temperature the gained mixture was stirred 1.5 hours.With DMF with the toluene coevaporation.EtOAc is added wherein, the gained mixture is filtered, and the gained resistates is washed with EtOAc.The filtrate that under reduced pressure is combined concentrates.With gained oil and NH
4The toluene solution reflux of OAc (20 equivalent) 2 hours utilizes the Dean-Stark trap with excessive N H simultaneously
4OAc and H
2O removes.Said mixture is cooled to room temperature, with EtOAc dilution and water (* 2), saturated NaHCO
3The aqueous solution, water (* 2) and salt water washing.Above-mentioned solution is carried out drying (Na
2SO
4), under reduced pressure concentrate and on silica gel, the gained brown oil carried out purifying by chromatography, with EtOAc/ sherwood oil wash-out, thereby obtain being light brown foamy title compound.
1H NMR (400MHz, CDCl
3) δ: 7.95-7.70 (5H, m), 7.56-7.41 (3H, m), 7.39-7.30 (5H, m), 5.59 (1H, bs), 5.19-5.10 (2H, m), 4.83-4.72 (1H, m), 2.22 (2H, t, J=7.4Hz), 2.09-1.97 (1H, m), and 1.82-1.55 (5H, m), 1.45 (9H, s), 1.49-1.38 (2H, m) .MS (ES) C
32H
37N
3O
4Desired value: 528, discovery value: 529 (M+H)
+.
Step 4:(7S)-and the 7-{[(benzyloxy) carbonyl] amino }-7-[5-(2-naphthyl)-1H-imidazoles-2-yl]
Enanthic acid (ZZ4)
Under 0 ℃, imidazoles (ZZ3) (1 equivalent) is dissolved among the TFA/DCM (1: 1), cooling bath is removed and at room temperature the gained mixture was stirred 60 minutes.Under reduced pressure solvent is removed and on silica gel, the gained resistates is carried out purifying, use EtOAc/AcOH (99: 1) wash-out, thereby obtain being light brown foamy title compound by chromatography.
1H NMR (400MHz, DMSO-d6) δ: 11.99 (1H, bs), 8.34 (1H, s), 8.10-7.98 (3H, m), 7.98-7.76 (3H, m), 7.63-7.50 (2H, m), and 7.43-7.28 (4H, m), 5.16-4.98 (2H, m), and 4.90-4.80 (1H, m), 2.19 (2H, t, J=7.2Hz), 2.00-1.83 (2H, m), 1.56-1.44 (2H, m), 1.42-1.24 (4H, m) .MS (ES) C
28H
29N
3O
4Desired value: 471, discovery value: 472 (M+H)
+.
Step 5:{ (1S)-7-amino-1-[5-(2-naphthyl)-1H-imidazoles-2-yl]-7-oxo heptyl } ammonia
Base benzyl formate (ZZ5)
In the ace pipe, acid (ZZ4) (1 equivalent) is dissolved among the DMF, HATU (2 equivalent) and DIPEA (2 equivalent) adding wherein and are at room temperature stirred said mixture 1 hour.With NH
3Dioxane solution (0.5N, 5 equivalents) add wherein, after at room temperature stirring 3 hours, under reduced pressure solvent is removed.The thick product of gained is used for following reaction like this.MS (ES) C
28H
30N
4O
3, desired value: 470, discovery value: 471 (M+H)
+
Step 6:(7S)-and 7-amino-7-[5-(2-naphthyl)-1H-imidazoles-2-yl] heptamide (ZZ6)
At N
2Down, the MeOH solution of acid amides (ZZ5) (1 equivalent) is cooled to 0 ℃, then Pd/C (10%wt) is added wherein.At two vacuum-H
2After the loop cycle, at H
2Under the atmosphere said mixture was stirred 2.5 hours.Catalyzer is leached and wash, under reduced pressure solvent is removed then with methyl alcohol.The thick product of gained is used for following reaction like this.MS (ES) C
20H
24N
4O, theoretical value: 336, measured value: 337 (M+H)
+
Step 7:2-((1S)-7-amino-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) acetyl
Base] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate (ZZ7)
At room temperature, with the DCM solution stirring of EDC.HCl (1.2 equivalent), HOBt (1.2 equivalent) and (5-methoxyl group-2-Methyl-1H-indole-3-yl) acetate (1.2 equivalent) 1 hour, this solution is joined in the DMF solution of amine (ZZ6) then.At room temperature said mixture is stirred and spend the night, use H then
2O (0.1%TFA) and MeCN (+0.1%TFA) (post: C18), RP-HPLC directly directly carries out purifying to the thick product of gained by preparation as elutriant.Desired components is carried out lyophilize, thereby obtain title compound into white solid.
1H NMR (400MHz, DMSO-d6) δ: 10.62 (1H, s), 8.61 (1H, d, J=6.3Hz), 8.34 (1H, s), 8.16 (1H, s), 8.07 (1H, d, J=8.8Hz), 8.01-7.93 (2H, m), 7.90 (1H, dd J
1=8.6, J
2=1.8Hz), 7.66-7.55 (2H, m), 7.19 (1H, s), 7.10 (1H, d, J=8.6Hz), 6.97 (1H, d, J=2.3Hz), 6.67 (1H, s), 6.62 (1H, dd J
1=8.6, J
2=2.3Hz), 5.10-5.00 (1H, m), 3.68 (3H, s), 3.64-3.48 (2H, m), 2.32 (3H, s), 2.00 (2H, t, J=7.3Hz), 2.05-1.87 (2H, m), 1.52-1.32 (3H, m), 1.32-1.20 (3H, m) .MS (ES) C
32H
35N
5O
3Desired value: 537, discovery value: 538 (M+H)
+.
Embodiment 326
2-((1S)-6-carboxyl-1-{[(dimethylamino) alkylsulfonyl] amino } hexyl)-5-(2-naphthyl)-
1H-imidazoles-3-trifluoroacetate (AAA1)
At room temperature, with embodiment 107, the DMF solution stirring of I5 (1 equivalent), DIPEA (2 equivalent) and dimethylamino SULPHURYL CHLORIDE (2 equivalent) is spent the night.Use H
2(post: C18), RP-HPLC carries out purifying to the thick product of gained by preparation, and desired components is carried out lyophilize, thereby obtains the title compound into white solid as elutriant for O (0.1%TFA) and MeCN (0.1%TFA).
1H NMR (400MHz, DMSO-d6) δ: 12.04 (1H, bs), 8.33 (1H, s), 8.12 (1H, bs), 8.09-8.00 (2H, m), 7.99-7.87 (3H, m), and 7.63-7.52 (2H, m), 4.62-4.51 (1H, m), 2.63 (6H, s), 2.19 (2H, t, J=7.2Hz), 2.02-1.84 (2H, m), 1.55-1.44 (2H, m), 1.44-135 (1H, m), 1.35-1.16 (3H, m) .MS (ES) C
22H
28N
4O
4The S desired value: 444, discovery value: 445 (M+H)
+.
Embodiment 327
2-((1S)-7-(methylamino)-7-oxo-1-{[(1-pyridine-2-phenylpiperidines-3-yl) carbonyl] amino }
Heptyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate (BBB1)
Step 1:{ (1S)-7-(methylamino)-1-[5-(2-naphthyl)-1H-imidazoles-2-yl]-7-oxo heptan
Base } benzyl carbamate (BBB1)
With embodiment 325, ZZ4 (1 equivalent) is dissolved among the DMF and with HATU (2 equivalent) and DIPEA (2 equivalent) and adds wherein, at room temperature said mixture is stirred 1 hour.With MeNH
2THF solution (2N, 5 equivalents) add wherein, after at room temperature stirring 3 hours, under reduced pressure solvent is removed.The thick product of gained is used for following reaction like this.MS (ES) C
29H
32N
4O
3, theoretical value: 484, measured value: 485 (M+H)
+
Step 2:(7S)-and 7-amino-N-methyl-7-[5-(2-naphthyl)-1H-imidazoles-2-yl] heptamide
(BBB2)
At N
2Down, the MeOH solution of acid amides (BBB1) (1 equivalent) is cooled to 0 ℃, then Pd/C (10%wt) is added wherein.At two vacuum-H
2After the loop cycle, at H
2Under the atmosphere said mixture was stirred 2.5 hours.Catalyzer is leached and wash, under reduced pressure solvent is removed then with methyl alcohol.The thick product of gained is used for following reaction like this.MS (ES) C
21H
26N
4O, desired value: 350, discovery value: 351 (M+H)
+
Step 3:2-((1S)-7-(methylamino)-7-oxo-1-{[(1-pyridine-2-phenylpiperidines-3-yl)
Carbonyl] amino } heptyl)-5-(2-naphthyl)-1H-imidazoles-3-trifluoroacetate (BBB3)
1-pyridine-2-phenylpiperidines-3-carboxylic acid (1.1 equivalent) is suspended among the DCM, DIPEA (1.1 equivalent) and HATU (1.1 equivalent) adding wherein and are at room temperature stirred said mixture 1 hour.DMF solution (0.1M solution) adding of above-mentioned amine (BBB2) wherein and with its stirring is spent the night.Use H
2O (0.1%TFA) and MeCN (+0.1%TFA) as elutriant (post: C18), direct above-mentioned thick product is carried out purifying by preparation RP-HPLC.Desired components is carried out lyophilize, thereby obtain title compound into white solid.
1H NMR (400MHz, DMSO-d6) δ: 8.72-8.64 (1H, m), 8.36 (1H, s), 8.20-8.14 (1H, m), 8.11-8.01 (2H, m), 8.01-7.88 (3H, m), 7.80-7.65 (2H, m), 7.64-7.56 (2H, m), 7.19-7.08 (1H, m), 6.80-6.71 (1H, m), 5.08-4.98 (1H, m), 4.28-4.20 (2H, m), 4.14-4.02 (2H, m), 3.23-2.98 (2H, m), 2.54 (3H, d, J=7.3Hz), 2.04 (2H, t, J=7.2Hz), 1.99-1.88 (2H, m), 1.82-1.60 (2H, m), 1.57-1.44 (3H, m), 1.42-1.21 (4H, m) .MS (ES) C
32H
38N
6O
2Desired value: 538, discovery value: 538 (M+H)
+.
Embodiment 328
2-[(1S)-and the 1-{[(benzylamino) carbonyl] amino }-7-(methylamino)-7-oxo heptyl]-5-(2-
Naphthyl)-1H-imidazoles-3-trifluoroacetate (CCC1)
To be obtained from embodiment 327, the amine of BB2 (1 equivalent) is dissolved among the DCM, then DIPEA (1 equivalent) and benzyl mustard oil is added wherein.After at room temperature stirring 1 hour, under reduced pressure solvent is removed, and used H
2(post: C18), RP-HPLC carries out purifying to the thick product of gained by preparation as elutriant for O (0.1%TFA) and MeCN (0.1%TFA).Desired components is carried out lyophilize, thereby obtain title compound into white solid.
1H NMR (400MHz, DMSO-d6) δ: 8.36 (1H, s), 8.16 (1H, s), 8.07 (1H, d, J=8.6Hz), 8.02-7.93 (2H, m), 7.91 (1H, dd, J
1=8.6Hz, J
2=1.5Hz), and 7.71-7.55 (3H, m), 7.35-7.19 (5H, m), and 6.75-6.67 (2H, m), 4.97-4.87 (1H, m), and 4.30-4.15 (2H, m), 2.53 (3H, d, J=4.6Hz), 2.04 (2H, t, J=7.4Hz), and 1.97-1.83 (2H, m), 1.55-1.44 (2H, m), 1.42-1.22 (4H, m) .MS (ES) C
29H
33N
5O
2Desired value: 483, discovery value: 484 (M+H)
+.
Embodiment 329
5-(2 methoxy quinoline-3-yl)-2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl]
Amino }-7-oxo nonyl)-1H-imidazoles-3--L-tartrate (DDD1)
Embodiment 305 is distributed in EtOAc and saturated NaHCO
3Between the aqueous solution.Further with EtOAc water is extracted, the organic phase that is combined is carried out drying (Na
2SO
4), filter and under reduced pressure it concentrated.Remaining water white oil is dissolved in H
2Add wherein in the mixture of O and MeCN and with L-tartrate (1 equivalent).The gained mixture is carried out lyophilize, thereby obtain white powder.
1H NMR (400MHz, DMSO-d6) δ: 12.16 (1H, br.s), 8.71 (1H, br.s), 8.52 (1H, d, J=8.2Hz), 8.13 (1H, d, J=7.7Hz), 7.84 (1H, d, J=8.2Hz), 7.66-7.54 (2H, m), 7.42 (1H, m), 5.05-4.91 (1H, m), 4.13 (3H, s), 4.04 (2H, s), and 3.99-3.85 (2H, m), 3.81-3.65 (2H, m), and 3.54-3.37 (1H, m), 2.59 (3H, s), and 2.44-2.32 (4H, m), 2.04-1.66 (2H, m), and 1.54-1.38 (2H, m), 1.36-1.16 (4H, m), 0.89 (3H, t, J=7.2Hz) .MS (ES) C
27H
35N
5O
3Desired value: 477, discovery value: 478 (M+H
+).
| Embodiment | Title | [M+H] +Observed value | The M desired value | Method according to embodiment No |
| 330 | 2-((1S)-1-{[(1-Methyl-1H-indole-3-yl) carbonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 443 | 442 | 1 |
| 331 | 2-((1S)-1-{[(5-methoxyl group-1H-indoles-2-yl) carbonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 459 | 458 | 1 |
| 332 | 2-((1S)-1-{[(6-fluoro-1H-indol-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 461 | 460 | 1 |
| 333 | 2-((1S)-1-{[(2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 457 | 456 | 1 |
| 334 | 2-{ (1S)-1-[(1H-indol-3-yl ethanoyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 443 | 442 | 1 |
| 335 | 2-{ (1S)-1-[(1H-indol-3-yl carbonyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 429 | 428 | 1 |
| 336 | 2-((1S)-1-{[(5-bromo-1H-indol-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 521 523 | 520 522 | 1 |
| 337 | 2-((1S)-1-{[(7-methoxyl group-6,7-dihydro-1-cumarone-2-yl) carbonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 460 | 461 | 1 |
| 338 | 2-{ (1S)-1-[(1-naphthyl ethanoyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 454 | 453 | 1 |
| 339 | 2-((1S)-1-{[(5-fluoro-1H-indol-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 461 | 460 | 1 |
| 340 | 2-((1S)-1-{[(5-chloro-1H-indol-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 477 | 477 | 1 |
| 341 | 2-{ (1S)-1-[(1H-indoles-2-base carbonyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 429 | 428 | 1 |
| 342 | 2-((1S)-1-{[(5-fluoro-1H-indoles-2-yl) carbonyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 448 | 446 | 1 |
| 343 | 2-((1S)-1-{[(5-methoxyl group-1H-indol-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 473 | 472 | 1 |
| 344 | 2-((1S)-1-{[(5-hydroxyl-1H-indol-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 459 | 458 | 1 |
| 345 | 2-((1S)-1-{[(6-methoxyl group-2-oxo-2,3-dihydro-1H-indoles-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 489 | 488 | 1 |
| 346 | 2-((1S)-1-{[(5-methoxyl group-2-oxo-2,3-dihydro-1H-indoles-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 489 | 488 | 1 |
| 347 | 6-(the 2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-3--2-yl) octyl group] amino } ethyl) [1,2,4] triazolo [1,5-a] pyrimidine-3-two (trifluoroacetate); | 446 | 445 | 1 |
| 348 | 3-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-3--2-yl) octyl group] amino } carbonyl)-3,4-dihydro spiral shell [different chromene-1,4 '-piperidines] two (trifluoroacetates); | 515 | 514 | 1 |
| 349 | 4-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-3--2-yl) octyl group] amino } carbonyl)-3,4-dihydro spiral shell [chromene-2,4 '-piperidines] two (trifluoroacetates); | 515 | 514 | 1 |
| 350 | 5-chloro-2-(the 2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-3--2-yl) octyl group] amino } ethyl)-1H-3,1-benzoglyoxaline-3-two (trifluoroacetate); | 478 | 477 | 1 |
| 351 | 2-((1S)-7-oxo-1-{[(2-oxo quinazoline-1 (2H)-yl) ethanoyl] amino } octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 472 | 471 | 1 |
| 352 | 2-((1S)-7-oxo-1-{[(2-oxo-1,3-benzoxazole-3 (2H)-yl) ethanoyl] amino } octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 461 | 460 | 1 |
| 353 | 2-{ (1S)-1-[(2H-indazolyl-2-base ethanoyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 444 | 443 | 1 |
| 354 | 3-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-3--2-yl) octyl group] amino } carbonyl)-2,3-dihydro spiral shell [indenes-1,4 '-piperidines] two (trifluoroacetates); | 499 | 498 | 1 |
| 355 | 2-((1S)-7-oxo-1-{[(2-oxo-1,2,3,4-tetrahydroquinoline-4-yl) carbonyl] amino } octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 459 | 458 | 1 |
| 356 | 2-((1S)-1-{[(5-cyano-1 H-indol--1-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 468 | 467 | 1 |
| 357 | 2-{ (1S)-1-[(2-naphthyl ethanoyl) amino]-7-oxo octyl group }-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 454 | 453 | 1 |
| 358 | 2-((1S)-1-{[(5-chloro-1-thionaphthene-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 494 | 494 | 1 |
| 359 | 2-((1S)-1-{[(5-chloro-1H-indazole-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-3-trifluoroacetate; | 478 | 477 | 1 |
| 360 | 2-(2-{ (1S)-1-[(1-azonia two ring [2.2.2] sufferings-4-base carbonyl) amino]-7-oxo nonyl }-1H-imidazoles-1--5-yl)-4-methoxy quinoline three (trifluoroacetate); | 518 | 517 | 307 |
| 361 | 4-methoxyl group-2-[2-((1S)-1-{ [(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] quinoline two (trifluoroacetate); | 582 | 581 | 307 |
| 362 | 5-methoxyl group-N-{ (1S)-1-[5-(2-naphthyl)-1,3-oxazole-2-yl]-7-oxo nonyl }-1H-indoles-2-carboxylic acid amides; | 524 | 523 | 137 |
| 363 | 1-methyl-4-[({ (1S)-1-[5-(2-naphthyl)-1,3-oxazole-2-yl]-7-oxo nonyl } amino) carbonyl] the piperidines trifluoroacetate; | 476 | 475 | 137 |
| 364 | 4-[({ (1S)-1-[5-(2-naphthyl)-1,3-oxazole-2-yl]-7-oxo nonyl } amino) carbonyl]-1-azonia two ring [2.2.2] octane trifluoroacetates; | 488 | 487 | 137 |
| 365 | N, N, 2-trimethylammonium-1-((1S)-and 1-[5-(2-naphthyl)-1,3-oxazole-2-yl]-7-oxo nonyl } amino)-1-oxo third-2-ammonium trifluoroacetate; | 464 | 463 | 137 |
| 366 | 1-methyl-3-[({ (1S)-1-[5-(2-naphthyl)-1,3-oxazole-2-yl]-7-oxo nonyl } amino) carbonyl] the azetidine trifluoroacetate; | 448 | 447 | 137 |
| 367 | N-{ (1S)-1-[5-(2-naphthyl)-1,3-oxazole-2-yl]-7-oxo nonyl } ethanamide; | 393 | 392 | 137 |
| 368 | N, N-dimethyl-N '-(1S)-and 1-[5-(2-naphthyl)-1,3-oxazole-2-yl]-7-oxo nonyl } oxalamide; | 450 | 449 | 137 |
| 369 | 8-[2-(1-{[(1-methyl piperidine-4-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] quinoline three (trifluoroacetate); | 476 | 475 | 1 |
| 370 | 2-((1S)-1-{[(1-methyl piperidine-4-yl) carbonyl] amino }-7-oxo nonyl)-6-phenylpyridine two (trifluoroacetate); | 436 | 435 | 140 |
| 371 | N-{ (1S)-1-[5-(2-naphthyl)-1,3-oxazole-2-yl]-7-oxo nonyl }-2-(2-oxo quinazoline-1 (2H)-yl) ethanamide; | 537 | 536 | 137 |
| 372 | 3-(2-ethyl-1H-benzoglyoxaline-1-yl)-N-{ (1S)-1-[5-(2-naphthyl)-1,3-oxazole-2-yl]-7-oxo nonyl } propionic acid amide; | 551 | 550 | 137 |
| 373 | N, N-dimethyl-2-((1S)-and 1-[5-(2-naphthyl)-1,3-oxazole-2-yl]-7-oxo nonyl } amino)-2-oxo second ammonium trifluoroacetate; | 436 | 435 | 137 |
| 374 | 2-ethyl-1-(3-oxo-3-[(1S)-and 7-oxo-1-(6-phenylpyridine-2-yl) nonyl] amino } propyl group)-1H-3,1-benzoglyoxaline-1-two (trifluoroacetate); | 511 | 510 | 140 |
| 375 | 4-([(1S)-and 7-oxo-1-(6-phenylpyridine-2-yl) nonyl] amino } carbonyl)-1-azonia two ring [2.2.2] octanes two (trifluoroacetate); | 448 | 447 | 140 |
| 376 | 2-((1S)-1-{[(benzylamino) carbonyl] amino }-7-oxo nonyl)-6-phenylpyridine trifluoroacetate; | 444 | 443 | 140 |
| 377 | 2-((1S)-7-[methoxyl group (methyl) amino]-1-{[(5-methoxyl group-2-methyl-1H-indol-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 532 | 531 | 108 |
| 378 | 2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-quinoxaline-2-base-1H-imidazoles-1-trifluoroacetate; | 553 | 552 | 1 |
| 379 | 2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(3-methoxyl group-2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 581 | 580 | 1 |
| 380 | 5-{[benzyl (methyl) amido (ammonio)] methyl }-2-(1-{ [(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-two (trifluoroacetate); | 558 | 557 | 311 |
| 381 | 2-{[2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] methyl }-1,2,3,4-tetrahydroisoquinoline two (trifluoroacetate); | 570 | 569 | 311 |
| 382 | 2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo decyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 515 | 514 | 316 |
| 383 | 2-(1-{[(5-methoxyl group-2-methyl-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-p-methoxy-phenyl)-1H-imidazoles-3-trifluoroacetate; | 531 | 530 | 304 |
| 384 | 2-(1-{[(5-methoxyl group-2-methyl-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(3-p-methoxy-phenyl)-1H-imidazoles-3-trifluoroacetate; | 531 | 530 | 304 |
| 385 | 6-[2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3--5-yl] quinoline two (trifluoroacetate); | 552 | 551 | 304 |
| 386 | 5-[2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3--5-yl]-2-toluquinoline two (trifluoroacetate); | 566 | 565 | 304 |
| 387 | 5-[2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3--5-yl] quinoline two (trifluoroacetate); | 552 | 551 | 304 |
| 388 | 5-[2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3--5-yl]-8-toluquinoline two (trifluoroacetate); | 566 | 565 | 304 |
| 389 | 8-methoxyl group-5-[2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3--5-yl] quinoline two (trifluoroacetate); | 582 | 581 | 304 |
| 390 | 5-(1-thionaphthene-7-yl)-2-(1-{ [(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate; | 557 | 556 | 304 |
| 391 | 5-(1H-indoles-5-yl)-2-(1-{ [(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate; | 540 | 539 | 304 |
| 392 | 5-[3-(3,5-dimethyl-1H-pyrazol-1-yl) phenyl]-2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate; | 595 | 594 | 304 |
| 393 | 5-(3-methoxyl group-2-naphthyl)-2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-1-two (trifluoroacetate); | 477 | 476 | 1 |
| 394 | 2-((1S)-1-{[(2-ethyl-5-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 499 | 498 | 1 |
| 395 | 2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-5-quinoxaline-2-base-1H-imidazoles-1-two (trifluoroacetate); | 449 | 448 | 1 |
| 396 | 2-((1S)-1-{[(2-ethyl-6-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 499 | 498 | 1 |
| 397 | 5-[4-(dimethyl amido (ammonio)) phenyl]-2-1-{ [(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-two (trifluoroacetate); | 544 | 543 | 304 |
| 398 | 5-(2-fluoro-4-p-methoxy-phenyl)-2-(1-{[(5-methoxyl group-2-methyl-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate; | 549 | 548 | 304 |
| 399 | 5-(3-fluoro-4-p-methoxy-phenyl)-2-(1-{[(5-methoxyl group-2-methyl-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate; | 549 | 548 | 304 |
| 400 | 5-(3-carboxyl phenyl)-2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate; | 545 | 544 | 304 |
| 401 | 5-xenyl-2-base-2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate; | 577 | 576 | 304 |
| 402 | 5-dibenzo [b, d] furans-4-base-2-(1-{[(5-methoxyl group-2-methyl-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate; | 591 | 590 | 304 |
| 403 | 2-(1-{[(5-methoxyl group-2-methyl-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[3-(piperidines-1-base carbonyl) phenyl]-1H-imidazoles-1-trifluoroacetate; | 612 | 611 | 304 |
| 404 | 2-(1-{[(5-methoxyl group-2-methyl-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-quinoxalin-6-yl-1H-imidazoles-1-trifluoroacetate; | 553 | 552 | 304 |
| 405 | 5-[(dimethyl amido (ammonio)) methyl]-2-(1-{ [(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-two (trifluoroacetate); | 482 | 481 | 311 |
| 406 | 5-(1,4-dimethoxy-2-naphthyl)-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate; | 611 | 610 | 1 |
| 407 | 2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-{[2-(methylthio group) ethyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 613 | 611 | 108 |
| 408 | 2-((1S)-7-(methoxyl group amino)-1-{ [(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 569 | 567 | 108 |
| 409 | 2-((1S)-7-(oxyethyl group amino)-1-{ [(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-trifluoroacetate; | 583 | 581 | 108 |
| 410 | 2-((1S)-1-{[(2-methyl-5-nitro-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 516 | 515 | 1 |
| 411 | 2-((1S)-1-{[(5-methoxyl group-2-methyl isophthalic acid H-indenes-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 500 | 499 | 1 |
| 412 | 2-((1S)-1-{[(5-hydroxy-2-methyl-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 487 | 486 | 1 |
| 413 | 2-((1S)-1-{[3-(propionyl of 5-methoxyl group-1H-benzimidazolyl-2 radicals-yl)] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 502 | 501 | 1 |
| 414 | 2-{ (1S)-1-[(1-thionaphthene-3-base ethanoyl) amino]-7-oxo nonyl }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 474 | 473 | 1 |
| 415 | 2-((1S)-1-{[(2,5-dimethyl-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 485 | 484 | 1 |
| 416 | 2-((1S)-1-{[3-(propionyl of 1H-benzimidazolyl-2 radicals-yl)] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 472 | 471 | 1 |
| 417 | 2-((1S)-1-{[(6-methoxyl group-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 487 | 486 | 1 |
| 418 | 2-{ (1S)-1-[(1H-indoles-6-base ethanoyl) amino]-7-oxo nonyl }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 457 | 456 | 1 |
| 419 | 2-((1S)-1-{[(2-methyl isophthalic acid, 3-benzothiazole-5-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 489 | 488 | 1 |
| 420 | 2-((1S)-1-{[3-(5-methoxyl group-2-oxo-1,3-benzoxazole-3 (2H)-yl) propionyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 519 | 518 | 1 |
| 421 | 2-((1S)-1-{[3-(7-methoxyl group-1H-indol-3-yl) propionyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 501 | 500 | 1 |
| 422 | 2-((1S)-1-{[3-(1,3-benzothiazole-2-yl) propionyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 489 | 488 | 1 |
| 423 | 2-((1S)-1-{[(5-methoxyl group-2-oxo-2,3-dihydro-1H-indoles-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 503 | 502 | 1 |
| 424 | 2-((1S)-1-{[(6-methoxyl group-2-oxo-2,3-dihydro-1H-indoles-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 503 | 502 | 1 |
| 425 | 2-((1S)-1-{[(benzylamino) carbonyl] amino }-7-oxo nonyl)-4-phenylpyridine trifluoroacetate; | 444 | 443 | 140 |
| 426 | 4-([(1S)-and 7-oxo-1-(4-phenylpyridine-2-yl) nonyl] amino } carbonyl)-1-azonia two ring [2.2.2] octanes two (trifluoroacetate); | 448 | 447 | 140 |
| 427 | 2-((1S)-1-{[2-(dimethyl amido (ammonio))-2-methylpropionyl] amino }-7-oxo nonyl)-4-phenylpyridine two (trifluoroacetate); | 424 | 423 | 140 |
| 428 | 5-(3,5-dimethoxy-2-naphthyl)-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate; | 611 | 610 | 1 |
| 429 | 2-((1S)-1-{[(benzyloxy) carbonyl] amino }-7-oxo nonyl)-4-phenylpyridine trifluoroacetate; | 445 | 444 | 140 |
| 430 | 2-((1S)-1-{[(1-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 471 | 470 | 1 |
| 431 | 2-((1S)-1-{[(7-fluoro-2-methyl-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 489 | 488 | 1 |
| 432 | 2-((1S)-1-{[(5-ethyl-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 499 | 498 | 1 |
| 433 | 2-(the 5-tertiary butyl-2-methyl isophthalic acid H-indol-3-yl)-N-[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-2-yl) nonyl] ethanamide; | 527 | 526 | 1 |
| 434 | 2-((1S)-1-{[(5-oxyethyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 515 | 514 | 1 |
| 435 | 2-[5-(benzyloxy)-2-methyl isophthalic acid H-indol-3-yl]-N-[(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-2-yl) nonyl] ethanamide; | 577 | 576 | 1 |
| 436 | 3-(1H-indoles-1-yl)-N-[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-2-yl) nonyl] propionic acid amide; | 471 | 470 | 1 |
| 437 | 2-((1S)-1-{[(5-methoxyl group-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 487 | 486 | 1 |
| 438 | 2-((1S)-7-oxo-1-{[3-(2-oxo-1,3-benzothiazole-3 (2H)-yl) propionyl] amino } nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 505 | 504 | 1 |
| 439 | 2-{ (1S)-7-oxo-1-[(quinoline-3-base ethanoyl) amino] nonyl }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 469 | 468 | 1 |
| 440 | 2-{ (1S)-7-oxo-1-[(quinoline-5-base ethanoyl) amino] nonyl }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 469 | 468 | 1 |
| 441 | 2-((1S)-1-{[3-(propionyl of 6-chloro-1H-benzimidazolyl-2 radicals-yl)] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 507 509 | 506 508 | 1 |
| 442 | 2-((1S)-1-{[3-(propionyl of 6-fluoro-1H-benzimidazolyl-2 radicals-yl)] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 490 | 489 | 1 |
| 443 | N-[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-2-yl) nonyl]-2-(5,6,7,8-naphthane-1-yl) ethanamide; | 472 | 471 | 1 |
| 444 | 2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-8-methyl-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 515 | 514 | 316 |
| 445 | 2-((1S)-6-carboxyl-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino } hexyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 409 | 488 | 107 |
| 446 | 2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-thienyl)-1H-imidazoles-3-trifluoroacetate; | 507 | 506 | 304 |
| 447 | 2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(1-naphthyl)-1H-imidazoles-3-trifluoroacetate; | 551 | 550 | 304 |
| 448 | 2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-quinoline-8-base-1H-imidazoles-3-trifluoroacetate; | 552 | 551 | 304 |
| 449 | 2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-morpholine-4-base phenyl)-1H-imidazoles-3-trifluoroacetate; | 586 | 585 | 304 |
| 450 | 2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(3-nitrophenyl)-1H-imidazoles-3-trifluoroacetate; | 546 | 545 | 304 |
| 451 | 3-[2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3--5-yl] pyridine two (trifluoroacetate); | 502 | 501 | 304 |
| 452 | 5-(3-cyano-phenyl)-2-((1S)-1-{ [(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate; | 526 | 525 | 304 |
| 453 | 2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[3-(trifluoromethoxy) phenyl]-1H-imidazoles-3-trifluoroacetate; | 585 | 584 | 304 |
| 454 | 2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[4-(trifluoromethoxy) phenyl]-1H-imidazoles-3-trifluoroacetate; | 585 | 584 | 304 |
| 455 | 2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[4-(trifluoromethyl) phenyl]-1H-imidazoles-3-trifluoroacetate; | 569 | 568 | 304 |
| 456 | 2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[3-(trifluoromethyl) phenyl]-1H-imidazoles-3-trifluoroacetate; | 569 | 568 | 304 |
| 457 | 2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[2-(trifluoromethyl) phenyl]-1H-imidazoles-3-trifluoroacetate; | 569 | 568 | 304 |
| 458 | 2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[2-fluoro-phenyl]-1H-imidazoles-3-trifluoroacetate; | 519 | 518 | 304 |
| 459 | 2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[3-(oxyethyl group) phenyl]-1H-imidazoles-3-trifluoroacetate; | 545 | 544 | 304 |
| 460 | 2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[4-(oxyethyl group) phenyl]-1H-imidazoles-3-trifluoroacetate; | 545 | 544 | 304 |
| 461 | 5-[4-(kharophen) phenyl]-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate; | 558 | 557 | 304 |
| 462 | 5-[2-(methoxycarbonyl) phenyl]-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate; | 559 | 558 | 304 |
| 463 | 2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[4-cyano group-phenyl]-1H-imidazoles-3-trifluoroacetate; | 526 | 525 | 304 |
| 464 | 2-((1S)-1-{[5-(3-methyl-5,6,7,8-tetrahydrochysene-1,8-naphthyridines-2-yl) pentanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 530 | 529 | 1 |
| 465 | 6-(the 2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } ethyl) imidazo [2,1-b] [1,3] thiazole-4-two (trifluoroacetates); | 464 | 463 | 1 |
| 466 | 2-{ (1S)-1-[(1-cumarone-5-base ethanoyl) amino]-7-oxo nonyl }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 458 | 457 | 1 |
| 467 | 2-{ (1S)-1-[(1-thionaphthene-2-base ethanoyl) amino]-7-oxo nonyl }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 474 | 473 | 1 |
| 468 | 2-((1S)-1-{[(2-ethyl-1H-benzoglyoxaline-1-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 486 | 485 | 1 |
| 469 | 2-(1-{[(5-methoxyl group-2-methyl-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate; | 425 | 424 | 304 then hydrogenated |
| 470 | 2-[2-((1S)-1-{[3-(dimethyl amido (ammonio)) propionyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl]-4-methoxy quinoline three (trifluoroacetate); | 480 | 479 | 307 |
| 471 | 5-(4-chloro-phenyl-)-2-((1S)-1-{ [(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate; | 535 537 539 | 534 536 538 | 1 |
| 472 | 5-(3, the 4-dichlorophenyl)-2-((1S)-1-{[(5-methoxyl group-2-methyl isophthalic acid H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate; | 569 571 573 | 568 570 572 | 1 |
| 473 | 5-(3-bromophenyl)-2-((1S)-1-{ [(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate; | 579 581 | 578 580 | 1 |
| 474 | 2-((1S)-7-methoxyl group-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 504 | 503 | 107 |
| 475 | 2-(1-{[(5-methoxyl group-2-methyl-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-phenylethyl)-1H-imidazoles-1-trifluoroacetate; | 529 | 528 | 315 |
| 476 | 7-(the 3-oxo-3-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } propyl group)-1,8-naphthyridines-1-two (trifluoroacetate); | 484 | 483 | 1 |
| 477 | 7-(the 3-oxo-3-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } propyl group)-1,2,3,4-tetrahydrochysene-1,8-naphthyridines-1-two (trifluoroacetate); | 488 | 487 | 1 |
| 478 | N 3，N 3-dimethyl-N-[{ (1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl }-the α-Bing Ansuan acid amides; | 451 | 450 | 308 |
| 479 | 2-{ (1S)-7-oxo-1-[(4,5,6,7-tetrahydrochysene-1H-indazolyl-3-base carbonyl) amino] nonyl }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 448 | 447 | 1 |
| 480 | 2-{ (1S)-7-oxo-1-[(4,5,6,7-tetrahydrochysene-1-thionaphthene-3-base carbonyl) amino] nonyl }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 464 | 463 | 1 |
| 481 | 2-((1S)-7-oxo-1-{[3-(1-oxo-1,3-dihydro-2H-isoindole-2-yl) propionyl] amino } nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 487 | 486 | 1 |
| 482 | 2-{ (1S)-1-[({2-[2-(dimethyl amido (ammonio)) ethyl]-3-oxo-2,3-dihydro-1H-isoindole-4-yl } carbonyl) amino]-7-oxo nonyl }-5-phenyl-1H-imidazoles-1-two (trifluoroacetate); | 530 | 529 | 1 |
| 483 | 6-benzyl-2-oxo-3-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } carbonyl)-1,2,5,6,7,8-six hydrogen-1,6-naphthyridines-6-two (trifluoroacetate); | 566 | 565 | 1 |
| 484 | 7-(the 4-oxo-4-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } butyryl radicals)-6,7,8, the 9-tetrahydropyridine is [2,3-b]-1 also, 6-naphthyridines-1-two (trifluoroacetate); | 567 | 566 | 1 |
| 485 | 2-((1S)-1-{[(2-ethanoyl-1,2,3,4-tetrahydroisoquinoline-1-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 515 | 514 | 1 |
| 486 | 2-methyl-3-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } carbonyl)-1,2,3,4-tetrahydroisoquinoline two (trifluoroacetate); | 473 | 472 | 1 |
| 487 | 2-(the 2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } ethyl)-1,2,3,4-tetrahydroisoquinoline two (trifluoroacetate); | 473 | 472 | 1 |
| 488 | 4-[2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3--5-yl] pyridine two (trifluoroacetate); | 502 | 501 | 304 |
| 489 | 2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(2-nitrophenyl)-1H-imidazoles-3-trifluoroacetate; | 546 | 545 | 304 |
| 490 | 5-(3-amido (ammonio) phenyl)-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-two (trifluoroacetate); | 516 | 515 | 304 |
| 491 | 5-(2,3-dihydro-1,4-Ben Bing Er Evil star-6-yl)-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate; | 559 | 558 | 304 |
| 492 | 5-(2, the 4-Dimethoxyphenyl)-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate; | 561 | 560 | 304 |
| 493 | 5-[2-fluoro-5-(trifluoromethyl) phenyl]-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate; | 587 | 586 | 304 |
| 494 | 5-[3-(amido (ammonio) methyl) phenyl]-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-two (trifluoroacetate); | 530 | 529 | 304 |
| 495 | 5-[2-(amido (ammonio) methyl)-4-fluorophenyl]-2-((1S)-1-{[(5-methoxyl group-2-methyl isophthalic acid H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-two (trifluoroacetate); | 548 | 547 | 304 |
| 496 | 5-xenyl-3-base-2-((1S)-1-{ [(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate; | 577 | 576 | 304 |
| 497 | 3-[2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3--5-yl] quinoline two (trifluoroacetate); | 552 | 551 | 304 |
| 498 | 5-(3-carboxyl phenyl)-2-((1S)-1-{ [(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate; | 545 | 544 | 304 |
| 499 | 2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[3-(1H-tetrazolium-5-yl) phenyl]-1H-imidazoles-3-trifluoroacetate; | 569 | 568 | 304 |
| 500 | 2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-(3-{[(methyl sulphonyl) amino] carbonyl } phenyl)-1H-imidazoles-3-trifluoroacetate; | 622 | 621 | 304 |
| 501 | 2-((1R)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles third-1-two (trifluoroacetate); | 447 | 446 | 1 |
| 502 | 2-[(1S)-1-({ [1-(2-tert.-butoxy-2-oxoethyl)-5-methoxyl group-2-Methyl-1H-indole-3-yl] ethanoyl } amino)-7-oxo nonyl]-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 615 | 614 | 1 |
| 503 | 2-[(1S)-1-({ [5-methoxyl group-2-methyl isophthalic acid-(pyridin-3-yl methyl)-1H-indol-3-yl] ethanoyl } amino)-7-oxo nonyl]-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 592 | 591 | 1 |
| 504 | 2-((1S)-1-{[(5-methoxyl group-1,2-dimethyl-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 515 | 514 | 1 |
| 505 | 2-[(1S)-1-({ [5-methoxyl group-2-methyl isophthalic acid-(2-tetramethyleneimine-1-base ethyl)-1H-indol-3-yl] ethanoyl } amino)-7-oxo nonyl]-5-phenyl-1H-imidazoles-1-two (trifluoroacetate); | 598 | 597 | 1 |
| 506 | 4-{2-[5-methoxyl group-2-methyl-3-(the 2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } ethyl)-1H-indoles-1-yl] ethyl } morpholine-4-two (trifluoroacetate); | 614 | 613 | 1 |
| 507 | 2-((1S)-1-{[(5-methyl isophthalic acid, 2-benzoisoxazole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 473 | 472 | 1 |
| 508 | 2-[(1S)-1-({ [5-(dimethyl amido (ammonio))-2-methyl-1H-indol-3-yl] ethanoyl } amino)-7-oxo nonyl]-5-phenyl-IH-imidazoles-1-two (trifluoroacetate); | 514 | 513 | 1 |
| 509 | 1-methyl-4-[({ (1S)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo undecyl } amino) carbonyl] piperidines two (trifluoroacetate); | 503 | 502 | 316 |
| 510 | 1-methyl-4-[({ (1S)-1-[5-(2-naphthyl)-1H-imidazoles-1--2-yl]-7-oxo decyl } amino) carbonyl] piperidines two (trifluoroacetate); | 489 | 488 | 316 |
| 511 | N-[1-(5-ethanoyl-1H-imidazoles-2-yl)-7-oxo nonyl]-2-(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanamide; | 467 | 466 | 314 |
| 512 | 2-[2-((1S)-1-{[3-(dimethyl amido (ammonio)) propionyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl]-4-methoxy quinoline trichloride; | 480 | 479 | 307 |
| 513 | 2-((1S)-1-{[(6-methoxyl group-1-cumarone-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 488 | 487 | 1 |
| 514 | 6-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } carbonyl) quinoline two (trifluoroacetate); | 455 | 454 | 1 |
| 515 | 6-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } carbonyl) isoquinoline 99.9 two (trifluoroacetate); | 455 | 454 | 1 |
| 516 | 5-methyl-6-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } carbonyl)-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-3,5-two or three (trifluoroacetate); | 463 | 462 | 1 |
| 517 | 2-(5-methyl isophthalic acid-thionaphthene-3-yl)-N-[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-2-yl) nonyl] ethanamide; | 488 | 487 | 1 |
| 518 | 2-[(1S)-1-({ [1-(carboxyl methyl)-5-methoxyl group-2-Methyl-1H-indole-3-yl] ethanoyl } amino)-7-oxo nonyl]-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 559 | 558 | 1 |
| 519 | 4-{[5-methoxyl group-2-methyl-3-(the 2-oxo-2-{[(1S)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } ethyl)-1H-indoles-1-yl] ethanoyl }-1-methylpiperazine-1-two (trifluoroacetate); | 641 | 640 | 1 |
| 520 | 7-methyl-2-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } carbonyl)-5,6,7, the 8-imidazolidine is [1,2-a] pyrazine-4 also, 7-two or three (trifluoroacetate); | 463 | 462 | 1 |
| 521 | 2-{ (1S)-1-[({5-[(dimethyl amido (ammonio)) methyl]-2-Methyl-1H-indole-3-yl } ethanoyl) amino]-7-oxo nonyl }-5-phenyl-1H-imidazoles-1-two (trifluoroacetate); | 528 | 527 | 1 |
| 522 | 5-bromo-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate; | 503 505 | 502 504 | 304 |
| 523 | 5-(4-carboxyl phenyl)-2-((1S)-1-{ [(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate; | 544 | 544 | 304 |
| 524 | 5-(3-hydroxy phenyl)-2-((1S)-1-{ [(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate; | 517 | 516 | 304 |
| 525 | 5-[2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] isoquinoline 99.9 two (trifluoroacetate); | 552 | 551 | 304 |
| 526 | 5-{4-[(dimethyl amido (ammonio)) methyl] phenyl }-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-two (trifluoroacetate); | 558 | 557 | 304 |
| 527 | 4-methoxyl group-2-[2-((1S)-1-{ [(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] quinoline three (trifluoroacetate); | 478 | 477 | 307 |
| 528 | 5-(2-carboxyl phenyl)-2-((1S)-1-{ [(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-trifluoroacetate; | 545 | 544 | 304 |
| 529 | 5-[4-(dimethyl amido (ammonio)) phenyl]-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-two (trifluoroacetate); | 544 | 543 | 304 |
| 530 | 2-((1S)-7-oxo-1-{ [(4,5,6,7-tetrafluoro-1H-indoles-3-yl) ethanoyl] amino } nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 529 | 528 | 1 |
| 531 | 2-((1S)-1-{[(5-fluoro-2-methyl-1H-indol-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 489 | 488 | 1 |
| 532 | 1-methyl-N-{ (1S)-1-[5-(2-naphthyl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl } azetidine-3-carboxylic acid amides; | 449 | 448 | 308 |
| 533 | 2-{ (1S)-7-oxo-1-[(1H-pyrrolo-[2,3-b] pyridin-3-yl ethanoyl) amino] nonyl }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 458 | 457 | 1 |
| 534 | 4-([(1S)-and 6-carboxyl-1-(5-phenyl-1H-imidazoles-1--2-yl) hexyl] amino } carbonyl)-1-azonia two ring [2.2.2] octanes two (trifluoroacetate); | 425 | 424 | 107 |
| 535 | 4-([(1S)-and 7-(methoxyl group amino)-7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) heptyl] amino } carbonyl)-1-azonia two ring [2.2.2] octanes two (trifluoroacetate); | 454 | 453 | 108 |
| 536 | 1-methyl-4-([(1S)-and 7-oxo-1-(4-phenyl-1H-imidazoles-3--2-yl)-7-(2-thienyl) heptyl] amino } carbonyl) piperidines two (trifluoroacetate); | 479 | 478 | 320 |
| 537 | 2-{ (1S)-7-oxo-1-[(1H-pyrrolo-[3,2-c] pyridin-3-yl ethanoyl) amino] nonyl }-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 458 | 457 | 1 |
| 538 | 2-((1S)-1-{[(5-methoxyl group-1H-pyrrolo-[2,3-c] pyridin-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-phenyl-1H-imidazoles-1-trifluoroacetate; | 488 | 487 | 1 |
| 539 | 5-(2-fluorine quinoline-3-yl)-2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-3-two (trifluoroacetate); | 466 | 465 | 305 |
| 540 | 2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-5-quinoxaline-6-base-1H-imidazoles-3-two (trifluoroacetate); | 449 | 448 | 305 |
| 541 | 8-methoxyl group-5-[2-((1S)-1-{ [(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-3--5-yl] quinoline three (trifluoroacetate); | 478 | 477 | 305 |
| 542 | 5-[4-(dimethylamino) phenyl]-2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-3-two (trifluoroacetate); | 440 | 439 | 305 |
| 543 | The 2-methyl isophthalic acid-([(1S)-and 7-oxo-1-(5-phenyl-1H-imidazoles-1--2-yl) nonyl] amino } carbonyl)-1,2,3,4-tetrahydroisoquinoline two (trifluoroacetate); | 473 | 472 | 1 |
| 544 | 5-(3-carboxyl phenyl)-2-{ (1S)-7-oxo-1-[(2-thienyl carbonyl) amino] nonyl }-1H-imidazoles-3-trifluoroacetate; | 453 | 454 | 307 |
| 545 | 4-methoxyl group-2-(2-{ (1S)-1-[(3-morpholine-4--4-base propionyl) amino]-7-oxo nonyl }-1H-imidazoles-1--5-yl) the quinoline trichloride; | 521 | 522 | 307 |
| 546 | 2-[2-((1S)-1-{[3-(1H-imidazoles-1--1-yl) propionyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl]-4-methoxy quinoline trichloride; | 502 | 503 | 307 |
| 547 | 2-[2-((1S)-1-{[(4-ethanoyl piperazine-1--1-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl]-4-methoxy quinoline trichloride; | 548 | 549 | 307 |
| 548 | 2-[2-((1S)-1-{[(dimethyl amido (ammonio)) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl]-4-methoxy quinoline trichloride; | 465 | 466 | 307 |
| 549 | 4-methoxyl group-2-(2-{ (1S)-7-oxo-1-[(piperidines-1-base ethanoyl) amino] nonyl }-1H-imidazoles-1--5-yl) the quinoline trichloride; | 505 | 506 | 307 |
| 550 | 4-methoxyl group-2-[2-((1S)-1-{ [(4-methylpiperazine-4--1-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] the quinoline trichloride; | 520 | 521 | 307 |
| 551 | 4-methoxyl group-2-[2-((1S)-1-{ [(4-methylmorpholine-4--2-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] quinoline three (trifluoroacetate); | 507 | 508 | 307 |
| 552 | 4-methoxyl group-2-[2-((1S)-1-{[3-(4-methylpiperazine-4--1-yl) propionyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] quinoline three (trifluoroacetate); | 534 | 535 | 307 |
| 553 | 4-methoxyl group-2-[2-((1S)-1-{ [(4-methylpiperazine-4--1-yl) (oxo) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1--5-yl] quinoline three (trifluoroacetate); | 534 | 535 | 307 |
| 554 | 2-[(1S)-1-({ [1-(N, N-dimethyl glycyl) azetidine-3-yl] carbonyl } amino)-7-oxo nonyl]-5-(4-methoxy quinoline-2-yl)-1H-imidazoles-1-trifluoroacetate; | 548 | 549 | 307 |
| 555 | 2-[(1S)-1-({ [1-(2-methoxy ethyl) azetidine-3-yl] carbonyl } amino)-7-oxo nonyl]-5-(4-methoxy quinoline-2-yl)-1H-imidazoles-1-two (trifluoroacetate); | 521 | 522 | 307 |
| 556 | 1-methyl-3-[({ (1S)-1-[5-(1,8-naphthyridines-2-yl)-1,3,4-Evil diazole-2-yl]-7-oxo nonyl } amino) carbonyl] the azetidine formate; | 450 | 451 | 309 |
| 557 | 1-methyl-3-[({ (1S)-1-[5-(1,6-naphthyridines-2-yl)-1,3,4-Evil diazole-2-yl]-7-oxo nonyl } amino) carbonyl] the azetidine formate; | 450 | 451 | 309 |
| 558 | 1-methyl-3-[({ (1S)-1-[5-(1,6-naphthyridines-8-yl)-1,3,4-Evil diazole-2-yl]-7-oxo nonyl } amino) carbonyl] the azetidine formate; | 450 | 451 | 309 |
| 559 | 3-((1S)-and 1-[5-(4-methoxy quinoline-2-yl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl } amino)-N, N-dimethyl-3-oxo third-1-ammonium formate; | 481 | 482 | 309 |
| 560 | 4-[({ (1S)-1-[5-(4-methoxy quinoline-2-yl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl } amino) carbonyl]-1-azonia two ring [2.2.2] octane formate; | 519 | 520 | 309 |
| 561 | 2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-5-(2-oxo-1,2-dihydroquinoline-3-yl)-1H-imidazoles-3-two (trifluoroacetate); | 463 | 464 | 305 |
| 562 | N-{ (1S)-1-[5-(4-methoxy quinoline-2-yl)-1,3,4-oxadiazole-2-yl]-7-oxo nonyl }-2-(1H-pyrrolo-[3,2-c] pyridin-3-yl) ethanamide; | 540 | 541 | 307 |
| 563 | 5-(4-methoxy quinoline-2-yl)-2-(1S)-and 7-oxo-1-[(1H-pyrrolo-[3,2-c] pyridin-3-yl ethanoyl) amino] nonyl }-1H-imidazoles-1-trifluoroacetate; | 538 | 539 | 307 |
| 564 | 5-(3-carboxyl phenyl)-2-((1S)-1-{ [(1-methyl piperidine-4-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-3-trifluoroacetate; | 468 | 470 | 307 |
| 565 | 5-(3-carboxyl phenyl)-2-{ (1S)-1-[(morpholine-4-base ethanoyl) amino]-7-oxo nonyl }-1H-imidazoles-3-trifluoroacetate; | 470 | 471 | 307 |
| 566 | 5-(3-carboxyl phenyl)-2-{ (1S)-1-[(N, N-dimethyl glycyl) amino]-7-oxo nonyl }-1H-imidazoles-3-trifluoroacetate; | 428 | 429 | 307 |
| 567 | 2-((1S)-1-{[(1-methyl piperidine-4-yl) carbonyl] amino }-7-oxo nonyl)-5-(3-{[(methyl sulphonyl) amino] carbonyl } phenyl)-1H-imidazoles-3-trifluoroacetate; | 545 | 546 | 307 |
| 568 | 2-((1S)-1-{[3-(3-methoxyl group azetidine-1-yl) propionyl] amino }-7-oxo nonyl)-5-quinoxalin-6-yl-1H-imidazoles-1-two (trifluoroacetate); | 492 | 493 | 305 |
| 569 | 3-([(1S)-and 7-oxo-1-(5-quinoxalin-6-yl-1H-imidazoles-3--2-yl) nonyl] amino } carbonyl)-1-azonia two ring [2.2.2] octanes two (trifluoroacetate); | 488 | 489 | 305 |
| 570 | 4-([(1S)-and 7-oxo-1-(5-quinoxalin-6-yl-1H-imidazoles-1--2-yl) nonyl] amino } carbonyl)-1-azonia two ring [2.2.2] octanes two (trifluoroacetate); | 488 | 489 | 305 |
| 571 | 5-(2 methoxy quinoline-3-yl)-2-((1S)-1-{[(1-methyl azetidine-3-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-3-dichloride; | 477 | 478 | 305 |
| 572 | 2-((1S)-1-{[(dimethyl amido (ammonio)) ethanoyl] amino }-7-oxo nonyl)-5-(4-methoxy quinoline-2-yl)-1H-imidazoles-1-dichloride; | 465 | 466 | 307 |
| 573 | 3-[({ (1S)-1-[5-(2 methoxy quinoline-3-yl)-1H-imidazoles-2-yl]-7-oxo nonyl } amino) carbonyl]-1-methyl azetidine muriate; | 477 | 478 | 305 |
| 574 | N-{ (1S)-1-[5-(2 methoxy quinoline-3-yl)-1H-imidazoles-2-yl]-7-oxo nonyl }-1-methyl azetidine-3-carboxylic acid amides; | 477 | 478 | 329 |
| 575 | N-{ (1S)-7-[methoxyl group (methyl) amino]-1-[5-(2 methoxy quinoline-3-yl)-1H-imidazoles-2-yl]-7-oxo heptyl }-1-methyl azetidine-3-carboxylic acid amides; | 508 | 509 | 316 |
Claims (13)
1. formula (I) compound:
P is 0,1,2,3,4 or 5;
Q is 3 or 4;
T is 0 or 1;
D represents not exist, (CH
2)
bPerhaps (CH=CH)
c
B is 1,2 or 3;
C is 1,2 or 3;
X is C;
Het contains 1,2,3 or 4 heteroatomic 5 membered unsaturated heterocycle that are independently selected from N, O and S, but wherein at the most a heteroatoms be O or S; Perhaps contain 1,2,3 or 4 heteroatomic 6 membered unsaturated heterocycle that are independently selected from N and O; Described heterocycle is optional to be independently selected from following group replacement by one or more: cyano group, halogen, hydroxyl, oxo, nitro, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
3-10Cycloalkyl, C
2-6Thiazolinyl, C
2-6Alkynyl and C
6-10Aryl;
R
1Be hydrogen, hydroxyl, halogen, C
1-6Alkyl-carbonyl, C
1-6Alkoxy carbonyl, C
1-6Alkyl, halo C
1-6Alkyl, N (R
h)
2, R wherein
hBe independently selected from hydrogen, C
1-6Alkyl, C
6-10Aryl and C
6-10Aryl C
1-6Alkyl; C
3-10Cycloalkyl, C
6-10Aryl, contain 1,2 or 3 heteroatomic 5 yuan or 6 yuan of saturated or fractional saturation heterocycle that are independently selected from N, O and S, contain 1,2,3 or 4 heteroatoms that is independently selected from O, N and S but wherein at the most one be 5 membered unsaturated heterocycles of O or S, 6 membered unsaturated heterocycles that contain 1,2 or 3 nitrogen-atoms perhaps contain the unsaturated or fractional saturation heterocycle of heteroatomic 8-13 unit that is independently selected from O, N and S; Any above-mentioned ring is all chosen wantonly by one or more and is independently selected from following group replacement: cyano group, halogen, nitro, oxo, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkyl-carbonyl, C
1-6Alkoxy carbonyl, carboxyl, C
6-10Aryl, C
6-10Aryloxy, C
6-10Aryl carbonyl, N (R
a)
2, R wherein
aBe independently selected from hydrogen, C
1-6Alkyl, C
6-10Aryl, C
1-6Alkyl-carbonyl and C
6-10Aryl carbonyl; C
1-6Alkyl N (R
a)
2(CO)
dR
k, wherein d is 0 or 1, and R
kThe following definition;
R
2Be C
1-6Alkyl;
R
3Be hydrogen, halogen, hydroxyl, cyano group, C
1-6Alkyl, halo C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
3-10Cycloalkyl, halo C
3-10Cycloalkyl, C
2-10Thiazolinyl, C
2-10Alkynyl, nitro, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, C
6-10Aryl, C
6-10Aryl C
1-6Alkyl, C
6-10Aryl C
1-6Alkoxyl group; 6-13 unit fractional saturation hydrocarbon ring; Contain 1,2 or 3 heteroatomic 4,5 or 6 yuan of saturated or fractional saturation heterocycle that are independently selected from N, O and S, its optional C that passes through
1-4Alkyl carries out bridge joint; Contain 1,2,3 or 4 heteroatoms that is independently selected from N, O and S but wherein at the most one be 5 membered unsaturated heterocycles of O or S; 6 membered unsaturated heterocycles that contain 1,2 or 3 nitrogen-atoms; Contain perhaps that the heteroatomic 7-15 unit that is independently selected from N, O or S is saturated, fractional saturation or unsaturated heterocycle; Above-mentioned any ring is optional to be selected from (CH by one or more
2)
m(CO)
nR
dGroup replace;
M is 0,1,2 or 3;
N is 0,1 or 2;
R
4And R
5Be independently selected from hydrogen and C
1-6Alkyl;
R
6And R
8Be hydrogen, C independently
1-6Alkyl, contain 1,2 or 3 heteroatomic 5 yuan or 6 yuan of saturated or fractional saturation heterocycle that are independently selected from N, O and S, perhaps contain 6 membered unsaturated heterocycles of 1,2 or 3 nitrogen-atoms; Each above-mentioned ring is optional to be independently selected from following group replacement by one or more: halogen, nitro, amino, cyano group, oxo, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
3-10Cycloalkyl, C
2-6Thiazolinyl and C
2-6Alkynyl; Perhaps
R
6And R
8Represent oxo group altogether;
R
gBe C
1-6Alkyl, halo C
1-6Alkyl, amino, C
1-6Alkylamino or two (C
1-6Alkyl) amino;
Each R
dBe halogen, hydroxyl, cyano group, C
1-6Alkyl, halo C
1-6Alkyl, halo C
1-6Alkyl-carbonyl, halo C
1-6Alkyl carbonyl oxy, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, carboxyl, C
1-6Alkyl-carbonyl, C
1-6Alkoxy carbonyl, nitro, oxo, SO
2N (R
e)
2, N (R
e)
2, R wherein
eBe independently selected from hydrogen, C
1-6Alkyl, C
1-6Alkyl-carbonyl, carboxyl and C
1-6Alkoxy carbonyl; C
1-6Alkyl N (R
e)
2, C
6-10Aryl; C
6-10Aryl C
1-6Alkoxyl group; Contain 1,2 or 3 heteroatomic 5 yuan or 6 yuan of saturated or fractional saturation heterocycle that are independently selected from N, O and S, its optional C that passes through
1-4Alkyl carries out bridge joint; Contain 1,2,3 or 4 heteroatoms that is independently selected from N, O and S but wherein at the most one be 5 membered unsaturated heterocycles of O or S; Contain 0,1 or 2 heteroatomic 5 yuan or 6 yuan of volution that are independently selected from N, O or S, perhaps contain 6 membered unsaturated heterocycles of 1,2 or 3 nitrogen-atoms; Any above-mentioned ring is optional to be independently selected from following group replacement by one or more: halogen, hydroxyl, amino, cyano group, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group and halo C
1-6Alkoxyl group;
R
kBe NHSO
2R
g, contain 1,2 or 3 heteroatomic 5 yuan or 6 yuan of saturated or fractional saturation heterocycle that are independently selected from N, O and S, perhaps contain 1,2,3 or 4 be independently selected from N, O and S but wherein at the most one be 5 membered unsaturated heterocycles of O or S; Any above-mentioned ring is optional to be independently selected from halogen and C by one or more
1-6The group of alkyl replaces;
Perhaps its pharmacy acceptable salt or tautomer.
2. according to the compound of claim 1, wherein:
R
1For contain the saturated or fractional saturation heterocycle of 1,2 or 3 heteroatomic 5 yuan or 6 yuan that are independently selected from N, O and S, contain 1,2,3 or 4 heteroatoms that is independently selected from O, N and S but wherein at the most heteroatoms 5 membered unsaturated heterocycles that are O or S, contain 6 membered unsaturated heterocycles of 1,2 or 3 nitrogen-atoms or contain the unsaturated or fractional saturation heterocycle of heteroatomic 8-13 unit that is independently selected from O, N and S; Any above-mentioned ring is all chosen wantonly by one or more and is independently selected from following group replacement: cyano group, halogen, nitro, oxo, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkyl-carbonyl, C
1-6Alkoxy carbonyl, carboxyl, C
6-10Aryl, C
6-10Aryloxy, C
6-10Aryl carbonyl, N (R
a)
2, R wherein
aBe independently selected from hydrogen, C
1-6Alkyl, C
6-10Aryl, C
1-6Alkyl-carbonyl and C
6-10Aryl carbonyl; C
1-6Alkyl N (R
a)
2(CO)
dR
k, wherein d is 0 or 1, and R
kSuch as claim 1 definition.
3. according to the compound of claim 1 or 2, wherein:
R
3Be azonia two ring [2.2.1] heptyl, azonia two ring [2.2.2] octyl groups, thiazolyl, pyrazolyl, different
Azoles base, thiadiazolyl group, benzothienyl, diazosulfide base, benzo
Azoles base, dihydro benzo furyl, thiazoline and pyrimidyl, dihydrobenzo two
Satellite-based, dihydrobenzo
Piperazine base, benzimidazolyl-, triazolopyrimidinyl, dihydrobenzo
Azoles base, indolinyl, dihydroquinazoline base, dihydro phthalazinyl, indazolyl, benzisoxa
The azoles base, the benzotriazole base, the tetrahydro-b-carboline base, dihydro-iso indolyl, the Tetrahydronaphthyridderivates base, tetrazyl, thio-morpholinyl, azetidinyl, the different benzopyranyl of dihydro, the dihydrobenzopyrans base, tetrahydric quinoline group, indenyl, the dihydro-benzothiazole base, the Imidazothiazole base, naphthyridinyl, the tetrahydrochysene indazole base, the tetrahydro benzo thienyl, hexahydro naphthalene pyridine base, tetrahydropyridine and naphthyridinyl, tetrahydro isoquinolyl, imidazolidine and pyridyl, imidazolidine and pyrazinyl or pyrrolopyridinyl; Any above-mentioned ring is optional to be independently selected from (CH by one or more
2)
m(CO)
nR
dGroup replace, wherein m, n and Rd such as claim 1 definition.
Claim 1 or 2, suc as formula the compound shown in the II
Wherein:
R
1, R
3, R
5, R
6, R
8, X, p and t such as claim 1-3 each define;
D represents not exist, CH
2, CH
2CH
2Perhaps CH=CH;
A represents CH or N;
Y represents NR
e, O or S;
Z represents N or CR
f
R
7Expression C
1-6Alkyl;
R
eExpression hydrogen or C
1-6Alkyl;
R
fExpression hydrogen, C
1-6Alkyl or optional quilt are up to two and are selected from halogen, cyano group, C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkyl or halo C
1-6The C that the group of alkoxyl group replaces
6-10Aryl;
Perhaps its pharmacy acceptable salt or tautomer.
According to claim 1 or 2 suc as formula the compound shown in the IB:
Wherein D, R
2With X in claim 1 or 2 definition;
R
1For containing the unsaturated or fractional saturation heterocycle of heteroatomic 8-13 unit that is independently selected from O, N and S; Any above-mentioned ring is optional to be independently selected from following group replacement by one or more: cyano group, halogen, nitro, oxo, hydroxyl, C
1-6Alkyl, halo C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, C
1-6Alkyl-carbonyl, C
1-6Alkoxy carbonyl, carboxyl, C
6-10Aryl, C
6-10Aryloxy, C
6-10Aryl carbonyl and N (R
a)
2, R wherein
aBe independently selected from hydrogen, C
1-6Alkyl, C
6-10Aryl, C
1-6Alkyl-carbonyl and C
6-10Aryl carbonyl; C
1-6Alkyl N (R
a)
2(CO)
dR
k, wherein d is 0 or 1;
R
kBe NHSO
2R
g, contain the saturated or fractional saturation heterocycle of 1,2 or 3 heteroatomic 5 yuan or 6 yuan that are independently selected from N, O and S or contain 1,2,3 or 4 heteroatoms that is independently selected from N, O and S but 5 membered unsaturated heterocycles that heteroatoms is O or S at the most wherein; Any above-mentioned ring is optional to be independently selected from halogen and C by one or more
1-6The group of alkyl replaces;
R
gBe C
1-6Alkyl, halo C
1-6Alkyl, amino, C
1-6Alkylamino or two (C
1-6Alkyl) amino;
R
3Be azonia two ring [2.2.1] heptyl, azonia two ring [2.2.2] octyl groups, thiazolyl, pyrazolyl, different
Azoles base, thiadiazolyl group, benzothienyl, diazosulfide base, benzo
Azoles base, dihydro benzo furyl, thiazoline and pyrimidyl, dihydrobenzo two
Satellite-based, dihydrobenzo
Piperazine base, benzimidazolyl-, triazolopyrimidinyl, dihydrobenzo
Azoles base, indolinyl, dihydroquinazoline base, dihydro phthalazinyl, indazolyl, benzisoxa
The azoles base, the benzotriazole base, the tetrahydro-b-carboline base, dihydro-iso indolyl, the Tetrahydronaphthyridderivates base, tetrazyl, thio-morpholinyl, azetidinyl, the different benzopyranyl of dihydro, the dihydrobenzopyrans base, tetrahydric quinoline group, the dihydro-benzothiazole base, the Imidazothiazole base, naphthyridinyl, the tetrahydrochysene indazole base, the tetrahydro benzo thienyl, hexahydro naphthalene pyridine base, tetrahydropyridine and naphthyridinyl, tetrahydro isoquinolyl, imidazolidine and pyridyl, imidazolidine and pyrazinyl or pyrrolopyridinyl; Any above-mentioned ring is optional to be independently selected from (CH by one or more
2)
m(CO)
nR
dGroup replace;
M is 0,1,2 or 3;
N is 0,1 or 2; With
R
dBe halogen, cyano group, C
1-6Alkyl, C
1-6Alkoxyl group, halo C
1-6Alkoxyl group, carboxyl, C
1-6Alkoxy carbonyl, nitro, amino-sulfonyl, (C
1-6Alkyl-carbonyl) amino, morpholinyl, piperazinyl, thiazolyl, pyrazolyl, different
Azoles base, pyridyl, oxo, halo C
1-6Alkyl, phenyl or pyrrolidyl, hydroxyl, piperidines volution, C
6-10Aryl C
1-6Alkoxyl group, two (C
1-6Alkyl) amino, C
1-6Alkyl-carbonyl or two (C
1-6Alkyl) amino C
1-6Alkyl; Any above-mentioned ring is optional to be independently selected from C by one or more
1-6Alkyl and halo C
1-6The group of alkyl replaces;
Perhaps its pharmacy acceptable salt or tautomer.
6. be selected from following compound:
2-{ (1S)-1-[(carboxyl carbonyl) amino]-7-oxo nonyl }-5-(2-naphthyl)-1H-imidazoles-1-
Trifluoroacetate;
2-((1S)-1-{[morpholine-4-base (oxo) ethanoyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-1-
Trifluoroacetate;
5-(2-naphthyl)-2-{ (1S)-7-oxo-1-[(trifluoroacetyl group) amino] nonyl }-1H-imidazoles-1-
Trifluoroacetate;
2-((1S)-1-{[(1-methyl azetidine
-3-yl) carbonyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-
Dichloride;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[4-(1H-pyrazol-1-yl) phenyl]-1H-imidazoles-3-
Trifluoroacetate;
5-(2 methoxy quinoline-3-yl)-2-((1S)-1-{[(1-methyl azetidine
-3-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-3-
Two (trifluoroacetates);
2-((1S)-1-{[3-(dimethyl amido) propionyl] amino }-7-oxo nonyl)-5-(2-naphthyl)-1H-imidazoles-3-
Dichloride;
4-methoxyl group-2-[2-((1S)-1-{[(1-methyl azetidine
-3-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-1-
-5-yl] quinoline
Trichloride;
N-{ (1S)-1-[5-(2-naphthyl)-1,3,4-
Diazole-2-yl]-5-oxo heptyl } quinine-4-carboxylic acid amides;
N-{ (1S)-1-[5-(4-methoxy quinoline-2-yl)-1,3,4-
Diazole-2-yl]-7-oxo nonyl }-1-methyl azetidine-3-carboxylic acid amides;
5-(hydroxymethyl)-2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-
Trifluoroacetate;
4-{[2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-
-5-yl] methyl } morpholine-4-
Two (trifluoroacetates);
2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-5-[(1E)-3-methoxyl group-3-oxo third-1-alkene-1-yl]-1H-imidazoles-1-
Trifluoroacetate;
5-(2-carboxy ethyl)-2-(1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-
Trifluoroacetate;
5-ethanoyl-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-
Trifluoroacetate;
5-cyclohexyl-2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo nonyl)-1H-imidazoles-1-
Trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo undecyl)-5-phenyl-1H-imidazoles-1-
Trifluoroacetate;
2-((1S)-7-cyclopropyl-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-phenyl-1H-imidazoles-1-
Trifluoroacetate;
2-((1S)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-9-methyl-7-oxo decyl)-5-phenyl-1H-imidazoles-1-
Trifluoroacetate;
2-((1S)-8-hydroxyl-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-phenyl-1H-imidazoles-1-
Trifluoroacetate;
2-((1S)-7-(2-furyl)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-1-
Trifluoroacetate;
2-[(1S)-and 1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-8-(methyl sulfinyl)-7-oxo octyl group]-5-(2-naphthyl)-1H-imidazoles-1-
Trifluoroacetate;
2-[(1S)-and 1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-8-(methyl sulphonyl)-7-oxo octyl group]-5-(2-naphthyl)-1H-imidazoles-1-
Trifluoroacetate;
2-((1S)-8-(amino-sulfonyl)-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo octyl group)-5-(2-naphthyl)-1H-imidazoles-1-
Trifluoroacetate;
1-methyl-4-([(1S)-7-oxo-1-(4-phenyl-1H-imidazoles-3-
-2-yl)-and 7-pyridine-2-base heptyl] amino } carbonyl) piperidines
Two (trifluoroacetates);
2-((1S)-7-amino-1-{[(5-methoxyl group-2-Methyl-1H-indole-3-yl) ethanoyl] amino }-7-oxo heptyl)-5-(2-naphthyl)-1H-imidazoles-3-
Trifluoroacetate;
2-((1S)-6-carboxyl-1-{[(dimethylamino) alkylsulfonyl] amino } hexyl)-5-(2-naphthyl)-1H-imidazoles-3-
Trifluoroacetate;
2-((1S)-7-(methylamino)-7-oxo-1-{[(1-pyridine-2-phenylpiperidines-3-yl) carbonyl] amino } heptyl)-5-(2-naphthyl)-1H-imidazoles-3-
Trifluoroacetate;
2-[(1S)-and the 1-{[(benzylamino) carbonyl] amino }-7-(methylamino)-7-oxo heptyl]-5-(2-naphthyl)-1H-imidazoles-3-
Trifluoroacetate;
5-(2 methoxy quinoline-3-yl)-2-((1S)-1-{[(1-methyl azetidine
-3-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-3-
-L-tartrate;
And pharmaceutically acceptable free alkali, salt, alternative salt and steric isomer.
7. each the tartrate of compound of claim 1～5.
8. a pharmaceutical composition comprises before compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of each claim.
9. the compound of claim 1 is 5-(2 methoxy quinoline-3-yl)-2-((1S)-1-{[(1-methyl azetidine
-3-yl) carbonyl] amino }-7-oxo nonyl)-1H-imidazoles-3-
-L-tartrate or its steric isomer.
10. the compound of claim 1 is N-{ (1S)-1-[5-(2 methoxy quinoline-3-yl)-1H-imidazoles-2-yl]-7-oxo nonyl }-1-methyl azetidine-3-methane amide or its pharmacy acceptable salt or its steric isomer.
11. pharmaceutical composition comprises in claim 9 and 10 each compound and pharmaceutically acceptable carrier.
12. claim 1～6 each compound or the purposes of its pharmacy acceptable salt, be used to make treatment or prevention by regulating the medicine of the active disease of alleviating of HDAC.
13. according to claim 1～6 each compound or the purposes of its pharmacy acceptable salt, be used to make the medicine that treatment or prevention are selected from cancer, neurodegenerative disease, schizophrenia, apoplexy, restenosis and retarded disease.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0427138.3 | 2004-12-10 | ||
| GB0427138A GB0427138D0 (en) | 2004-12-10 | 2004-12-10 | Therapeutic compounds |
| GB0516435.5 | 2005-08-11 | ||
| GB0516435A GB0516435D0 (en) | 2005-08-11 | 2005-08-11 | Therapeutic compounds |
| PCT/GB2005/004743 WO2006061638A2 (en) | 2004-12-10 | 2005-12-09 | Heterocycle derivatives as histone deacetylase (hdac) inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101115742A CN101115742A (en) | 2008-01-30 |
| CN101115742B true CN101115742B (en) | 2011-06-22 |
Family
ID=34073539
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2005800476341A Active CN101115742B (en) | 2004-12-10 | 2005-12-09 | Heterocycle derivatives as histone deacetylase (hdac) inhibitors |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101115742B (en) |
| GB (1) | GB0427138D0 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102838625B (en) * | 2011-06-22 | 2015-04-15 | 中国科学院上海药物研究所 | Tetrahydropyridothiazole compounds, preparation method, drug compositions containing the same, and uses thereof |
| CN107735087B (en) * | 2015-05-07 | 2021-09-03 | Chdi基金会股份有限公司 | Histone deacetylase inhibitors, compositions and methods of use thereof |
| CN115073424A (en) * | 2021-03-10 | 2022-09-20 | 微境生物医药科技(上海)有限公司 | Histone deacetylase inhibitor and application thereof |
-
2004
- 2004-12-10 GB GB0427138A patent/GB0427138D0/en not_active Ceased
-
2005
- 2005-12-09 CN CN2005800476341A patent/CN101115742B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN101115742A (en) | 2008-01-30 |
| GB0427138D0 (en) | 2005-01-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5197014B2 (en) | Heterocyclic derivatives as histone deacetylase (HDAC) inhibitors | |
| CN101855221B (en) | Pyridazinone derivatives as PARP inhibitors | |
| US6803374B2 (en) | Compounds useful for treating hepatitis C virus | |
| JP6321045B2 (en) | Heterocyclic amides as kinase inhibitors | |
| TWI460176B (en) | Indole compound | |
| CN100422158C (en) | Inhibitors of Akt activity | |
| US20040082607A1 (en) | Fused heterocyclic compounds | |
| US20040215014A1 (en) | Piperidine compounds for use as orexin receptor antagonist | |
| CN101600706A (en) | The AKT activity inhibitor | |
| CN101501006A (en) | Pyridinone and pyridazinone derivatives as inhibitors of poly(ADP-ribose)polymerase (PARP) | |
| WO2008011130A2 (en) | Amide compounds | |
| CN101133024A (en) | Amide derivatives as inhibitors of histone deacetylase | |
| JP2009544616A (en) | Amide compounds | |
| WO2006062224A1 (en) | Carboxamide derivative | |
| WO2006112549A1 (en) | Fused heterocyclic compound | |
| JP2008524339A (en) | Inhibitor of AKT activity | |
| CN1997626A (en) | Inhibitors of histone deacetylase | |
| TW201002685A (en) | Heterocyclic compound and use thereof | |
| TW200819443A (en) | An imidazole derivative | |
| KR20030045187A (en) | Tetrahydrobenzazepine Derivatives Useful as Modulators of Dopamine D3 Receptors(Antipsychotic Agents) | |
| JP5390859B2 (en) | Heterocyclic substituted amide and sulfur amide derivatives as histone deacetylase (HDAC) inhibitors | |
| CN101115742B (en) | Heterocycle derivatives as histone deacetylase (hdac) inhibitors | |
| AU2006212951A1 (en) | Inhibitors of checkpoint kinases | |
| CN101107220A (en) | Amide derivatives as inhibitors of histone deacetylase |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: MSD ITALY S. P. A. Free format text: FORMER OWNER: ANGELETTI P. IST RICHERCHE BIO. Effective date: 20140702 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20140702 Address after: Rome Italy Patentee after: MSD Italy S. p. A. Address before: Italy Pomezia Patentee before: Angeletti P. Ist Richerche Bio. |