CN101374810A - Modulators of alpha7 nicotinic acetylcholine receptors and therapeutic uses thereof - Google Patents
Modulators of alpha7 nicotinic acetylcholine receptors and therapeutic uses thereof Download PDFInfo
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- CN101374810A CN101374810A CNA2007800032922A CN200780003292A CN101374810A CN 101374810 A CN101374810 A CN 101374810A CN A2007800032922 A CNA2007800032922 A CN A2007800032922A CN 200780003292 A CN200780003292 A CN 200780003292A CN 101374810 A CN101374810 A CN 101374810A
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Abstract
Compounds with a7 nicotinic acetylcholine receptor (a7 nAChR) agonistic activity, processes for their preparation, pharmaceutical compositions containing the same and the use thereof for the treatment of neurological and psychiatric diseases.
Description
Compound, its preparation method of (α 7nAChR) agonist activity that the present invention relates to have alpha 7 nicotinic acetylcholine receptors, the pharmaceutical composition that comprises it and the purposes in treatment nervous system disease and mental disorder thereof.
Background of invention
Nicotine potential neuroprotective in the neurodegeneration model of various animals and culturing cell is all pointed in many nearest observations, and described model relates to excitotoxin damage (1-5), nutritive deficiency (6), local asphyxia (7), wound (8), the neuronal death (9-11) of A β-mediation and the neuronal degeneration (9 that albumen-gathering mediated; 12).Demonstrate in many situations of neuroprotective at nicotine, by comprise α 7 hypotypes acceptor participate in (7 directly; 11-15), this activation that shows the nAChR that comprises α 7 hypotypes may be worked in the neuroprotective of mediation nicotine.Obtainable data show, as for the agonist/positive modulators of neuroprotective molecule, alpha 7 nicotinic acetylcholine receptors has been represented effective molecular target for exploitation.In fact, determined some alpha 7 nicotinic receptor agonists, and its possible lead compound as the exploitation nerve protection medicine has been carried out estimating (16-20).Recently, alpha 7 nicotinic acetylcholine receptors participates in inflammatory process and also obtains describing (21).Therefore, the new conditioning agent of exploitation this receptor will cause the new therapy of nervous system disease, mental disorder and inflammatory diseases.
Prior art
Find that some different compounds have aryl/hetaryl-urea groups or carbamyl group and basic nitrogen, and demonstrate the affinity of nicotine type nicotinic and mAChR or be required for alzheimer's disease, describe for these compounds are existing: condensed pyridazine derivatives (WO03070707); The method (US2004127536) of treatment inflammatory diseases; Aza-bicyclo N-diaryl amides (WO03078431); Heterocyclic urea derivative (WO0266468); Spirocyclic piperidine (WO2004004714); The indoles of phenyl-replacement and indazole class (WO0174773); The imidazopyridine of phenyl-replacement (WO0174815);
Find that some heterogeneous ring compounds have basic nitrogen and demonstrate polytype biologic activity, describe for these compounds are existing: the compound of anti-herpesvirus (US6288091); 2H-phthalazines-1-ketone derivatives (WO00044726); 1,4-dihydro-2 (2H) iloquinoline derivative (DE2406490); Pyridine compounds (JP06016638); Piperidine amide (WO0198268); Imidazopyrazine (US2005009832) as the 8-amino-aryl-replacement of kinase inhibitor;
In Heterocycles (1997), 45 (4), heterogeneous ring compound is also disclosed among the 723-734: 1-[ω [(arylamino) carbonyl] alkyl]-4-(benzo cycloalkyl) piperazines.
According to functional group, connection chain or substitution pattern, can easily these reference compounds and compound disclosed herein structurally be distinguished; These formerly document do not have open or point out the unique combination of some structure fragment, described structure fragment to be presented as new omega-amino-alkyl urea or the carboxyl acylamide that has nicotine type nicotinic α 7 receptor actives disclosed herein.
Summary of the invention
The invention provides as alpha 7 nicotinic acetylcholine receptors (α 7 nAChR) wholly or in part agonist compound, comprise the pharmaceutical composition of described compound, with and the disease that can benefit from alpha 7 nicotinic acetylcholine receptors activation in treatment, as the purposes in nervous system disease and mental disorder, particularly alzheimer's disease and the schizophrenia.
Detailed Description Of The Invention
The invention provides the compound of formula (I)
Wherein
W, h and k are 0,1,2 or 3 independently of one another, and condition is 3≤w+h+k≤5;
At k〉1 o'clock, K1 and K2 are connected on the identical or different carbon atom, represent hydrogen independently of one another; Halogen; (C
1-C
5) alkyl, alkoxyl group, fluoro-alkyl, alkylidene group, fluoro alkylidene group; Hydroxyalkyl; Or K1 and K2 can form alkylidene group or fluoro alkylidene group together; Or K1 forms (C with K2 with the carbon atom that they were connected
3-C
6) group of naphthene base; Perhaps when k 〉=2, two ()
kCarbon atom can form unsaturated link(age); Perhaps when w be 1,2 or 3 and k when being 1, K1 can form oxo group with the carbon atom that they were connected with K2;
J is 0,1 or 2;
X is a following radicals
Z is CH
2, N, O, S, S (=O) or S (=O)
2
P is 0,1,2 or 3;
N is 0,1 or 2;
S is 1 or 2;
Q and q ' are 1 to 4 integer independently of one another;
T ' is representation hydroxy independently of one another; Sulfydryl; Amino; Cyano group; Nitro; Straight chain, side chain or cyclic (C
1-C
6) alkyl, three alkylhalide groups, hydroxyalkyl, aminoalkyl group, mercaptoalkyl, alkoxyl group, alkylthio, alkyl-carbonyl, alkoxy carbonyl, alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
6) alkylamino; Straight chain, side chain or cyclic (C
1-C
6) alkoxyl group-(C
1-C
6) alkyl, list-or two-(C
1-C
6) alkylamino-(C
1-C
6) alkyl, or (C
1-C
6) alkylthio-(C
1-C
6) alkyl; (C
1-C
3) alkyl sulfonyl-amino; Single-or two-(C
1-C
3) alkyl amino sulfonyl; Sulfamyl; Straight chain, side chain or cyclic (C
1-C
6) alkyl amino-carbonyl; Carbamyl; Perhaps, when p was 2 or 3, two T ' formed 5 to 8 yuan of volutions or condensed ring;
U and U ' represent independently of one another
Hydrogen; Cyano group; Hydroxyl; Amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
6) alkylamino group; (the C of straight or branched
1-C
6) alkoxy base; Straight chain, side chain or cyclic (C
1-C
6) alkyl, azepine alkyl, oxa alkyl chain, it is randomly replaced by following radicals: hydroxyl, sulfydryl, amino, cyano group, nitro, oxo, trihalogenmethyl, three halogen methoxyl groups, carbamyl, sulfamyl, straight chain, side chain or cyclic (C
1-C
6) alkyl, hydroxyalkyl, aminoalkyl group, mercaptoalkyl, alkoxyl group, alkylthio, alkyl-carbonyl, alkoxy carbonyl, alkyl-carbonyl-amino, list-or two-straight chain, side chain or cyclic (C
1-C
6) alkyl amino-carbonyl, list-or two-(C
5-C
10) aryl-or heteroaryl amino carbonyl, (C
5-C
10) aryl-or heteroarylsulfonyl amino, (C
1-C
3) alkyl sulfonyl-amino, (C
5-C
10) aryl-or heteroarylsulfonyl, (C
1-C
3) alkyl sulphonyl, list-or two-(C
5-C
10) aryl-or heteroaryl sulfamyl, list-or two-(C
1-C
3) alkylsulfamoyl group, list-or two-straight chain, side chain or cyclic (C
1-C
6) alkylamino;
Randomly be independently selected from the following straight chain, side chain or the cyclic (C that are connecting 5 to 10 yuan of aryl or heteroaryl groups that group replaced by one or more
1-C
6) alkyl, azepine alkyl, oxa alkyl chain: hydroxyl, sulfydryl, amino, cyano group, nitro, trihalogenmethyl, three halogen methoxyl groups, straight chain, side chain or cyclic (C
1-C
6) alkyl, hydroxyalkyl, aminoalkyl group, mercaptoalkyl, alkoxyl group, alkylthio, alkyl-carbonyl, alkoxy carbonyl, alkyl-carbonyl-amino, list-or two-, straight chain, side chain or cyclic (C
1-C
6) alkylamino, straight chain, side chain or cyclic (C
1-C
6) alkoxyl group-(C
1-C
6) alkyl, list-or two-(C
1-C
6) alkylamino-(C
1-C
6) alkyl or (C
1-C
6) alkylthio-(C
1-C
6) alkyl, carbamyl, (C
5-C
10) aryl-or heteroarylsulfonyl amino, (C
1-C
3) alkyl sulfonyl-amino, list-or two-(C
5-C
10) aryl-or heteroaryl sulfamyl, (C
1-C
3) alkylsulfamoyl group, sulfamyl, list-or two-, straight chain, side chain or cyclic (C
1-C
6) alkyl amino-carbonyl, list-or two-(C
5-C
10) aryl-or the heteroaryl amino carbonyl;
Randomly be independently selected from following 5 to 10 yuan of aromatic rings or hetero-aromatic rings that group replaced: hydroxyl by one or more; Halogen; Sulfydryl; Amino; Cyano group; Nitro; Trihalogenmethyl; Three halogen methoxyl groups; Straight chain, side chain or cyclic (C
1-C
6) alkyl, hydroxyalkyl, aminoalkyl group, mercaptoalkyl, alkoxyl group, alkylthio, alkyl-carbonyl-, alkoxy carbonyl, alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
6) alkylamino; Straight chain, side chain or cyclic (C
1-C
6) alkoxyl group-(C
1-C
6) alkyl, single-or two-(C
1-C
6) alkylamino-(C
1-C
6) alkyl, or (C
1-C
6) alkylthio-(C
1-C
6) alkyl; Carbamyl; (C
5-C
10) aryl-or heteroarylsulfonyl amino; (C
1-C
3) alkyl sulfonyl-amino; Single-or two-(C
5-C
10) aryl-or the heteroaryl sulfamyl; Single-or two-(C
1-C
3) alkylsulfamoyl group; Sulfamyl; Single-or two-(C
5-C
10) aryl-or the heteroaryl amino carbonyl; Single-or two-, straight chain, side chain or cyclic (C
1-C
6) alkyl amino-carbonyl;
-Y-Q-is-C (=O) NH-Q-or-NH-C (=O)-NH-Q;
Q is 5 to 10 yuan of aromatic rings or hetero-aromatic rings;
R represents 5 to 10 yuan of aromatic rings or hetero-aromatic rings, and it randomly is independently selected from following group and replaces by one or more: halogen; Hydroxyl; Sulfydryl; Cyano group; Nitro; Amino; Straight chain, side chain or cyclic (C
1-C
6) alkyl, three alkylhalide groups, alkoxyl group or alkyl-carbonyl; Straight chain, side chain or cyclic (C
1-C
6) alkyl-carbonyl-amino, single-or two-(C
5-C
10) aryl-or the heteroaryl amino carbonyl; Single-or two, straight chain, side chain or cyclic (C
1-C
6) alkyl amino-carbonyl; Carbamyl; Straight chain, side chain or cyclic (C
1-C
6) alkyl sulfonyl-amino; Straight chain, side chain or cyclic (C
1-C
6) alkyl sulphonyl; Single-or two-(C
5-C
10) aryl-or the heteroaryl sulfamyl; Single-or two-straight chain, side chain or cyclic (C
1-C
6) alkylsulfamoyl group; Straight chain, side chain or cyclic (C
1-C
6) alkoxyl group-(C
1-C
6) alkyl, single-or two-(C
1-C
6) alkylamino-(C
1-C
6) alkyl, (C
1-C
6) alkylthio-(C
1-C
6) alkyl;
When j=2, R ' represents halogen independently of one another; Hydroxyl; Sulfydryl; Cyano group; Nitro; Trihalogenmethyl; Three halogen methoxyl groups; Straight chain, side chain or cyclic (C
1-C
6) alkyl, three alkylhalide groups, alkoxyl group, hydroxyalkyl, mercaptoalkyl, alkoxy carbonyl, alkyl-carbonyl, alkyl sulphonyl; Straight chain, side chain or cyclic (C
1-C
6) alkyl-carbonyl-amino; Single-or two, straight chain, side chain or cyclic (C
1-C
6) alkyl amino-carbonyl; Carbamyl; Straight chain, side chain or cyclic (C
1-C
6) alkylsulfamoyl group; Straight chain, side chain or cyclic (C
1-C
6) alkoxyl group-(C
1-C
6) alkyl, single-or two-(C
1-C
6) alkylamino-(C
1-C
6) alkyl, (C
1-C
6) alkylthio-(C
1-C
6) alkyl.
Condition be when k be 0 and the summation of w and h when being 4, T ' is a sulfydryl; Amino; Three alkylhalide groups; Hydroxyalkyl; (C
1-C
6) aminoalkyl group; Mercaptoalkyl; Alkylthio; Alkoxy carbonyl; Alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
6) alkylamino; Straight chain, side chain or cyclic (C
1-C
6) alkoxyl group-(C
1-C
6) alkyl, single-or two-(C
1-C
6) alkylamino-(C
1-C
6) alkyl, or (C
1-C
6) alkylthio-(C
1-C
6) alkyl; Single-or two-(C
1-C
3) alkyl amino sulfonyl, or j ≠ 0;
And when j is 0 and the summation of w, h and k when being 4, K1 and K2 can not be hydrogen;
And get rid of following compound:
1--[4-(2-amino-thiazolyl--5-yl)-phenyl]-3-(3-imidazoles-1-base-propyl group)-urea; 1-(biphenyl-4-yl)-3-(5-(spiral shell (indane-1,4 ＇-piperidines-10-yl)-amyl group)-urea; 1-(biphenyl-4-yl)-3-(4-(spiral shell (indane-1,4 ＇-piperidines-10-yl)-butyl)-urea; 3-{4-[3-(3-morpholine-4-base-propyl group)-urea groups]-phenyl }-1H-indazole-5-benzoic acid amides; 3-{4-[3-(3-piperidines-1-base-propyl group)-urea groups]-phenyl }-1H-indazole-5-benzoic acid amides; 1-[4-(8-methylamino-imidazo [1,2-a] pyrazine-3-yl)-phenyl]-3-(3-morpholine-4-base-propyl group)-urea;
1-[4-(8-cyclopropyl amino-imidazo [1,2-a] pyrazine-3-yl)-phenyl]-3-(3-tetramethyleneimine-1-base-propyl group)-urea; 1-(2-hydroxyl-3-morpholine-4-base-propyl group)-3-[4-(8-methylamino-imidazo [1,2-a] pyrazine-3-yl)-phenyl]-urea; 1-[4-(8-cyclopropyl amino-imidazo [1,2-a] pyrazine-3-yl)-phenyl]-3-(3-morpholine-4-base-propyl group)-urea; 1-[4-(8-methylamino-imidazo [1,2-a] pyrazine-3-yl)-phenyl]-3-(3-tetramethyleneimine-1-base-propyl group)-urea; N-biphenyl-4-base-4-piperazine-1-base-butyramide.
In above-mentioned formula I compound, most preferred is that wherein X is the compound of following formula:
The compound group that is more preferably is that wherein X is the compound of following formula:
In one embodiment, the invention provides the compound that is called G1 hereinafter, wherein:
X is:
Z is selected from CH
2, N, O;
When p greater than 1 the time, T ' is representation hydroxy independently of one another; Amino; Cyano group; Nitro; Straight chain, side chain or cyclic (C
1-C
6) alkyl, three alkylhalide groups, hydroxyalkyl, aminoalkyl group, mercaptoalkyl, alkoxyl group, alkylthio, alkyl-carbonyl, alkoxy carbonyl, alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
6) alkylamino; Straight chain, side chain or cyclic (C
1-C
6) alkoxyl group-(C
1-C
6) alkyl, single-or two-(C
1-C
6) alkylamino-(C
1-C
6) alkyl or (C
1-C
6) alkylthio-(C
1-C
6) alkyl; (C
1-C
3) alkyl sulfonyl-amino; Single-or two-(C
1-C
3) alkyl amino sulfonyl; Sulfamyl; Straight chain, side chain or cyclic (C
1-C
6) alkyl amino-carbonyl; Carbamyl; Perhaps when p was 2 or 3, two T ' substituting groups formed 5 to 8 yuan of volutions or condensed ring;
U and U ' represent hydrogen independently of one another; Straight chain, side chain or cyclic (C
1-C
6) alkyl, azepine alkyl, oxa alkyl chain, it is randomly by hydroxyl, oxo, trihalogenmethyl, three halogen methoxyl groups, carbamyl, sulfamyl, pyridyl, straight chain, side chain or cyclic (C
1-C
3) alkyl-carbonyl, alkoxy carbonyl, alkyl-carbonyl-amino, single-or two-straight chain, side chain or cyclic (C
1-C
3) alkyl amino-carbonyl, (C
1-C
3) alkyl sulfonyl-amino, (C
1-C
3) alkyl sulphonyl, list-or two-(C
1-C
3) alkylsulfamoyl group, list-or two-straight chain, side chain or cyclic (C
1-C
6) alkylamino;
Q is 6 to 10 yuan of aromatic rings or hetero-aromatic rings;
R represents 5 to 10 yuan of aromatic rings or hetero-aromatic rings, and it randomly is independently selected from following group and replaces by one or more: halogen; Hydroxyl; Sulfydryl; Cyano group; Nitro; Amino; Straight chain, side chain or cyclic (C
1-C
6) alkyl, three alkylhalide groups, alkoxyl group or alkyl-carbonyl; Straight chain, side chain or cyclic (C
1-C
6) alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
6) alkyl amino-carbonyl; Carbamyl; Straight chain, side chain or cyclic (C
1-C
6) alkyl sulfonyl-amino; Straight chain, side chain or cyclic (C
1-C
6) alkyl sulphonyl; Single-or two-straight chain, side chain or cyclic (C
1-C
6) alkylsulfamoyl group; Straight chain, side chain or cyclic (C
1-C
6) alkoxyl group-(C
1-C
6) alkyl, list-or two-(C
1-C
6) alkylamino-(C
1-C
6) alkyl;
When j=2, R ' represents halogen independently of one another; Hydroxyl; Trihalogenmethyl; Three halogen methoxyl groups; Straight chain, side chain or cyclic (C
1-C
3) alkyl, three alkylhalide groups, alkoxyl group, hydroxyalkyl, alkoxy carbonyl, alkyl-carbonyl, alkyl sulphonyl; Straight chain, side chain or cyclic (C
1-C
3) alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
3) alkyl amino-carbonyl; Carbamyl; (C
1-C
3) alkyl sulfonyl-amino; Straight chain, side chain or cyclic (C
1-C
3) alkylsulfamoyl group; Straight chain, side chain or cyclic (C
1-C
3) alkoxyl group-(C
1-C
3) alkyl, list-or two-(C
1-C
3) alkylamino-(C
1-C
3) alkyl, (C
1-C
3) alkylthio-(C
1-C
3) alkyl;
In one aspect of the invention, G1 provides a group of compound, the wherein w+h+k=4 that is called G1a hereinafter.
In G1a, special embodiment provides this compounds, wherein
K is 0;
X is the group of following formula:
U and U ' represent hydrogen independently of one another; Straight chain, side chain or cyclic (C
1-C
6) alkyl, azepine alkyl, oxa alkyl chain, it is randomly replaced by trihalogenmethyl, three halogen methoxyl groups, carbamyl, sulfamyl, pyridyl;
-Y-be group-C (=O) NH-or-NH-C (=O) NH-;
J is 0 or 1;
R represents 5 to 10 yuan of aromatic rings or hetero-aromatic rings, and it randomly is independently selected from following group and replaces by one or more: halogen; Hydroxyl; Straight chain, side chain or cyclic (C
1-C
6) alkyl, three alkylhalide groups, alkoxyl group; Straight chain, side chain or cyclic (C
1-C
3) alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
3) alkyl amino-carbonyl; Carbamyl;
R ' represents halogen; Trihalogenmethyl; Three halogen methoxyl groups; Straight chain, side chain or cyclic (C
1-C
3) alkyl, alkoxyl group.
In another embodiment, the invention provides the one group of compound that is called G2 hereinafter, wherein:
w+h+k＝4
K1 and K2 represent hydrogen independently of one another; Halogen; (C
1-C
3) alkyl, alkoxyl group;
X is the group of following formula:
Z is CH
2, N, O;
P is 0 or 1;
T ' represents straight chain, side chain or cyclic (C
1-C
3) alkyl, three alkylhalide groups, alkyl-carbonyl, alkoxy carbonyl, alkyl-carbonyl-amino; Straight chain, side chain or cyclic (C
1-C
3) alkyl amino-carbonyl; Carbamyl;
R represents 5 to 10 yuan of aromatic rings or hetero-aromatic rings, and it randomly is independently selected from following group and replaces by one or more: halogen; Hydroxyl; Straight chain, side chain or cyclic (C
1-C
3) alkyl, three alkylhalide groups, alkoxyl group or alkyl-carbonyl; Straight chain, side chain or cyclic (C
1-C
3) alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
3) alkyl amino-carbonyl; Carbamyl; Straight chain, side chain or cyclic (C
1-C
3) alkyl sulfonyl-amino; Straight chain, side chain or cyclic (C
1-C
6) alkyl sulphonyl; Single-or two-straight chain, side chain or cyclic (C
1-C
6) alkylsulfamoyl group; Straight chain, side chain or cyclic (C
1-C
6) alkoxyl group-(C
1-C
6) alkyl, list-or two-(C
1-C
6) alkylamino-(C
1-C
6) alkyl;
When j=2, R ' represents halogen independently of one another; Hydroxyl; Trihalogenmethyl; Three halogen methoxyl groups; Straight chain, side chain or cyclic (C
1-C
3) alkyl, three alkylhalide groups, alkoxyl group; Straight chain, side chain or cyclic (C
1-C
3) alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
3) alkyl amino-carbonyl; Carbamyl; (C
1-C
3) alkyl sulfonyl-amino; Straight chain, side chain or cyclic (C
1-C
3) alkylsulfamoyl group; Straight chain, side chain or cyclic (C
1-C
3) alkoxyl group-(C
1-C
3) alkyl, list-or two-(C
1-C
3) alkylamino-(C
1-C
3) alkyl, (C
1-C
3) alkylthio-(C
1-C
3) alkyl;
In G2, special embodiment has defined the one group of compound that is called G3 hereinafter, wherein:
K1 and K2 represent hydrogen independently of one another; Halogen; (C
1-C
3) alkyl;
X is the group of following formula:
Z is CH
2, N;
Q and q ' are 1 to 3 integer independently of one another;
T ' represents straight chain, side chain or cyclic (C
1-C
3) alkyl, alkyl-carbonyl;
R represents 5 to 10 yuan of aromatic rings or hetero-aromatic rings, and it randomly is independently selected from following group and replaces by one or more: halogen; Straight chain, side chain or cyclic (C
1-C
3) alkyl, three alkylhalide groups, alkoxyl group; Straight chain, side chain or cyclic (C
1-C
3) alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
3) alkyl amino-carbonyl; Carbamyl;
When j=2, R ' represents halogen independently of one another; Trihalogenmethyl; Straight chain, side chain or cyclic (C
1-C
3) alkyl, alkoxyl group.
In one aspect, G3 provides the one group of compound that is called G4a hereinafter, wherein-and Y-is group-C (=O) NH-.
In G4a, special embodiment is this compounds, wherein:
Q is phenyl or pyridyl ring;
J is 1 or 2;
R represents phenyl, pyridyl or pyrazoles basic ring, and it randomly is independently selected from following group and replaces by one or more: halogen; Straight chain, side chain or cyclic (C
1-C
3) alkyl, three alkylhalide groups, alkoxyl group; Straight chain, side chain or cyclic (C
1-C
3) alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
3) alkyl amino-carbonyl; Carbamyl.
On the other hand, G3 provides the one group of compound that is called G4b hereinafter, wherein:
-Y-be group-NH-C (=O)-NH-.
In G4b, special embodiment is this compounds, wherein:
K1 and K2 represent hydrogen independently of one another; Halogen; (C
1-C
3) alkyl;
X is the group of following formula:
Z is CH
2, N;
P is 0 or 1;
Q and q ' are 1 to 3 integer independently of one another;
T ' represents straight chain, side chain or cyclic (C
1-C
3) alkyl, alkyl-carbonyl;
-Y-be group-NH-C (=O)-NH-;
Q is phenyl or pyridyl;
R represents phenyl, pyridyl or pyrazoles ring, and it randomly is independently selected from following group and replaces by one or more: halogen; Straight chain, side chain or cyclic (C
1-C
3) alkyl, three alkylhalide groups, alkoxyl group; Straight chain, side chain or cyclic (C
1-C
3) alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
3) alkyl amino-carbonyl; Carbamyl;
In another aspect of the present invention, G1 also provides the one group of compound that is called G5 hereinafter, wherein
w+h+k＝3；
X is
In G5, an embodiment provides the one group of compound that is called G5a hereinafter, wherein:
Q and q ' are 1 to 3 integer independently of one another;
When p greater than 1 the time, T ' is representation hydroxy independently of one another; Cyano group; Oxo; Straight chain, side chain or cyclic (C
1-C
6) alkyl, three alkylhalide groups, hydroxyalkyl, alkoxyl group, alkyl-carbonyl, alkoxy carbonyl, alkyl-carbonyl-amino; Straight chain, side chain or cyclic (C
1-C
6) alkoxyl group-(C
1-C
6) alkyl; (C
1-C
3) alkyl sulfonyl-amino; Single-or two-(C
1-C
3) alkyl amino sulfonyl; Sulfamyl; Straight chain, side chain or cyclic (C
1-C
6) alkyl amino-carbonyl; Carbamyl; Straight chain, side chain or cyclic (C
1-C
3) alkoxyl group-(C
1-C
3) alkyl; (C
1-C
3) alkyl sulfonyl-amino; Single-or two-(C
1-C
3) alkylsulfamoyl group; (C
1-C
3) alkylsulfonyl;
-Y-be group-NH-C (=O)-NH-;
R represents 5 to 6 yuan of aromatic rings or hetero-aromatic rings, and it randomly is independently selected from following group and replaces by one or more: halogen; Hydroxyl; Cyano group; Straight chain, side chain or cyclic (C
1-C
3) alkyl, three alkylhalide groups, alkoxyl group; Straight chain, side chain or cyclic (C
1-C
3) alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
3) alkyl amino-carbonyl; Carbamyl; Straight chain, side chain or cyclic (C
1-C
3) alkyl sulfonyl-amino; Straight chain, side chain or cyclic (C
1-C
3) alkyl sulphonyl; Single-or two-straight chain, side chain or cyclic (C
1-C
3) alkylsulfamoyl group; Straight chain, side chain or cyclic (C
1-C
3) alkoxyl group-(C
1-C
3) alkyl;
When j=2, R ' represents halogen independently of one another; Trihalogenmethyl; Three halogen methoxyl groups; Straight chain, side chain or cyclic (C
1-C
3) alkyl, alkoxyl group.
In G5a, special embodiment is represented this compounds, wherein:
K is 0;
P is 0 or 1;
When p greater than 1 the time, T ' represents straight chain, side chain or cyclic (C independently of one another
1-C
3) alkyl, alkyl-carbonyl, alkoxy carbonyl, alkyl-carbonyl-amino; Straight chain, side chain or cyclic (C
1-C
3) alkyl amino-carbonyl; Carbamyl;
-Y-be group-NH-C (=O)-NH-;
Q is phenyl or pyridyl;
J is 0 or 1;
R represents phenyl or pyridyl ring, and it randomly is independently selected from following group and replaces by one or more: halogen; Hydroxyl; Straight chain, side chain or cyclic (C
1-C
6) alkyl, alkoxyl group; Straight chain, side chain or cyclic (C
1-C
3) alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
3) alkyl amino-carbonyl; Carbamyl;
R ' represents halogen.
Compound of the present invention can prepare by many synthetic routes, has wherein exemplified some routes among the flow process 1-5 below:
A) flow process 1
According to flow process 1, amino alcohol (is for example worked as k=1 and K1=K2=-CH
3The time be 3-amino-2,2-dimethyl-third-1-alcohol) react in organic solvent such as methylene dichloride, tetrahydrofuran (THF), dimethyl formamide or its mixture with for example isocyanic ester or chloroformamide (this sentences aromatic isocyanate is example), finish up to reaction.Then hydroxyurea 3 (for example polite oxidizing reaction (Swernoxidation)) under standard conditions is carried out oxidation, the aldehyde 4 of gained then reacts under the reductive alkylation condition of standard with the amine 6 of suitable replacement, for example use sodium triacetoxy borohydride, obtain Compound I α.At R is under the situation of halogen or boric acid ester, and I α can be further processed, for example by cross-coupling reaction, for example under Suzuki linked reaction condition with boric acid or aryl or heteroaryl halide reaction, obtain Compound I β.
B) flow process 2
According to flow process 2, ω-haloalkane acyl chlorides and (mixing) arylamine 8 are reacted in the presence of organic bases, obtain ω-halogenated alkane acid amides 9.With itself and amine 6 substituted in reaction halogens, obtain Compound I α.At R is under the situation of halogen or boric acid ester, and I α can be further processed, for example by cross-coupling reaction, for example under Suzuki linked reaction condition, with boric acid or aryl or heteroaryl halide reaction, obtains Compound I β.
C) flow process 3
According to flow process 3, suitable activatory omega-halogenated alkyl groups phthalic imidine and amine X, are reacted in the presence of alkali such as triethylamine or salt of wormwood for example in (but being not limited to) 2-butanone or the dimethyl formamide at organic solvent.For example, the mixture of amine (or its hydrochloride) and omega-halogenated alkyl groups phthalic imidine is refluxed in the presence of basic carbonate in methylethylketone, finish up to reaction, follow reaction mixture, by removing by filter insolubles, filtrate is concentrated into filtrate and washings dried with chloroform or washed with dichloromethane.Next step for example by the mixture back flow reaction in ethanol with omega-amino-alkyl phthalic imide and hydrazine hydrate, changes into ω-diamines with the omega-amino-alkyl phthalic imide.Described ω-diamines and activatory reactant such as isocyanic ester or chloroformamide react in organic solvent such as methylene dichloride, tetrahydrofuran (THF), dimethyl formamide or its mixture, obtain the compound of formula I α.At R is under the situation of halogen, boric acid or boric acid ester, and I α can be further processed, for example by cross-coupling reaction, for example under Suzuki linked reaction condition with boric acid or aryl or heteroaryl halide reaction, obtain the compound of formula I.
D) flow process 4
According to flow process 4, suitable aldehyde precursor such as amino alcohol when k=1 and K1=K2=H (for example when be aminopropanol) are reacted in organic solvent such as methylene dichloride, tetrahydrofuran (THF), dimethyl formamide or its mixture with isocyanic ester or chloroformamide (this sentences aromatic isocyanate is example), finish up to reaction.Then thus obtained aldehyde precursor conversion is become aldehyde, for example (as polite oxidizing reaction) carries out oxidation under the situation of alcohol under standard conditions, subsequently aldehyde is reacted under the reductive alkylation condition of standard with the amine X that suitably replaces, for example use sodium triacetoxy borohydride, obtain Compound I α.At R is under the situation of halogen, boric acid or boric acid ester, and I α can be further processed, for example by cross-coupling reaction, for example under Suzuki linked reaction condition with boric acid or aryl or heteroaryl halide reaction, obtain the compound of formula I.
E) flow process 5
According to flow process 5, with suitable activatory ω-halogenated-chain acid (for example, wherein group C (=O)-LG represent acyl chlorides or activatory ester or acylimidazole (imidazolide)) in the presence of organic bases with (mixing) arylamine reaction, obtain ω-halogenated alkane acid amides.It is further reacted to replace ω-halogen atom with amine X, obtain the compound of formula I α.At R is under the situation of halogen, boric acid or boric acid ester, and I α can be further processed, for example by cross-coupling reaction, for example under Suzuki linked reaction condition with boric acid or aryl or heteroaryl halide reaction, obtain the compound of formula I.
F) flow process 6
According to flow process 6, with omega-amino-alkanoic acids with reagent as (but being not limited to) 1,1 '-carbonyl dimidazoles is suitably activation in solvent such as methylene dichloride, dimethyl formamide or its mixture, and with suitable heterocyclic amine reaction, obtain the target compound of formula I.
G) flow process 7
According to flow process 7, with omega-amino-alkanoic acids with reagent as (but being not limited to) 1,1 '-carbonyl dimidazoles is suitably activation in solvent such as methylene dichloride, dimethyl formamide or its mixture, and with suitable bromo aryl or the reaction of heteroaryl amine, obtain bromo aryl or heteroaryl amide, then it is further reacted under cross-coupling reaction such as Suzuki linked reaction condition, obtain the target compound of formula I.
Flow process 8 has shown a kind of acid of chain replacement, the possible synthetic route of formula I compound precursor.
According to flow process 8, with the diester malonate of alkyl-replacement in solvent such as tetrahydrofuran (THF) or dimethyl formamide with alkali for example (but being not limited to) sodium hydride handle, and and α, ω-saturated dihalide reaction.Dibasic diester malonate of gained is hydrolyzed, and handles with strong acid such as Hydrogen bromide and to carry out list-decarboxylation.Then for example carry out esterification with the acid treatment of methyl alcohol and catalytic amount.Use suitable amine, heat in as (but being not limited to) toluene, can finish the replacement of ω-halogen at solvent.At last, the aqueous hydrolysis ester functional group with alkali obtains the above-mentioned activatory intermediate that is used for preparation I compound.
Compound of the present invention can be prepared according to some standard synthetic methods that the organic chemistry filed technician uses always usually.In general, can prepare acid amides by the nucleophilic addition(Adn) or the affine substitution reaction of base catalysis between suitable carboxylic acid and the suitable amine of selecting, wherein the carboxylic acid halides of Shi Yi amine and selection, acid anhydrides or ester reaction obtain required acid amides.With acid and amine coupling the time, can be under hydroxybenzotriazole (HOBt) existence or non-existent condition, the chemical coupling agent of use standard, as carbonyl dimidazoles (CDI), 1,3-dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3 '-dimethylaminopropyl) carbodiimide hydrochloride (EDCI).In replacement scheme, carboxylic acid and for example thionyl chloride or oxalyl chloride reaction are converted into corresponding carboxylic acid halides.Subsequently carboxylic acid halides is joined in the suitable amine of selecting, adopt reaction method well known in the art such as Xiao Deng-Bao Manfa (Schotten-Baumann) to obtain acid amides.
Described carboxylic acid and amine can perhaps can use method preparation well-known in the art easily from commercial purchase.Chemical compound lot is commercially available, for example buys from aldrich company (AldrichChemicals), and perhaps when compound can't be purchased, they can adopt direct conversion reaction well-known in the art easily to prepare from the precursor that can buy.For example, carboxylic acid can prepare by the carbonating of nitrile hydrolysis, organometallic compound or the oxidation of primary alconol or aldehyde.Particularly from corresponding alkyl acetonitrile by using as hexamethyldisilazane sodium and methyl iodide or dibromobutane is converted into dialkyl group or the spirane radical derivative prepares the branched-chain alkyl nitrile, hydrolysis obtains required carboxylic acid under acidity or alkaline condition subsequently.The bronsted lowry acids and bases bronsted lowry that suits in hydrolysis reaction is H2SO4 and KOH for example.Can use microwave heating to carry out this hydrolysis reaction easily.
Formula I compound, its optically active isomer or diastereomer can carry out purifying or separation according to well-known method, include but not limited to use the chromatography and the Steppecd crystallization of chirality matrix.
In the in vitro tests that the cell that utilizes the stable transfection alpha 7 nicotinic acetylcholine receptors carries out, proved the pharmacological activity of representational formula I compound group, it optionally contrasts as check with the cell of express alpha 1 and α 3 nAChRs and 5HT3 acceptor in described test.Therefore, according on the other hand, the present invention relates to treat the method for nervous system disease and mental disorder, this method comprises to its individuality, the formula I compound that preferred human individual uses significant quantity of needs.The nervous system disease and the mental disorder that can benefit from the treatment that The compounds of this invention carries out include but not limited to senile dementia, attention deficit disorder, alzheimer's disease and schizophrenia.Generally speaking, formula I compound can be used for the treatment of any disease, illness or dysfunction that can benefit from the alpha 7 nicotinic acetylcholine receptors activation, include but not limited to Parkinson's disease, Huntington Chorea, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, memory or deficiency of learning ability, panic disorder, cognitive disorder, dysthymia disorders, Sepsis and sacroiliitis.
The compound dosage that is used for the treatment of can change according to the character and the severity of for example route of administration, disease.Generally speaking, adopt the per daily dose of 0.01-200mg/kg can in the people, obtain acceptable pharmacotoxicological effect.
On the other hand, the invention still further relates to the pharmaceutical composition that comprises one or more formulas I compound and pharmaceutically acceptable carrier and vehicle.Described pharmaceutical composition can be the form of solid, semisolid or liquid preparation, is preferably the form of solution, suspensoid, pulvis, granule, tablet, capsule, syrup, suppository, aerosol or controlled delivery system.Said composition can be used by all means, comprise oral, in skin, subcutaneous, intravenously, intramuscular, rectum and nose, and preferably be formulated into unit dosage form, each dosage contain have an appointment 1 to about 1000mg, preferred 1 to 600mg activeconstituents.Compound of the present invention can be the form of free alkali or acid salt, preferably with the formed salt of pharmaceutically acceptable acid.The present invention also comprises isolating isomer and diastereomer or its mixture (for example racemic mixture) of Compound I.The principle of pharmaceutical compositions and method are described in for example Remington ＇ s Pharmaceutical Science, and Mack Publishing Company is among the Easton (PA).
Synthesizing of experimental technique-compound
General remark
Except as otherwise noted, otherwise all nuclear magnetic resonance spectrums all use the Varian Mercury Plus 400MHz spectrometer that is equipped with PFG ATB wideband probe to carry out record.
HPLC-MS analyzes and uses Waters 2795 separation modules that are equipped with Waters Micromass ZQ (ES ionization) and Waters PDA 2996 to carry out, and uses Waters XTerraMS C18 3.5 μ m2.1 * 50mm post.
Preparation type HLPC is with having Gradient Module Waters 2525 pumps of binary and carry out with Waters Micromass ZQ (ES) or Waters 2487 DAD link coupled Waters 2767 systems, using Supelco Discovery HS C18 5.0 μ m10 * 21.2mm post.
Gradient elution carries out with 0.1% formic acid/water and 0.1% formic acid/acetonitrile, shown in use 5/95 to 95/5 gradient in working time.
All column chromatographies are all according to Still, C; The method of J.Org Chem 43,2923 (1978) is carried out.All TLC analyze and carry out on silica gel (Merck 60 F254), and by the dyeing of UV video picture and KMnO4 or triketohydrindene hydrate under 254nm spot are displayed.
When being elaborated to Array Method is synthetic, heating is at Buchi
Carry out in the system.
All microwave reactions all carry out in CEM Discover stove.
Used abbreviation in the experimental technique
CDI N, N '-carbonyl dimidazoles
The DCM methylene dichloride
DCE 1, the 2-ethylene dichloride
DMEA N, the N-dimethyl amine
DMF N, dinethylformamide
DMSO, the dmso dimethyl sulfoxide (DMSO)
The DAM N,N-dimethylacetamide
The SCX strong cat ion exchange column
The TEA triethylamine
The TFA trifluoroacetic acid
The THF tetrahydrofuran (THF)
The TLC thin-layer chromatography
LC-MS, LCMS liquid chromatograph mass spectrography technology
The HPLC high performance liquid chromatography
Aminoalkyl group amine synthetic universal method-phthalic imidine route
N-(3-bromopropyl) phthalic imidine (1 equivalent) is added amine (1 equivalent), sodium iodide (0.5 equivalent) and salt of wormwood (1.1 equivalent) in the suspension of 2-butanone (about 20 volumes with respect to the weight of phthalic imidine).The gained suspension was stirred 18 hours down at 85 ℃, follow the filtering reaction thing, vacuum distilling removes and desolvates; The oily matter of gained washes with water, reclaims with DCM.Solvent removed by evaporation at reduced pressure obtains amino-phthalic imidine product, and its purity enough is used for next step without being further purified.
The phthalic imidine (1 equivalent) of gained is dissolved in EtOH (with respect to the about 7-10 volume of the weight of phthalic imidine), drips hydrazine monohydrate (2 equivalent).With mixture 80 ℃ of heating 4 hours, subsequently with 37%HCl with the reactant acidifying, by filtering precipitated solid is removed.Vacuum concentrated solution is dissolved in 1N HCl.By removing by filter 2 of all remnants, 3-dihydro-phthalazines-1,4-diketone.With aqueous solution vacuum-evaporation to reclaim pure products.
In the situation of the derivative of acid-sensitive sense, reaction mixture is filtered, with the EtOH washing, vacuum concentration and be dissolved in toluene and DCM in, remaining 2 to remove, 3-dihydro-phthalazines-1,4-diketone.Solvent removed by evaporation at reduced pressure obtains pure products.
1-[4-(3-amino-propyl group)-piperazine-1-yl]-ethyl ketone
With 2-[3-(4-ethanoyl-piperazine-1-yl)-propyl group]-isoindole-1, the 3-diketone (5.0g 16mmol) is dissolved in EtOH (50mL), and adding hydrazine monohydrate (1.5mL, 32mmol).Mixture was heated 1 hour at 80 ℃.
1-(4-bromo-phenyl)-3-(3-piperidines-1-base-propyl group)-urea
A) 2-(3-piperidines-1-base-propyl group)-isoindole-1, the 3-diketone
With N-(3-bromopropyl) phthalic imidine (5.36g, 20mmol) add piperidines (1.98mL, 20mmol), sodium iodide (3.9g, 26mmol) and salt of wormwood (4.15g is 21mmol) in the suspension of 2-butanone (100mL).The gained suspension stirred 24 hours at 90 ℃.
The filtering reaction thing is to remove inorganic salt, and vacuum distilling removes and desolvates; Gained oily matter is washed with water, reclaim with DCM.Solvent removed by evaporation at reduced pressure obtains the required product (productive rate: 81%) of 4.39g white solid.
C16H20N2O2 mass spectrum (calculated value) [272.35]; Measured value [M+H
+]=273
1H-NMR(400MHz，CDCl3)1.25-1.47(6H，m)，1.76-1.92(2H，m)，2.14-2.42(6H，m)，3.63-3.68(2H，m)，7.63-7.73(2H，m)，7.76-7.86(2H，m).
B) 3-piperidines-1-base-propyl group amine salt acidulants
With 2-(3-piperidines-1-base-propyl group)-isoindole-1, the 3-diketone (7.5g 18.34mmol) is dissolved in EtOH (45mL), and adding hydrazine monohydrate (1.78mL, 34.5mmol).Mixture was heated 1 hour at 80 ℃.Then cool off reactant, with the 37%HCl acidifying of 5mL, by removing by filter 2,3-dihydro-phthalazines-1,4-diketone.Vacuum concentrated solution, the 1N HCl of adding 10mL, filtering mixt is to remove 2 of remnants, 3-dihydro-phthalazines-1,4-diketone once more.The vacuum-evaporation aqueous solution is recovered to 3.0g (productive rate 48%) pure products.
C8H18N2 mass spectrum (calculated value) [142.25]; (measured value) [M+H
+]=143
NMR(400MHz，dmso-d6)：1.25-1.45(2H，m)，1.57-1.92(4H，m)，1.93-2.17(2H，m)，4.05-5.37(4H，m).
Urea synthetic universal method
The aryl or the heteroaryl isocyanic ester that in the solution of refrigerative amine (1 equivalent), add equimolar amount at methylene dichloride.At amine is in the situation of hydrochloride or two-hydrochloride, adds the TEA of equimolar amount, so that amine becomes free alkali.
Mixture was stirred 1-4 hour at 0 ℃.Usually right-bromophenyl the urea of white solid is separated out from solution, with its filtered and recycled, if necessary, passes through Et
2O washs or carries out further purifying by flash chromatography.Solvent removed by evaporation at reduced pressure compartment-bromophenyl urea, and pass through from AcOEt/Et
2Crystallization comes purifying in the mixture of O.
Perhaps, at N
2Under the air-flow, in the solution of DCM (0.32mmol/mL), add triphosgene (1 equivalent) to the aniline that is cooled to 0 ℃; Form white precipitate, add NEt
3(1.1 equivalent), this mixture becomes yellow solution usually.After 30 minutes, add amine, reactant was stirred 2 hours at 0 ℃, the common demonstration of LC-MS this moment transforms fully.If there is precipitation, it is filtered to obtain the urea product, in addition solution is used 10%NaOH solution washing, concentrating under reduced pressure organic phase.Then crude product is passed through from Et
2Crystallization comes purifying among the O.
1-(4-bromo-phenyl)-3-(3-piperidines-1-base-propyl group)-urea
To refrigerative 3-piperidines-1-base-propyl group amine dihydrochloride (0.96g, 4mmol) in the solution of methylene dichloride (20mL), add TEA (1.11mL, 8mmol).
Add subsequently right-bromophenyl isocyanic ester (0.78g, 4mmol), and with mixture 0 ℃ of stirring, after 2 hours, separate out white precipitate in the solution.Leach this white solid, use Et
2The O washing obtains the pure title compound of 1.4g.
C15H22BrN3O mass spectrum (calculated value) [340.27]; (measured value) [M+H
+]=340-342
Lc Rt (10 fens clock methods)=2.69,92%
NMR (400MHz, dmso-d6): 1.26-1.63 (8H, m); 2.14-2.36 (4H, m); (2.45-2.51 2H, m is under DMSO); 3.00-3.13 (2H, m); 6.11-6.26 (1H, m), 7.33 (4H, s), 8.52-8.66 (1H, s).
1-(2-chloro-4-bromo-phenyl)-3-(4-piperidines-1-base-butyl)-urea
By urea synthetic universal method preparation (passing through isocyanic ester).
Productive rate: 76%
NMR(400MHz，dmso-d6)：1.27-1.52(10H，m)，2.14-2.37(6H，m)，3.03-3.4(2H，m)，7.04(1H，t)，7.40(1H，dd)，7.60(1H，d)，8.50(1H，s)，8.12(1H，d).
1-(2-fluoro-4-bromo-phenyl)-3-(4-piperidines-1-base-butyl)-urea
By urea synthetic universal method preparation (passing through isocyanic ester).
Productive rate: 88%
NMR(400MHz，dmso-d6)：1.22-1.50(10H，m)，2.12-2.37(6H，m)，3.00-3.13(2H，m)，6.62(1H，t)，7.25(1H，d)，7.47(1H，dd)，8.10(1H，t)，8.33(1H，s).
1-(2,6-two fluoro-4-bromo-phenyl)-3-(4-piperidines-1-base-butyl)-urea
By urea synthetic universal method preparation (passing through isocyanic ester).
Productive rate: 67%
C16H22BrF2N3O mass spectrum (calculated value) 390; (measured value) [M+H
+]=390-392
Lc?Rt＝2.04(100％)，10’
NMR(400MHz，dmso-d6)：1.31-1.51(10H，m)，2.17-2.37(6H，m)，2.98-3.09(2H，m)，6.36(1H，t)，7.44(1H，d)，7.82(1H，s).
1-(2-fluoro-4-bromo-phenyl)-3-(3-piperidines-1-base-propyl group)-urea
By urea synthetic universal method preparation (passing through isocyanic ester).
Productive rate: 86%
C15H21BrFN3O mass spectrum (calculated value) 358; (measured value) [M+H
+]=358-360
Lc?Rt＝2.18(100％)，10’
NMR(400MHz，dmso-d6)：1.31-1.40(2H，m)，1.41-1.49(4H，m)，1.50-1.57(2H，m)，2.17-2.35(6H，m)，3.07(2H，q，J＝5.8Hz)，6.59(1H，t)，7.25(1H，dt)，7.46(1H，dd)，8.08(1H，t)，8.34(1H，s).
1-(2-chloro-4-bromo-phenyl)-3-(3-piperidines-1-base-propyl group)-urea
By urea synthetic universal method preparation (passing through isocyanic ester).
Productive rate: 78%
C15H21BrClN3O mass spectrum (calculated value) 374; (measured value) [M+H
+]=374-376
Lc?Rt＝2.46(98％)，10’
NMR(400MHz，dmso-d6)：1.30-1.39(2H，m)，1.42-1.49(4H，m)，1.50-1.60(2H，m)，2.16-2.37(6H，m)，3.08(2H，q，J＝4.7)，7.01(1H，t)，7.40(1H，dd)，7.62(1H，d)，8.48(1H，s)，8.11(1H，d).
Universal method from ω-haloalkane acyl chlorides synthesizing amide
The one kettle way of the amine R1R2NH of low molar excess
In round bottom two neck flasks, triethylamine (1 equivalent) is added aryl or heteroaryl amine (1 equivalent) in the solution of 1 volume DCE, so that obtain the amine aqueous solution of 1.2M; Then the DCE solution form of 5-bromine valeryl chloride (0.95 equivalent) with 1.2M dropwise added, and will react and at room temperature stir 1 hour 30 minutes.Then amine R1R2NH (3 equivalent) and the solution of triethylamine (1 equivalent) in DCE with 1.8M adds, and reaction mixture was stirred 4-16 hour at 55 ℃, detects demonstration up to LCMS and reacts completely.Reaction mixture is distributed among water and the DCM subsequently; With saturated NaCl washing organic phase, use Na
2SO
4Dry.Solvent evaporated under reduced pressure, the gained acid amides passes through Et
2O grinds or passes through purification by flash chromatography.
The one kettle way of the amine R1R2NH of high molar excess
Perhaps, the solution (0.2mmol/mL) in methylene dichloride is cooled to 0 ℃ under nitrogen atmosphere with aniline (1 equivalent) and triethylamine (1 equivalent).Slowly add the solution (0.3mmol/mL) of 5-bromo-valeryl chloride (1 equivalent) in methylene dichloride.Mixture stirring at room 1.5 hours, is added amine R1R2NH (5 equivalent) and triethylamine (1 equivalent) afterwards immediately, and restir reaction at room temperature 40 hours.With salt water washing organic solution, dry also removing desolvated.Product is with 1/1 grinding of hexane/ether or pass through purification by flash chromatography.
One kettle way-Array Method of the amine R1R2NH of high molar excess
Slowly add 5-bromo-valeryl chloride (the amine R1R2NH with respect to used every molar equivalent is 1 equivalent) to aniline (the amine R1R2NH with respect to used every molar equivalent is 1 equivalent) and triethylamine (the amine R1R2NH with respect to used every molar equivalent is 1 equivalent) in the solution in methylene dichloride (is 0.3mmol/mL with respect to every kind of used amine R1R2NH), and mixture was at room temperature stirred 2 hours.The aliquot that then this solution is divided into a plurality of five equilibriums is used for the reaction array of various kinds of amine, adds the sample that a bottle contains certain amine R1R2NH (5 equivalent) and triethylamine (1 equivalent) in each part.Then these reactions were at room temperature vibrated 40 hours.With salt water washing organic solution, collect dry (Na
2SO
4) and evaporating solvent.By the preparation HPLC purified product.
Use the two-step approach of the amine R1R2NH of equimolar amount
5-bromine valeric acid-(4-bromophenyl)-acid amides
With 4-bromo-aniline (6g, 0.035mol) and the NEt of 0.035mol
3(4.87mL) be dissolved in the 120mL methylene dichloride and be cooled to 0 ℃.
The 5-bromine valeryl chloride (5.4mL) that in this solution, slowly adds 0.038mol, and the gained mixture stirred 1 hour at 0 ℃.
After all raw material consumption (by the LCMS monitoring), with solution 50mL 0.4M Na
2CO
3Washing is reclaimed organic layer by extraction, and is used Na
2SO
4Dry.Solvent removed by evaporation at reduced pressure obtains the title compound (productive rate 86%) of 10g white solid.
C11H13Br2NO mass spectrum (calculated value) [335]; (measured value) [M+H
+]=335
Lc Rt=2.64,100% (5 fens clock methods)
NMR(400MHz，CDCl3)1.70-2.00(4H，m)，2.35-2.45(2H，m)，3.38-3.48(2H，m)，7.30-7.50(4H，m).
1 normal alkylating reagent by last preparation is dissolved in butanone (5-10mL/mmol substrate), and to wherein adding 1 equivalent NaI and 1.1 normal amine R1R2NH.Mixture was stirred 24 hours at 70 ℃.Cooling mixture.When product with the salt form post precipitation, it is water-soluble, transfer to pH=10 by adding 10%NaOH, make it to be converted into free alkali, and use dichloromethane extraction.When there not being product to be settled out now, solvent removed by evaporation at reduced pressure is dissolved in methylene dichloride with crude product, extracts after transferring to pH=10 with 10%NaOH.If necessary, product is further passed through purification by flash chromatography.
5-azepan-1-base-valeric acid (4-bromo-3-fluoro-phenyl)-acid amides
According to acid amides synthetic universal method, with 3-fluoro-4-bromaniline (66mg, 0.35mmol) and triethylamine (35mg 0.35mmol) is dissolved in DCE (0.5mL), and is added dropwise to 5-bromine valeryl chloride (66mg, DCE 0.33mmol) (0.5mL) solution.After 1.5 hours, with azepan (118mg, 0.105mmol) and triethylamine (35mg, 0.35mmol) solution in DCE (0.5mL) adds, and with reaction mixture 55 ℃ of heating 4 hours.After aftertreatment,, obtain the title compound (87mg, 77%) of formate form by preparation HPLC.
C17H24BrFN2O mass spectrum (calculated value) [371.30]; Measured value [M+H
+]=371.33/373.35.
LC Rt=2.23,100% (10 fens clock methods)
NMR(400MHz，CDCl
3)：1.7(4H，s)；1.88-1.84(8H，m)；2.44(2H，mt)；2.98(2H，m)；3.15(4H，bs)；7.27(1H，m)；7.4(1H，dd，J＝8.8，7.6)；7.80(1H，dd，J＝10.8，2.4)；8.63(1H，HCOOH，s)；9.8(1H，bs).
5-azepan-1-base-valeric acid (4-bromo-3-trifluoromethyl-phenyl)-acid amides
According to universal method, with 4-bromo-3-trifluoromethyl-aniline (82mg, 0.35mmol) and triethylamine (35mg 0.35mmol) is dissolved in DCE (0.5mL), and is added dropwise to 5-bromine valeryl chloride (66mg, 0.33mmol) solution in DCE (0.5mL).After 1 hour 30 minutes, with azepan (118mg, 0.105mmol) and triethylamine (35mg, 0.35mmol) solution in DCE (0.5mL) adds, with reaction mixture 55 ℃ of heating 4 hours.After aftertreatment,, obtain the title compound (29mg, 20%) of its formate form by preparation HPLC.
C18H24BrF3N2O mass spectrum (calculated value) [421.30]; (measured value) [M+H
+]=421.29/423.29.
LC Rt=2.52,98% (10 fens clock methods)
5-[methyl-(2-pyridine-2-base-ethyl)-amino]-valeric acid (3-bromo-phenyl)-acid amides
Be prepared according to acid amides synthetic universal method,, obtain the title compound of 106mg (47%) formate form by the preparation HPLC purifying.
C
19H
24N
3OBr.HCO
2H mass spectrum (calculated value) [390.33-46.03]; Measured value [M+H
+]=390.23,
Lc?Rt＝1.73，100％
NMR(400MHz，CD
3OD)：1.73-1.89(4H，m)；2.46-2.50(2H，m)；2.91(3H，s)；3.19-3.27(4H，m)；3.49-3.55(2H，m)；7.19-7.24(2H，m)，7.31(1H，br?dd，J＝5.2Hz，6.8Hz)；7.38(1H，ddd，J＝6.8Hz，1.6Hz，2.0Hz)；7.80(1H，ddd，J＝8.0Hz，7.6Hz，1.6Hz)；7.91(1H，s)；8.46(1H，s)；8.51(1H，brd，J＝4.8Hz).
5-(methyl-amyl group-amino)-valeric acid (4-bromo-phenyl)-acid amides
Be prepared according to acid amides synthetic universal method,, obtain the title compound of 123mg (60%) formate form by the preparation HPLC purifying.
C
17H
27N
2Obr HCO
2H mass spectrum (calculated value) [355.32-46.03]; Measured value [M+H
+]=355.27,
Lc?Rt＝1.98，100％
NMR(400MHz，CD
3OD)：0.95(3H，t，J＝6.8Hz)；1.32-1.44(4H，m)；1.67-1.81(6H，m)；2.43-2.49(2H，m)；2.81(3H，s)；3.04-3.13(4H，m)；7.42-7.45(2H，m)，7.49-7.52(2H，m)，8.51(1H，s).
Make
Universal method with the cross-coupling reaction of boric acid
The heating condition of urea (A=N)
In the de-gassed solution of aryl for preparing according to above-mentioned urea synthetic universal method or heteroaryl bromide (1 equivalent), add the acetonitrile/0.4N Na that is dissolved in 40 volumes (being the 1mL/g substrate)
2CO
3(1/1) suitable boric acid (1.3 equivalent), the Pd[(PPh in the aqueous solution
3)]
4(10%mol).With solution at round-bottomed flask or at Buchi
The device glass test tube in, spend the night in refluxed under nitrogen.
The separating acetonitrile phase, and with SCX or the required product of silicagel column purifying.The flow point that will comprise required product merges drying under reduced pressure.
The microwave condition of urea (A=N)
In the de-gassed solution (1 equivalent) of the bromide for preparing according to urea synthetic universal method, add suitable boric acid (1 equivalent) and the Na in the acetonitrile/water (1/1) that is dissolved in 20 volumes (being the 1mL/g substrate)
2CO
3(3 equivalent), Pd[(PPh
3)]
4(10%mol).
Use following parameter: power 200W; Heating-up time 1min; Hold-time 20min; 90 ℃ of temperature; Pressure 200psi shines described solution with microwave oven.The separating acetonitrile phase, solvent removed by evaporation at reduced pressure, and with SCX column purification crude product (with DCM/MeOH, MeOH, NH
3/ MeOH gradient elution).The flow point that will comprise product merges drying under reduced pressure.
Acid amides (A=CH
2
) microwave condition
The Pd[(PPh that in 5-alkyl-valeric acid aryl-acid amides (0.1g, 1 equivalent), the degassing mixture of aryl boric acid (1.1 equivalent) in acetonitrile/0.4M sodium carbonate solution 1/1 (4mL), adds catalytic amount
3)]
4(5mmol%).Reaction mixture at 20 minutes (150W, peak pressure) of 90 ℃ of microwave irradiation heating, is then repeated 20 minutes again.Separate organic layer and concentrated, be further purified by the SCX post and/or by preparation HPLC.Solvent removed by evaporation at reduced pressure obtains corresponding product.
Use the universal method of the cross-coupling reaction of aryl/hetaryl bromide
[4-(4 to omega-amino-alkanoic acids, 4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-phenyl]-acid amides (0.16g, 0.4mmol, 1 equivalent) (according to above-mentioned universal method preparation) and aryl/hetaryl bromide (0.4mmol, 1 equivalent) add the Pd[(PPh of catalytic amount in the degassing mixture of acetonitrile/0.4M sodium carbonate solution 1/1 (8mL)
3)]
4(5mmol%).Reaction mixture was stirred 18 hours under nitrogen at 90 ℃, and monitor the formation of product by LCMS.Separate organic layer, warp
Layer filters, solvent removed by evaporation at reduced pressure.Crude product is by preparation HPLC or purification by flash chromatography.
By reduction amination and the synthetic 1-(4-aryl-phenyl) of cross-coupling reaction-3-(4-aminoalkyl group-Ding
Base)-universal method of urea
A) 1-(4-bromo-phenyl)-3-(4,4-diethoxy-butyl)-urea
At N
2Down, with 4-amino butyraldehyde diethyl acetal (0.88mL, 5mmol) solution in anhydrous DCM (10mL) go through 30 ' add be cooled to 0 ℃ (ice/water-bath) 4-bromophenyl isocyanic ester (1g, 5mmol, 1 equivalent) in the solution of anhydrous DCM (25mL); Form thick white urea precipitation after 1 hour.The filtered and recycled solid is used Et
2(3 * 20mL) washings obtain 1-(4-bromo-phenyl)-3-(4,4-diethoxy-butyl)-urea (1.78g) with quantitative productive rate basically to O.
C15H23BrN2O3 mass spectrum (calculated value) [359.27]; (measured value) [M+Na+]=381.11/383.25
LC Rt=3.54,100% (10 fens clock methods)
NMR(400MHz，dmso-d6)：1.08(6H，t，J＝5.85Hz)；1.42(2H，m)；1.50(2H，m)；3.06(2H，m)；3.41(2H，q)；3.54(2H，q)；4.45(1H，t)；6.19(1H，t)；7.37(4H，s)；8.54(1H，s).
B) 1-(4-bromo-phenyl)-3-(4-aminoalkyl group-butyl)-urea
1-(4-bromo-phenyl)-3-(4,4-diethoxy-butyl)-urea (0.72g, 2mmol, 1 equivalent) at room temperature is dissolved among the anhydrous DCM (10mL), adds montmorillonite K-5 (0.145g).At room temperature stirring reaction is 2 hours, shows up to LC-MS to be converted into aldehyde fully.
Filter reaction mixture adds amine (6mmol, 3 equivalents) and NaBH (OAc) successively to remove all solids
3(4mmol, 2 equivalents).At room temperature stirring reaction is 24 hours.
In case (by the LC-MS monitoring) finished in reaction, solvent removed by evaporation at reduced pressure is passed through the SCX column purification with the gained resistates, successively with DCM:MeOH 1:1 and 2M NH
3The MeOH eluant solution.
C) 1-(4-aryl-phenyl)-3-(4-aminoalkyl group-butyl)-urea
In the mixture that 1-(4-bromo-phenyl)-3-(4-aminoalkyl group-butyl)-urea (0.11g, 1 equivalent) and the phenylo boric acid that replaces or boric acid pinacol ester (1.5 equivalent) outgas in acetonitrile/0.4M sodium carbonate solution 1/1 (3mL), the Pd[(PPh of adding catalytic amount
3)]
4(5mmol%).With reaction mixture under microwave irradiation (150W) in 90 ℃ the heating 10 minutes, if necessary, then shone again 10 minutes.Separate organic layer, by the SCX post or by preparation HPLC (standard acidic condition) purifying.
1-methyl-4-piperidines-1-base-butylamine
A) N-Boc-5-N-methyl-2-2-pyrrolidone N-
At room temperature with dimethyl dicarbonate butyl ester (12.1g; 55.5mmol) drips of solution in acetonitrile (20mL) adds 5-N-methyl-2-2-pyrrolidone N-(5.0g; 50mmol) with 4-dimethylamino-pyridine (0.31g; 5mol%) in the solution of acetonitrile (50mL).Mixture was stirred 7 hours, and evaporating solvent is dissolved in the gained crude product ethyl acetate and uses saturated NaHCO
3Solution washing.Collected organic layer and dry (Na
2SO
4), evaporating solvent obtains purified product.
9.41g；90％
C
10H
17NO
3Calculated value 199; Measured value 126/144
Lc Rt (5 minutes)=1.73,99%
NMR(400MHz，dmso-d6)：1.22(3H，d，J＝6.4Hz)；1.43(9H，s)；1.50-1.57(1H，m)；2.04-2.14(1H，m)；2.26(1H，ddd，J＝3.2Hz，9.2Hz，17.2Hz)；2.56(1H，ddd，J＝9.2Hz，10.42Hz，17.2Hz)；4.07-4.15(1H，m).
B) (1-methyl-4-oxo-4-piperidines-1-base-butyl)-t-butyl carbamate
With N-Boc-5-N-methyl-2-2-pyrrolidone N-(0.7g; 3.52mmol) and piperidines (1.55g; 18.2mmol, 1.8mL) mix, 150 ℃ of microwave irradiation heating 40 minutes.Mixture dilutes with methylene dichloride, with twice of 1.0M HCl solution washing of solution.Dry organic layer (Na
2SO
4) and evaporating solvent.Crude product is by flash chromatography (hexanaphthene: ethyl acetate) purifying.
0.522g；73％
C
15H
28N
2O
3Calculated value 284; Measured value 285
Lc Rt (3 minutes)=1.31,99%
NMR(400MHz，dmso-d6)：0.99(3H，d，J＝6.8Hz)；1.35(9H，s)；1.36-1.40(2H，m)；1.43-1.48(2H，m)；1.50-1.58(4H，m)；2.15-2.30(2H，m)；3.30-3.46(5H，m)；6.63(1H，d，J＝8.8Hz).
C) 4-amino-1-piperidines-1-base-penta-1-ketone
At 0 ℃ with (1-methyl-4-oxo-4-piperidines-1-base-butyl)-t-butyl carbamate (3.50g; 12.3mmol) be dissolved in CH
2Cl
2(40mL), slowly add 37%HCl solution (6mL).After 15 minutes, remove ice bath, with mixture stirring at room 4 hours.Slowly add 2N NaOH solution, make pH 8, collected organic layer, dry and evaporating solvent.
2.0g；88％
C
10H
20N
2O calculated value 184; Measured value 185
Lc Rt (5 minutes)=0.35,100%
NMR(400MHz，dmso-d6)：0.95(3H，d，J＝6.4Hz)；1.32-1.57(8H，m)；2.20-2.36(2H，m)；2.68-2.76(1H，m)；3.21(4H，br?m).
D) 1-methyl-4-piperidines-1-base-butylamine
(2.0g 10.9mmol) is dissolved in THF (50mL), slowly adds the 1.0M lithium aluminum hydride at THF (22mL, 22mmol) solution in 4-amino-1-piperidines-1-base-penta-1-ketone under 0 ℃.Mixture was stirred 30 minutes at 0 ℃, at room temperature stirred subsequently 4 hours.In solution, add entry (0.8mL) and evaporating solvent.Resistates ether and 15%NaOH solution-treated.Collected organic layer is also dry.Evaporating solvent obtains product, and its purity is enough used without being further purified.
1.21g；65％
C
10H
22N
2Calculated value 170; Measured value 171
Lc Rt (5 minutes)=0.35,100%
NMR(400MHz，dmso-d6)：0.89(3H，d，J＝6.4Hz)；1.10-1.17(2H，m)；1.30-1.37(4H，m)；1.39-1.45(6H，m)；2.10-2.14(2H，m)；2.23(4H，br?m)；2.65-2.69(1H，m).
2,2-two fluoro-4-piperidines-1-base-butylamines
A) 3,3-two fluoro-succinamic acids
To 2,2-two fluoro-succsinic acids (2.0g, 13mmol) in the solution of the iPrOAc of 20mL disposable adding trifluoroacetic anhydride (2.2mL, 15.6mmol).
With solution at N
2Stirred 1 hour in 50 ℃ under the atmosphere.After the small amount of methanol quencher, confirm 2 by LCMS, the formation [C of 2-two fluoro-succinyl oxides
5H
6F
2O
4Calculated value 168; Measured value M-167; Lc Rt (5 minutes)=1.05].
Then, under nitrogen atmosphere, be added dropwise to NH with the solution cool to room temperature
3Methanol solution (7N, 15mL, 105mmol) in, simultaneously holding temperature is lower than 20 ℃.
Evaporating solvent subsequently is dissolved in resistates and uses Na
2CO
3In the less water (pH8-9) of alkalization.Water washs with EtOAc, is acidified to pH1 with 6N HCl, and uses Et
2O and CHCl
3Extraction product for several times.
Collected organic layer is also dry.Evaporating solvent obtains the 0.877g crude product, and it uses without being further purified.
Productive rate: 45%
C
4H
5F
2NO
3Calculated value 153; Measured value M-152
Lc Rt (5 minutes)=0.32
NMR(400MHz，dmso-d6)：3.16(2H，t，J＝15.4)；7.86(1H，s)；8.09(1H，s)；12.90(1H，s).
B) 2,2-two fluoro-4-oxos-4-piperidines-1-base-butyramide
With 3,3-two fluoro-succinamic acids (0.18g 1.2mmol) is dissolved in the 10mL acetonitrile, and with mixture at 0 ℃ in N
2Cool off under the atmosphere.Add N, and the N-dicyclohexylcarbodiimide (0.266g, 1.3mmol), in 0 ℃ of following restir mixture 10 minutes.Then add I-hydroxybenzotriazole hydrate (0.308g, about 2mmol), and remove ice bath.
After 20 minutes, (0.115mL, 1.2mmol), and at room temperature stirring reaction spends the night at room temperature to add piperidines.
Evaporating solvent is dissolved in methylene dichloride with resistates.Organic phase is successively used 0.16N HCl and water washing.
Then evaporate organic solvent, resistates is passed through SiO
2Post (elutriant: purifying EtOAc:DCM 9:1).
Obtain the 0.113g pure products.
Productive rate: 43%
C
9H
14F
2N
2O
2Calculated value 220; Measured value M+221
Lc Rt (5 minutes)=1.16
NMR(400MHz，dmso-d6)：1.35-1.57(6H，m)；3.25-3.36(6H，m)；7.71(1H，s)；7.92(1H，s).
C) 2,2-two fluoro-4-piperidines-1-base-butylamine
0 ℃, under nitrogen atmosphere to 2, (0.323g 1.5mmol) slowly adds THF (5.88mL, 5.9mmol) solution of 1.0M lithium aluminum hydride to 2-two fluoro-4-oxos-4-piperidines-1-base-butyramide in the solution of the anhydrous THF of 10mL.With mixture stirring at room 3 days.Then the excessive hydride of water quencher removes and desolvates.Dilute resistates with methyl alcohol subsequently, by
Filter.Solution SCX column purification, gained oily matter uses without being further purified.
Obtain the 0.169g product.
Productive rate: 59%
C
9H
18F
2N
2Calculated value 192; Measured value M+193
Lc Rt (5 minutes)=0.19
19F-HNMR (400MHz, dmso-d6) :-106.16 (quintets)
2,2-dimethyl-4-piperidine-1-base-butylamine
A) 2,2-dimethyl-4-oxo-4-piperidines-1-base-butyric acid
At room temperature to 2, the 2-dimethyl succinic anhydride (1.0g, 7.8mmol) and triethylamine (0.79g is 078mmol) at CH
2Cl
2(0.66g is 7.8mmol) at CH slowly to add piperidines in the solution (40mL)
2Cl
2Solution (10mL).Stirred the mixture 4 hours.Add 1.0M NaOH solution, collect water and be acidified to pH4 with 2.0M HCl solution subsequently.Use CHCl
3Extraction and evaporating solvent obtain crude product, and its purity is enough used without being further purified.
1.63g；98％
C
11H
19NO
3Calculated value 213; Measured value M+214/M-212
Lc Rt (5 minutes)=1.56
NMR(400MHz，dmso-d6)：1.10(6H，s)；1.32-1.37(2H，m)；1.40-1.44(2H，m)；1.50-1.55(2H，m)；2.50(2H，s)；3.31-3.35(4H，m)；11.7(1H，br?s).
B) 2,2-dimethyl-4-oxo-4-piperidines-1-base-butyramide
Room temperature under nitrogen atmosphere to 2, (2.0g is 9.4mmol) at CH for 2-dimethyl-4-oxo-4-piperidines-1-base-butyric acid
2Cl
2Slow adding oxalyl chloride in the solution (40mL) (2.98g, 23.5mmol).Mixture was stirred 3 hours.Behind evaporating solvent and the excessive oxalyl chloride, the gained crude product is dissolved in CH
2Cl
2(20mL), and join in the solution of ammonia Zai diox (200mL) of 0.5M.Adding saturated NaHCO
3Behind the solution, extraction organic layer twice is collected and drying.Evaporating solvent obtains crude product, and it is by purification by flash chromatography (CH
2Cl
2/ CH
3OH=96/4).
0.93g；46％
C
11H
20N
2O
2Calculated value 212; Measured value M+213
Lc Rt (5 minutes)=1.32
NMR(400MHz，CD
3OD)：1.27(6H，s)；1.48-1.54(2H，m)；1.56-1.61(2H，m)；1.63-1.69(2H，m)；2.64(2H，s)；3.45-3.49(4H，m).
C) 2,2-dimethyl-4-piperidine-1-base-butylamine
0 ℃, under nitrogen atmosphere to 2, (2.0g 9.43mmol) slowly adds the THF solution (28.3mL) of 1.0M lithium aluminum hydride to 2-dimethyl-4-oxo-4-piperidines-1-base-butyramide in the solution of THF.Mixture was stirred 6 hours.In solution, add entry (1.0mL), evaporating solvent.Resistates ether and 1.0M NaOH solution-treated, collected organic layer is also dry.Evaporating solvent obtains the 1.4g crude product, and it uses without being further purified.
1.40g；80％
C
11H
24N
2Calculated value 185; Measured value M+186
Lc Rt (10 minutes)=0.21
NMR(400MHz，dmso-d6)：0.75(6H，s)；1.26-1.29(2H，m)；1.32-1.36(2H，m)；1.41-1.47(4H，m)；2.13-2.17(2H，m)；2.25(4H，br?m)；2.26(2H，brs).
4-piperidines-1-base-amylamine
A) 2-(4-bromo-amyl group)-isoindole-1, the 3-diketone
At room temperature with 1,4-two bromo-pentanes (2.9g, 15,7mmol) add potassium phthalimide in the solution of 2-butanone, and with mixture stirring at room 24 hours, then stirred 10 hours at 50 ℃.Cooling back evaporating solvent is with crude product purification by flash chromatography (cyclohexane/ethyl acetate).
4.0g；86％
NMR (400MHz, acetone): 1.68 (3H, d, J=6.8Hz); 1.80-1.93 (4H, m); 3.69 (2H, m); 4.26-4.34 (1H, tq, J=6.8Hz, 4.8Hz); (7.85 4H, br m).
B) 2-(4-piperidines-1-base-amyl group)-isoindole-1, the 3-diketone
With 2-(4-bromo-amyl group)-isoindole-1, the 3-diketone (0.3g, 1mmol), piperidines (0.1mL, 1mmol) and salt of wormwood (0.14g, 1mmol) mixture in DMF (3mL) mixed 6 hours in 80 ℃ in penstock.Filter the back evaporating solvent, the gained resistates is passed through purification by flash chromatography (hexane/ethyl acetate).
0.19g；62％
NMR(400MHz，dmso-d6)：0.82(3H，d，J＝6.4Hz)；1.30-1.45(8H，m)；1.53-1.62(2H，m)；2.20-2.25(2H，m)；2.35-2.40(2H，m)；2.52-2.55(1H，m)；3.54(2H，m)；7.80-7.86(4H，br?m).
C) 4-piperidines-1-base-amylamine
With 2-(4-piperidines-1-base-amyl group)-isoindole-1, (0.19g 0.63mmol) is dissolved in ethanol to the 3-diketone.Add hydrazine hydrate (0.06g, 1.27mmol) after, with mixture stirring and refluxing 6 hours, then place ambient temperature overnight.After crossing filter solid, vacuum concentration organic solution is with scx-column purification crude product.
0.05g；46％
NMR(400MHz，dmso-d6)：0.84(3H，d，J＝6.4Hz)；1.28-1.46(10H，m)；2.25-2.30(2H，m)；2.37-2.51(5H，m).
3-amino-5-aryl/hetaryl pyrazoles synthetic universal method
Used in an embodiment 3-amino-5-aryl/hetaryl pyrazoles can synthesize by the route shown in the schema below commercial purchase or employing.
Aryl/hetaryl ss-ketonitriles synthetic universal method (A1):
At N
2Down to aryl or heteroaryl methyl-formiate (6.5mmol) in the solution of dry toluene (6mL) careful add NaH (dispersion liquid of 50-60% in mineral oil, 624mg, 13mmol).Mixture 80 ℃ of heating down, is then dripped anhydrous CH
3CN (1.6mL, 30.8mmol).Reacting by heating 18 hours, product precipitates from reaction mixture with the Na salt form usually.
To react cool to room temperature subsequently, filter formed solid, then that it is water-soluble.Solution is with the acidifying of 2N HCl solution subsequently, (depends on the replacement on the ring of aryl/hetaryl system) when pH2-6, and the product precipitation also leaches it.If precipitation does not occur, use the DCM extraction product.
After aftertreatment, product is used for next step without being further purified usually.General productive rate is 40-80%.
Aryl/hetaryl ss-ketonitriles synthetic universal method (route A1 two):
Under nitrogen to the anhydrous alkane nitrile that is cooled to-78 ℃ just be added dropwise in the solution of toluene (1mmol/mL, 5 equivalents)-butyllithium just-solution in the hexane (1.6N, 3.5 equivalents).Mixture was stirred 20 minutes at-78 ℃, and the solution (0.75mmol/mL, 1 equivalent) in toluene adds with aryl or heteroaryl methyl-formiate subsequently, and makes reaction reach room temperature.In case afterreaction was finished in about 20 minutes, and mixture is cooled to 0 ℃, add 2N HCl and be transferred to pH2.Reclaim organic phase, use Na
2SO
4Drying, concentrating under reduced pressure obtains title compound, and it uses without being further purified usually.
Arylamino pyrazoles synthetic universal method (route A2):
In the solution of ss-ketonitriles (7.5mmol) in pure EtOH (15mL), add the hydrazine monohydrate (0.44mL, 9.0mmol), with reactant reflux 18 hours.Make the reaction mixture cool to room temperature, solvent evaporated under reduced pressure.Resistates is dissolved in DCM and washes with water.
The concentrating under reduced pressure organic phase obtains crude product, and it passes through SiO
2Post or by from Et
2O precipitates purifying.
Productive rate is generally 65-90%.
5-(1H-indoles-5-yl)-2H-pyrazole-3-yl amine
A) 1-triisopropylsilyl-1H-indole-5-carboxylic acid methyl esters
(the 50-60% dispersion liquid in mineral oil 5.7mmol), and is cooled to 0 ℃ with mixture to add the NaH of 273mg to 1g indole-5-carboxylic acid methyl esters (5.7mmol) in the solution of 10mL dry DMF.(1.06g, 5.7mmol), LC-MS shows that raw material is converted into title product fully after 1 hour to drip the triisopropyl chlorosilane.Mixture is with 30mL DCM dilution, with saturated Na2CO3 washing.Organic phase Na
2SO
4Drying, concentrating under reduced pressure.Crude product SiO
2Column purification, with just-the hexane wash-out.Obtain title compound (500mg, productive rate 26%).
C
19H
29NO
2Si
Mass spectrum (calculated value) [331]; (measured value) [M+H
+]=332
LC Rt=3.39,100% (5 fens clock methods)
1H-NMR:(dmso-d
6): 1.06 (d, 18H, J=7.52), 1.75 (quintet, 3H, J=7.52), 6.75 (m, 1H), 7.48 (m, 1H), 7.60 (m, 1H), 7.72 (m, 1H), 8.25 (s, 1H).
B) 3-oxo-3-(1-triisopropylsilyl-1H-indoles-5-yl)-propionitrile
To the anhydrous CH of 393 μ L that is cooled to-78 ℃
3CN (7.5mmol) is added dropwise to the hexane solution (1.6N) of 5.35mL butyllithium in the solution of 6mL dry toluene.Mixture was stirred 20 minutes at-78 ℃, then add the 500mg 1-triisopropylsilyl-solution of 1H-indole-5-carboxylic acid methyl esters (1.5mmol) in the 2mL dry toluene, and make reaction reach room temperature.In case finish after being reflected at 20 minutes, mixture be cooled to 0 ℃ and add 2N HCl and transfer to pH2.Separate organic phase, use Na
2SO
4Drying, concentrating under reduced pressure obtains the 490mg title product, and it is used for next step (productive rate=96%) without being further purified.
C
20H
28N
2OSi
Mass spectrum (calculated value) [340]; (measured value) [M+H
+]=341[M-H
+]=339
LC Rt=3.10,89% (5 fens clock methods)
1H-NMR:(dmso-d
6): 1.06 (18H, d, J=7.52), 1.76 (3H, quintet, J=7.52), 4.76 (1H, d), 7.78-7.81 (1H, m), 7.48-7.52 (1H, m), 7.60-7.73 (2H, m), 8.25 (s, 1H).
C) 5-(1H-indoles-5-yl)-2H-pyrazole-3-yl amine
(490mg 1.44mmol) adds 720 μ L hydrazine monohydrates (14.4mmol) in the solution in the pure EtOH of 15mL, will react and reflux 18 hours to 3-oxo-3-(1-triisopropylsilyl-1H-indoles-5-yl)-propionitrile.The LC-MS demonstration is converted into amino-pyrazol fully and sloughs silica-based protection.The concentrating under reduced pressure mixture with SiO2 column purification (the elutriant gradient is from 100%DCM to DCM:MeOH9:1), obtains title compound (120mg, productive rate: 41%).
C
11H
10N
4
Mass spectrum (calculated value) [198]; (measured value) [M+H
+]=199
LC Rt=0.84,100% (3 fens clock methods)
5-pyridin-3-yl-2H-pyrazole-3-yl amine
A) 3-oxo-3-pyridin-3-yl-propionitrile
According to amino-pyrazol synthetic universal method (route A1) preparation product.
1H-NMR(400MHz，MeOH-d
4)：9.07(1H，d)，8.81(2H，dd)，8.26(1H，dt)，7.59(1H，dd)，4.79(2H，s).
B) 5-pyridin-3-yl-2H-pyrazole-3-yl amine
According to amino-pyrazol synthetic universal method (route A2) preparation product.
Crude product is with SiO2 post (5g) purifying, with the gradient elution of 100%DCM to DCM-NH3 (the MeOH solution of 2N) 95:5.Obtain title product (371mg, 68% productive rate).
1H-NMR(400MHz，MeOH-d
4)：8.82(1H，d)，8.41(1H，dd)，7.98(1H，dt)，7.37(1H，dd)，5.82(2H，s)
3-imidazo [1,2-a] pyridine-6-base-3-oxo-propionitrile
According to universal method A1, begin from imidazo [1,2-a] pyridine-6-methyl-formiate, obtain product.
Productive rate 39%
C10H7N3O mass spectrum (calculated value) [185]; (measured value) [M+H+]=186[M-H]=184
LC Rt=0.23,100% (3 fens clock methods)
1H-NMR：(dmso-d6)：4.72(2H，s)，7.61-7.65(2H，m)，7.70(1H，m)，8.07(1H，s)，9.40(s，1H).
5-imidazo [1,2-a] pyridine-6-base-1H-pyrazole-3-yl amine
According to universal method A2, begin from 3-imidazo [1,2-a] pyridine-6-base-3-oxo-propionitrile, obtain title compound.
Productive rate: 84%
C10H9N5 mass spectrum (calculated value) [199]; (measured value) [M+1]=200
LCMS (5 fens clock methods), RT=0.21 minute,
NMR(1H，400MHz，MeOH-d
4)3，34(s，2H)，5，90(br?s，1H)，7，57(s，1H)，7，63(br?s，1H)，7，86(s，1H)，8，73(s，1H).
5-(3-fluoro-phenyl)-1H-pyrazole-3-yl-amine
A) 3-(3-fluoro-phenyl)-3-oxo-propionitrile
The preparation product of improving one's methods according to general routes outlined A1.At N
2Down to the 3-fluorophenyl carbamate (3g, 18mmol) in the solution of dry toluene (25mL) careful add NaH (dispersion liquid of 50-60% in mineral oil, 1.44g, 36mmol).
Mixture 90 ℃ of heating, is dripped anhydrous CH subsequently
3CN (4.45mL, 85.2mmol).To react heating 18 hours, product precipitates from reaction mixture with its sodium-salt form.To react cool to room temperature, filter formed solid, then water-soluble again, with 2N HCl solution is acidified to pH5-6, observe precipitation afterwards.Cross filter solid from the aqueous solution, obtain 2.12g title compound (72% productive rate), it is directly used in next step.
B) 5-(3-fluoro-phenyl)-1H-pyrazole-3-yl-amine
Method according to the slight improvement of route A2 prepares product.To 3-(3-fluoro-phenyl)-3-oxo-propionitrile (1.92g, 11.77mmol) in the solution of pure EtOH (32mL), add the hydrazine monohydrate (0.685mL, 14.12mmol), and with reactant reflux 2 hours.Make the reaction mixture cool to room temperature, solvent evaporated under reduced pressure.Crude product is handled and is filtered with ether, is recovered to 1.71g title compound (82% productive rate).
C
9H
8FN
3
Mass spectrum (calculated value) [177]; (measured value) [M+H
+]=190
LC Rt=1.13,69% (5 fens clock methods)
5-pyridin-4-yl-1H-pyrazole-3-yl amine
3-oxo-3-pyridin-4-yl-propionitrile
The preparation product of improving one's methods according to route A1.At N
2Down to 3g (22mmol) iso methyl nicotinate in the solution of dry toluene (30mL) careful add NaH (dispersion liquid of 50-60% in mineral oil, 1.75g, 44mmol).
At 90 ℃ of these mixtures of heating, then be added dropwise to anhydrous CH
3CN (5.39mL, 103mmol).Reacting by heating 18 hours, product precipitates from reaction mixture with sodium-salt form.Make the reaction cool to room temperature and filter the solid that forms, subsequently that it is water-soluble, be acidified to pH5-6 with 6N HCl solution, and use the DCM extraction product.The pH of water is readjusted to 4-5, once more with the DCM extraction, to obtain more product.
Merge organic phase, dry and concentrated.Product is directly used in next step.The productive rate of crude product is: 58%.
B) 5-pyridin-4-yl-1H-pyrazole-3-yl amine
The preparation product of improving one's methods according to route A2.(1.86g, (0.74mL 15.29mmol), and will react reflux 2 hours 12.74mmol) to add the hydrazine monohydrate in the solution in pure EtOH (35mL) to 3-oxo-3-pyridin-4-yl-propionitrile.Then make the reaction mixture cool to room temperature, solvent evaporated under reduced pressure.Crude product washs with ether, obtains title compound (productive rate: 39%).
C
8H
8N
4
Mass spectrum (calculated value) [160]; (measured value) [M+H
+]=161
LC Rt=0.23,100% (5 fens clock methods)
1H-NMR(400MHz，dmso-d6)：5.02(2H，s)；5.85(1H，s)；7.59(2H，d，J＝6Hz)；8.50(2H，d，J＝6Hz)；11.93(1H，s).
The chloro cinnamyl nitrile synthesizes (route B 1)
So that temperature is no more than 10 ℃ drop rate, with POCl
3(is 2 equivalents with respect to the aryl/hetaryl methyl phenyl ketone) is added dropwise in the dry DMF of 4 molar equivalents that are cooled to 0 ℃.Then drip methyl phenyl ketone (1 equivalent), and make reactant reach room temperature.
Then restir reactant 30 ' adds the 0.4mmol oxammonium hydrochloride subsequently.Then reaction is heated to 50 ℃, stops heating subsequently, drip 4 normal oxammonium hydrochlorides (be no more than with temperature 120 ℃ speed) again.Reaction stirred is reduced to 25 ℃ naturally up to the temperature of mixture subsequently.Then add entry (100mL), and use the extracted with diethyl ether mixture.Organic phase Na
2SO
4Drying, concentrating under reduced pressure.Crude product is used for next step without being further purified.
The arylamino pyrazoles synthesizes (route B 2)
In the solution of pure EtOH, add 2 normal hydrazine monohydrates to chloro cinnamyl nitrile (0.5mmol/mL, 1 equivalent), and will react reflux 4 hours.With reaction mixture cool to room temperature, solvent evaporated under reduced pressure.Resistates Et
2O grinds, and to reclaim title compound, it uses without being further purified usually.
5-(3-bromo-phenyl)-2H-pyrazole-3-yl amine
A) 3-(3-bromo-phenyl)-3-chloro-vinyl cyanide
In being cooled to 0 ℃ 30.9mL dry DMF (400mmol), drip the POCl of 18.3mL
3(200mmol), make temperature keep below 10 ℃ simultaneously.In this mixture, drip 19.9g (100mmol) 1-(3-bromophenyl) ethyl ketone, and make reaction reach room temperature.
Add finish after, with reactant restir 30 minutes, then add 2.7g (40mmol) oxammonium hydrochloride, and reaction be heated to 50 ℃.Stop heating subsequently, property ground adds the oxammonium hydrochloride (making temperature keep below 120 ℃ simultaneously) of 27g (400mmol) again.
After last adding was finished, reaction stirred was spontaneously reduced to 25 ℃ up to the temperature of mixture.Then add entry (100mL), and use the extracted with diethyl ether mixture.Use Na
2SO
4Dry organic phase, concentrating under reduced pressure.
Crude product is used for next step without being further purified.
C
9H
5BrClN
1H-NMR(400MHz，dmso-d
6)：7.03(s，1H)，7.44-7.54m，1H)，7.72-7.84(m，2H)，8.00(br?s，1H).
Productive rate 68%
B) 5-(3-bromo-phenyl)-2H-pyrazole-3-yl amine
To 3-(3-bromo-phenyl)-3-chloro-vinyl cyanide (10mmol) in the solution of pure EtOH (20mL), add the hydrazine monohydrate (1mL, 20mmol), and with reactant reflux 4 hours.Then with reaction mixture cool to room temperature, solvent evaporated under reduced pressure.Resistates Et
2O grinds, and is recovered to the title compound (productive rate 54%) of 1.8g pure products form.
C
9H
8BrN
3
1H-NMR (400MHz, dmso-d
6): 4.58,5.03 (1H, 2 tautomerism peaks), 5.64,5.84 (1H, 2 tautomerism peaks), 7.28 (1H, s), 7.35 (1H, s), 7.53-7.65 (1H, m), 7.77 (1H, s), 11.56,11.97 (1H, 2 tautomerism peaks).
The universal method of synthetic ω-bromo-paraffinic acid (1H-pyrazole-3-yl-5-aryl)-acid amides
At N
2Down the solution of ω-bromoalkane acyl chlorides (15.7mmol, 1 equivalent) in anhydrous DMA (35mL) is cooled to-10 ℃ (ice/water-bath); Go through 30 ' the solution adding in anhydrous DMA (15mL) with 5-aryl/hetaryl-1H-pyrazole-3-yl amine (15.7mmol, 1 equivalent) and diisopropylethylamine (15.7mmol, 1 equivalent).At-10 ℃ after following 2 hours, detect by LC-MS and to observe reaction usually and finish (also detecting the acidylate on the pyrazoles ring).Then add H
2O (about 50mL) quencher reaction; Form thick white precipitate after adding water, by filtering with its recovery.Use Et
2(3 * 10mL) washings can effectively be removed the by product of pyrazoles ring acidylate to O usually.
The universal method of synthetic omega-amino--paraffinic acid (1H-pyrazole-3-yl-5-aryl)-acid amides
ω-bromo-paraffinic acid [5-aryl-1H-pyrazole-3-yl]-acid amides (0.6mmol, 1 equivalent) is dissolved in DMF (4mL), successively adds sodium iodide (0.6mmol, 1.0 equivalents), secondary amine (1.5mmol, 2.5 equivalents) and diisopropylethylamine (0.6mmol, 1 equivalent).Follow reactant at N
2Stirred 18 hours in+50 ℃ down.
In case (by the LC-MS monitoring) finished in reaction, solvent removed by evaporation at reduced pressure is dissolved in gained oily resistates among the DCM (20mL), uses saturated Na
2CO
3(2 * 20mL) solution and saturated NaCl (2 * 20mL) solution washings; Organic layer Na
2SO
4Drying, solvent removed by evaporation at reduced pressure.Title compound is passed through silicagel column or preparation HPLC purifying.
One kettle way synthesizes the general synthetic side of omega-amino--paraffinic acid (1H-pyrazole-3-yl-5-aryl)-acid amides
Method: acidylate-nucleophilic substitution reaction
To the ω-bromoalkane acyl chlorides (0.94mmol that is cooled to 0 ℃, 1 equivalent) in the solution of DMA (1mL), adds 3-amino-5-aryl/hetaryl pyrazoles (0.94mmol, 1 equivalent) and diisopropylethylamine (1.88mmol, 2 equivalents) solution in DMA (2mL), and reactant stirred 1 hour at 0 ℃.Then add secondary amine (2.35mmol, 2.5 equivalents) and NaI (0.94mmol, 1 equivalent).For the carbochain derivative of 3 carbon, reaction is finished after at room temperature 2 hours usually.For the carbochain derivative of 4 carbon, reaction mixture heated 24-48 hour down at 60 ℃ usually.In case the bromo-intermediate transforms (by the LC-MS monitoring), solvent removed by evaporation at reduced pressure fully.Resistates is dissolved in DCM (2mL) and uses saturated Na
2CO
3Solution washing.The concentrating under reduced pressure organic phase, with crude product from CH
3Recrystallization or pass through SiO among the CN
2Post (gradient from 100%DCM to DCM-NH3MeOH 2N solution 8:2) or preparation HPLC (standard acidic condition) purifying.
Synthesize the general of omega-amino--paraffinic acid (1H-pyrazole-3-yl-5-aryl)-acid amides through the amino acid approach
Method
In toluene (15mL) solution of amine X (65mmol), add ω-bromo paraffinic acid ethyl ester (26mmol), and with reaction mixture refluxed 10 hours.With the mixture cool to room temperature, the filtering all solids washs with ether.Concentrating under reduced pressure filtrate obtains the omega-amino-ester, and it is used for next step without being further purified.
(1.4g 25mmol), and refluxes mixture heating up 16 hours to add NaOH in the suspension of thick omega-amino-alkanoic acids ethyl ester (about 25mmol) in 15mL water from above-mentioned steps.Then, use 6N HCl acidifying, concentrating under reduced pressure down at 0 ℃ with the reactant cool to room temperature.Resistates is handled with EtOH, with sedimentary sodium-chlor filtering.Solvent evaporated under reduced pressure obtains the omega-amino acid of white solid.To omega-amino acid (7.93mmol) 2, add N in the suspension of 2-ethylene dichloride (20mL), and N '-carbonyl dimidazoles (1.2g, 7.4mmol), and in this mixture of stirring at room 2 hours (when all amino acid all are activated, observe suspension usually and dissolve fully).Then add 3-amino-5-aryl/hetaryl pyrazoles (5.29mmol), with reactant restir 10 hours.In case (by LC-MS monitoring) finished in reaction, form two kinds of isomer if observe, then with mixture 50 ℃ of heating, be converted into title compound (by the LC-MS monitoring) until the isomer of observing less stable.Use saturated Na
2CO
3The solution washing solvent, extraction and solvent removed by evaporation at reduced pressure.With crude product from CH
3Recrystallization or pass through SiO among the CN
2Post or preparation HPLC purifying.
Embodiment 1
5-azepan-1-base-valeric acid (2-chloro-2 ＇, 3 ＇-two fluoro-biphenyl-4-yl)-acid amides
A) 5-azepan-1-base-valeric acid (4-bromo-3-chloro-phenyl)-acid amides
According to universal method, with 4-bromo-3-chloroaniline (72mg, 0.35mmol) and triethylamine (35mg 0.35mmol) is dissolved in DCE (0.5mL), Dropwise 5-bromine valeryl chloride (66mg, 0.33mmol) solution in DCE (0.5mL).After 1 hour 30 minutes, add azepan (118mg, 0.105mmol) and triethylamine (35mg, the 0.35mmol) solution in DCE (0.5mL), and reaction mixture heated 4 hours at+55 ℃.After aftertreatment, obtain the title compound (23mg, 17%) of formate form by preparation HPLC.
C17H24BrClN2O mass spectrum (calculated value) [387.75]; (measured value) [M+H
+]=389.28.
LC Rt=2.34,100% (10 fens clock methods)
B) 5-azepan-1-base-valeric acid (2-chloro-2 ＇, 3 ＇-two fluoro-biphenyl-4-yl)-acid amides
According to the universal method of the cross-coupling reaction under the microwave condition, (70mg, 0.18mmol) with 2, (31mg 0.2mmol) is dissolved in acetonitrile/0.4M Na to 3-difluorophenyl boric acid with 5-azepan-1-base-valeric acid (4-bromo-3-chloro-phenyl)-acid amides
2CO
31/1 (each 1.5mL) adds Pd[P (Ph)
3]
4(11mg, 0.01mmol).After irradiation 20 minutes,, obtain the title compound (23mg, 27%) of the white solid of corresponding formate form through the preparation HPLC purifying.
C23H27ClF2N2O mass spectrum (calculated value) [420.93]; (measured value) [M+H
+]=421.38
LC Rt=2.04,100% (10 fens clock methods)
NMR(400MHz，CDCl
3)：1.63(4H，s)；1.80(8H，m)；2.43(2H，m)；2.94(2H，m)；3.1(4H，bs)；6.96(1H，m)；7.05-7.02(2H，m)；7.11(1H，d，J＝8)；7.16(1H，d，J＝8.4)；7.53(1H，d，J＝8.4)；7.9(1H，s)；8.56(1H，s，HCOOH)；9.68(1H，s，NH).
Embodiment 2
4 ＇-5-[methyl-(2-pyridine-2-base-ethyl)-amino]-pentanoyl amino }-biphenyl-3-benzoic acid amides
According to the universal method of acid amides synthetic universal method and the cross-coupling reaction under microwave irradiation, obtain 0.07g title compound (62%).
C
26H
30N
4O
2Mass spectrum (calculated value) [430.55]; (measured value) [M+H
+]=431.42
Lc?Rt＝1.59，100％
NMR(400MHz，dmso-d6)：1.37-1.45(2H，m)；1.51-1.59(2H，m)；2.17(3H，s)；2.28-2.36(4H，m)；2.62-2.66(2H，m)，2.81-2.85(2H，m)；7.14(1H，br?dd，J＝7.6Hz，4.8Hz)；7.24(1H，d，J＝8.0Hz)；7.40(1H，br?s)；7.48(1H，dd，J＝8Hz，7.6Hz)；7.61-7.7.0(5H，m)；7.78(2H，m)；8.06(1H，s)；8.11(1H，s)；9.96(1H，s).
Embodiment 3
1-(2,2 '-dimethoxy-biphenyl-4-yl)-3-(4-piperidines-1-base-butyl)-urea
1-(4-bromo-3-methoxyl group-phenyl)-3-(4-piperidines-1-base-butyl)-urea (according to the preparation of urea synthetic universal method, adopting isocyanate reaction) is weighed, and (100mg 0.26mmol) and with it is dissolved in acetonitrile (1mL) in the microwave container of packing into.To wherein add 2-anisole ylboronic acid (47mg, 0.312mmol) and tetrakis triphenylphosphine palladium (20mg, 0.017mmol) and sodium carbonate solution (1mL, 0.4M).Then reaction mixture is exposed under the microwave irradiation 20 minutes under 250psi and 90 ℃ of conditions.After the LCMS detection reaction is finished, isolating organic phase is shifted out from reaction mixture, and make it by
Layer.Collected crude product is splined on the SCX post, with methanol solution (20% ammonia) the wash-out required compound of ammonia.The flow point that will comprise required compound merges, and drying obtains title compound (30mg, 0.073mmol, 28% productive rate).
C24H33N3O3 mass spectrum (calculated value) [411.55]; (measured value) [M+H
+]=412
LC Rt=2.03,98% (10 fens clock methods)
NMR(400MHz，CDCl
3)：1.57-1.67(11H，m)；2.42-2.50(5H，m)；3.29(2H，m)；3.77(6H，s)；5.85(1H，s)；6.61(1H，s)；6.75-6.77(1H，d)；6.95-7.00(2H，m)；7.15(1H，d)；7.21-7.22(1H，m)7.23-7.33(2H，m).
Embodiment 4
5-imidazoles-1-base-valeric acid (3 ＇-acetylaminohydroxyphenylarsonic acid biphenyl-4-yl)-acid amides
A) 5-bromine valeric acid-(4-bromophenyl)-acid amides
With 4-bromo-aniline (6g, 0.035mol) and the NEt of 0.035mol
3(4.87mL) be dissolved in the 120mL methylene dichloride, and be cooled to 0 ℃.
In this solution, slowly add 0.038mol5-bromine valeryl chloride (5.4mL), the gained mixture was stirred 1 hour at 0 ℃.
After all raw material consumption (by the LCMS monitoring), with the 0.4M Na of solution with 50mL
2CO
3Washing is reclaimed organic layer by extraction, uses Na
2SO
4Dry.Solvent removed by evaporation at reduced pressure obtains the title compound (productive rate 86%) of 10g white solid.
C11H13Br2NO mass spectrum (calculated value) [335]; (measured value) [M+H
+]=335
Lc Rt=2.64,100% (5 fens clock methods)
NMR(400MHz，CDCl3)1.70-2.00(4H，m)，2.35-2.45(2H，m)，3.38-3.48(2H，m)，7.30-7.50(4H，m).
B) 5-imidazoles-1-base valeric acid-(4-bromophenyl)-acid amides
5-bromine valeric acid-(4-bromophenyl)-acid amides and the 800mg imidazoles (11.7mmol) of 400mg (1.19mmol) are suspended in 2mL toluene: in the mixture of EtOH 1:1.Reaction mixture was heated 10 minutes in 160 ℃ under microwave condition.Solvent removed by evaporation at reduced pressure is dissolved in DCM (10mL) with crude mixture, with 1M NaOH washed twice.Use Na
2SO
4Drying solution is filtered and is removed and desolvate, and obtains the required product (240mg productive rate 62%) of white powder.
NMR(400MHz，dmso-d6)：7.65(1H，s)，7.56-7.52(2H，m)，7.46-7.42(2H，m)，7.42(1H，m)，6.87(1H，m)，3.95(2H，t，J＝12Hz)，2.30(2H，t，J＝7.2Hz)，1.75-1.68(2H，m)，1.55-1.45(2H，m).
C) 5-imidazoles-1-base-valeric acid (3 ＇-acetylaminohydroxyphenylarsonic acid biphenyl-4-yl)-acid amides
0.4M Na with 1mL
2CO
3The mixture of solution and 1mL DMF add be equipped with 5-imidazoles-1-base valeric acid-(4-bromophenyl)-acid amides (100mg, 0.31mmol), 3-acetyl amino phenyl ylboronic acid (83.4mg, 0.46mmol) and [Pd (PPh
3)
4] (16mg is in microwave tube 0.03mmol).Reaction mixture was heated 20 minutes in 90 ℃ under microwave condition.Mixture is diluted with MeOH, and solution is passed through
Layer.Solvent removed by evaporation at reduced pressure is dissolved in DCM with crude mixture, washs with 1MNaOH.Organic phase is filtered solvent removed by evaporation at reduced pressure by the MgSO4 drying.Through the SCX purifying, and from EtOAC/Et
2Crystallization among the O obtains 43mg pure products (productive rate 37%).
C22H24N4O2 mass spectrum (calculated value) [376]; (measured value) [M+H
+]=377
Lc Rt 2.11 (10 minutes)
Purity 98%
NMR(400MHz，dmso-d6)：10.03(1H，s)，8.85(1H，d，J＝2.0Hz)，8.50(1H，dd，J＝4.8Hz，1.6Hz)，8.03(1H，m)，7.67(4H，m)，7.63(1H，s)，7.44(1H，m)，6.87(1H，m)，3.98(2H，t，J＝7.2Hz)，2.34(2H，t，J＝7.2Hz)，1.74(2H，m)，1.53(2H，m).
Embodiment 5
1-(2,2 ＇-two fluoro-biphenyl-4-yl)-3-(4-piperidines-1-base-butyl)-urea
A) 1-(4-bromo-3-fluoro-phenyl)-3-(4-piperidines-1-base-butyl)-urea
According to urea synthetic universal method preparation (activating aniline) with triphosgene.
Productive rate: 71%
C16H23BrFN3O mass spectrum (calculated value) 372; (measured value) [M+H
+]=372-374
Lc?Rt＝2.26(100％)，10’
NMR(400MHz，dmso-d6)：128-1.56(10H，m)，2.16-2.38(6H，m)，3.00-3.15(2H，m)，6.30(1H，t)，6.99(1H，dd)，7.46(1H，t)，7.59(1H，dd)，8.81(1H，s).
B) 1-(2,2 ＇-two fluoro-biphenyl-4-yl)-3-(4-piperidines-1-base-butyl)-urea
(4-bromo-3-fluoro-phenyl)-3-(4-piperidines-1-base-butyl)-(100mg is 0.26mmol) at DME/H for urea to 1-
2Add in the de-gassed solution among the O (1.8mL/0.3mL) 2-fluorophenyl boric acid (55mg, 0.39mmol), Na
2CO
3(55mg, 0.52mmol), Pd (OAc)
2(6mg, 10%mol) and three-neighbour-tolylphosphine (34mg, 20%mol).The power of solution with 200W was shone 20 minutes under microwave condition.
Organic phase is diluted with 1mL AcOEt and is separated.
Crude product preparation HPLC purifying (36mg, 40% productive rate).
Molecular formula: C22H27F2N3O
Mass spectrum (calculated value) [387]; (measured value) [M+H
+]=388
Lc Rt (10 fens clock methods)=399,97%
1H-NMR(400MHz，d
6-DMSO)：1.27-1.54(10H，m)，2.25-2.44(6H，m)，2.94-3.13(2H，m)，6.33-6.45(1H，m)，7.09-7.14(1H，m)，7.21-7.30(3H，m)，7.34-7.45(2H，m)，7.48-7.55(1H，m)，8.16(1H，s)，8.85(1H，s).
Embodiment 6
3 ＇-fluoro-4 ＇-[3-(4-piperidines-1-base-butyl)-urea groups]-biphenyl-3-benzoic acid amides
A) 1-(2-fluoro-4-bromo-phenyl)-3-(4-piperidines-1-base-butyl)-urea
Prepare according to urea synthetic universal method (isocyanic ester).
Productive rate: 88%
NMR(400MHz，dmso-d6)：1.22-1.50(10H，m)，2.12-2.37(6H，m)，3.00-3.13(2H，m)，6.62(1H，t)，7.25(1H，d)，7.47(1H，dd)，8.10(1H，t)，8.33(1H，s)
B) 3 ＇-fluoro-4 ＇-[3-(4-piperidines-1-base-butyl)-urea groups]-biphenyl-3-benzoic acid amides
To 1-(2-fluoro-4-bromo-phenyl)-3-(3-piperidines-1-base-propyl group)-urea (100mg, add in de-gassed solution 0.27mmol) 3-benzamide-phenyl-boron dihydroxide (66mg, 0.44mmol) and Na
2CO
3(3 equivalent) solution, Pd[(PPh in the acetonitrile/water (1/1) of 20 volumes (w/v)
3)]
4(10%mol).
Adopt following parameter in microwave oven, to shine solution: power 200W; Heating-up time 1min; Hold-time 20min; 90 ℃ of temperature; Pressure 200psi.
The separating acetonitrile phase, solvent removed by evaporation at reduced pressure, and with SCX column purification crude product (with DCM/MeOH, MeOH, NH
3/ MeOH gradient elution).The flow point that will comprise required product merges, and drying under reduced pressure is further purified (productive rate 15%) by preparation HPLC then.
Molecular formula: C22H27F2N3O
Mass spectrum (calculated value) [387]; (measured value) [M+H
+]=388
Lc Rt (10 fens clock methods)=399,97%
1H-NMR(400MHz，CD3OD)：1.40-1.67(10H，m)，2.26-2.58(6H，m)，3.21-3.27(2H，m)，7.13-7.20(1H，m)，7.21-7.28(1H，m)，7.30-7.39(1H，m)，7.40-7.51(2H，m)，7.56(1H，s，)，8.11-8.16(1H，m).
Embodiment 7
4 ＇-5-[methyl-(2-pyridine-2-base-ethyl)-amino]-pentanoyl amino }-biphenyl-3-benzoic acid amides
According to acid amides link coupled universal method (one kettle way of excessive amine is the universal method of utilizing the cross-coupling of boric acid subsequently, microwave condition), obtain 0.07g (productive rate=62%) title compound.
C
26H
30N
4O
2Mass spectrum (calculated value) [430.55]; (measured value) [M+H
+]=431.42
Lc?Rt＝1.59，100％
NMR(400MHz，dmso-d6)：1.37-1.45(2H，m)；1.51-1.59(2H，m)；2.17(3H，s)；2.28-2.36(4H，m)；2.62-2.66(2H，m)，2.81-2.85(2H，m)；7.14(1H，br?dd，J＝7.6Hz，4.8Hz)；7.24(1H，d，J＝8.0Hz)；7.40(1H，br?s)；7.48(1H，dd，J＝8Hz，7.6Hz)；7.61-7.7.0(5H，m)；7.78(2H，m)；8.06(1H，s)；8.11(1H，s)；9.96(1H，s).
Embodiment 8
1-(4 ＇-methoxyl group-biphenyl-4-yl)-3-(1-methyl-4-piperidines-1-base-butyl)-urea
A) 1-(4-bromo-phenyl)-3-(1-methyl-4-piperidines-1-base-butyl)-urea
(1.07g is 6.3mmol) at CH to 1-methyl-4-piperidines-1-base-butylamine under 0 ℃
2Cl
2(1.25g is 6.3mmol) at CH slowly to add 4-bromophenyl isocyanic ester in the solution (15mL)
2Cl
2Solution (15mL).Mixture was stirred 30 minutes down at 0 ℃, then stirring at room 3 hours.Evaporating solvent is with SCX column purification resistates.The gained solid washs with ether.
1.57g；68％
C
17H
26BrN
3O calculated value 368; Measured value 368/370
Lc Rt (5 minutes)=1.35,100%
NMR(400MHz，dmso-d6)：1.02(3H，d，J＝6.8Hz)；1.30-1.45(5H，m)；2.13-2.17(5H，m)；2.13-2.17(2H，m)；2.23(4H，br?m)；3.57-3.64(1H，m)；5.97(1H，J＝8Hz)；7.29-7.34(4H，m)；8.36(1H，s).
B) 1-(4 ＇-methoxyl group-biphenyl-4-yl)-3-(1-methyl-4-piperidines-1-base-butyl)-urea
To 1-(4-bromo-phenyl)-3-(1-methyl-4-piperidines-1-base-butyl)-urea (0.3g, 0.81mmol) and 4-anisole ylboronic acid (186mg, 1.22mmol) Pd[(PPh of adding catalytic amount in the degassing mixture in acetonitrile/0.4M sodium carbonate solution 1/1 (8mL)
3)]
4(47mg, 5mmol%).Reaction mixture was heated 20 minutes in 90 ℃ under microwave condition.After adding ethyl acetate (1mL), separate organic layer, and by the scx column purification.
0.27g；84％
C
17H
26BrN
3O calculated value 395; Measured value 396
Lc Rt (10 minutes)=2.23,100%
NMR(400MHz，dmso-d6)：1.05(3H，d，J＝6.4Hz)；1.33-1.47(10H，m)；2.06-2.18(2H，m)；2.26(4H，br?m)；3.61-3.67(1H，m)；3.75(3H，s)；5.95(1H，J＝8Hz)；6.95-6.97(2H，m)；7.39-7.46(4H，m)；7.50-7.52(2H，m)；8.30(1H，s).
Embodiment 9
1-(2,2-dimethyl-4-piperidine-1-base-butyl)-3-[4-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl]-urea
A) 1-(4-bromo-phenyl)-3-(2,2-dimethyl-4-piperidine-1-base-butyl)-urea
To 2, (1.4g is 7.6mmol) at CH for 2-dimethyl-4-piperidine-1-base-butylamine under 0 ℃
2Cl
2(1.5g is 7.6mmol) at CH slowly to add 4-bromophenyl isocyanic ester in the solution (20mL)
2Cl
2Solution (15mL).Mixture was stirred 20 minutes down at 0 ℃, then at room temperature stirred 4 hours.Evaporating solvent is handled resistates and separate solid with ether.Solution is passed through the SCX column purification.The gained solid uses without being further purified.
0.825g(28％)
C
18H
28BrN
3O calculated value 382; Measured value M+382/384
Lc Rt (5 minutes)=1.39
NMR(400MHz，dmso-d6)：0.80(6H，s)；1.28-1.34(4H，m)；1.41-1.46(4H，m)；2.17-2.21(2H，m)；2.28(4H，br?m)；2.90(2H，d，J＝6Hz)；6.15(1H，t，J＝6Hz)；7.33-7.35(4H，m)；8.51(1H，s).
B) 1-(2,2-dimethyl-4-piperidine-1-base-butyl)-3-[4-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl]-urea
To 1-(4-bromo-phenyl)-3-(2,2-dimethyl-4-piperidine-1-base-butyl)-urea (0.11g, 0.29mmol) and 1-methyl-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-4-yls)-1H-pyrazoles (90mg, 0.43mmol) Pd[(PPh of adding catalytic amount in the degassing mixture in acetonitrile/0.4M sodium carbonate solution 1/1 (4mL)
3)]
4(17mg, 5mmol%).Reaction mixture was heated 20 minutes in 90 ℃ under microwave condition.After adding ethyl acetate (1mL), separate organic layer, successively use scx post and preparation HPLC purifying.
0.067g；61％
C
22H
33N
5O calculated value 383; Measured value M+384
Lc Rt (10 minutes)=1.61
NMR(400MHz，dmso-d6)：0.82(6H，s)；1.35-1.40(4H，m)；1.48-1.54(4H，m)；2.40-2.44(2H，m)；2.46-2.50(4H，br?m)；2.91(2H，d，J＝6Hz)；3.81(3H，s)；6.32(1H，t，J＝6Hz)；7.33-7.39(4H，m)；7.72(1H，s)；7.97(1H，s)；8.23(1H，s)；8.56(1H，s).
Embodiment 10
1-(4-piperidines-1-base-amyl group)-3-(4-pyridin-3-yl-phenyl)-urea
A) 1-(4-bromo-phenyl)-3-(4-piperidines-1-base-amyl group)-urea
(0.20g is 1.18mmol) at CH to 4-piperidines-1-base-amylamine under 0 ℃
2Cl
2(0.23g is 1.18mmol) at CH slowly to add 4-bromophenyl isocyanic ester in the solution (4mL)
2Cl
2Solution (2mL).Mixture was stirred 5 minutes at 0 ℃, then at room temperature stirred 1 hour.Evaporating solvent, resistates uses without being further purified.
0.39g；90％
NMR(400MHz，CD
3OD)：0.96(3H，d，J＝6.4Hz)；1.25-1.59(10H，m)；2.46-2.55(5H，m)；3.11(2H，t，J＝6.8Hz)；7.25-7.28(2H，m)；7.32-7.36(2H，m).
B) 1-(4-piperidines-1-base-amyl group)-3-(4-pyridin-3-yl-phenyl)-urea
To 1-(4-bromo-phenyl)-3-(4-piperidines-1-base-amyl group)-urea (130mg, 0.35mmol) and pyridine-3-boric acid (65mg 0.53mmol) adds the Pd[(PPh of catalytic amount in the mixture of the degassing in acetonitrile/0.4M sodium carbonate solution 1/1 (4mL)
3)]
4(17mg, 5mmol%).Reaction mixture was heated 10 minutes in 90 ℃ under microwave condition.After adding ethyl acetate (1mL), separate organic layer, successively use SCX post and preparation HPLC purifying.
0.025g；19％
C
22H
30N
4O calculated value 366; Measured value 367
Lc Rt (10 minutes)=0.24-0.81
NMR(400MHz，dmso-d6)：0.82(6H，d，J＝6.8)；1.24-1.55(10H，m)；2.46-2.68(5H，m)；3.05-3.09(2H，m)；6.38(1H，t，J＝5.6Hz)；7.41(1H，ddd，J＝8.0Hz，4.8Hz，0.8Hz)；7.49-7.52(2H，m)；7.57-7.60(2H，m)；7.99(1H，ddd，J＝8.0Hz，2.0Hz，1.6Hz)；8.21(1H，s)；8.47(1H，dd，J＝4.8Hz，1.6
Hz)；8.74(1H，s)；8.82(1H，dd，J＝2.0Hz，0.8Hz).
Embodiment 11
1-[4-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl]-3-[4-(3,3,3-three fluoro-propyl group amino)-butyl]-urea
A) 1-(4-bromo-phenyl)-3-[4-(3,3,3-three fluoro-propyl group amino)-butyl]-urea
1-(4-bromo-phenyl)-3-(4,4-diethoxy-butyl)-urea (0.72g, 2mmol, 1 equivalent) at room temperature is dissolved among the anhydrous DCM (10mL), adds montmorillonite K-5 (0.145g).At room temperature stirring reaction is 2 hours, shows up to LC-MS to be converted into aldehyde fully.Reaction mixture is filtered to remove all solids, add trifluoropropyl amine hydrochlorate (0.9g, 6mmol, 3 equivalents) and diisopropylethylamine (1.05mL, 6mmol, 3 equivalents), add NaBH (OAc) subsequently
3(1.2g, 4mmol, 2 equivalents).At room temperature stirring reaction is 24 hours.In case (by LC-MS monitoring) finished in reaction, solvent removed by evaporation at reduced pressure, with the gained resistates by the SCX column purification, successively with the MeOH eluant solution of DCM:MeOH 1:1 and 2M NH3.Obtain 1-(4-bromo-phenyl)-3-[4-(3,3,3-trifluoro propyl amino)-butyl]-urea (0.33g, 40% productive rate).
C14H19BrF3N3O mass spectrum (calculated value) [382.23]; (measured value) [M+H
+]=381.25 (ESI-)
LC Rt=0.63,90% (10 fens clock methods)
B) 1-[4-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenyl]-3-[4-(3,3,3-three fluoro-propyl group amino)-butyl]-urea
To 1-(4-bromo-phenyl)-3-[4-(3,3,3-trifluoro propyl amino)-butyl]-urea (0.11g, 0.3mmol), 1-methyl-4-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-(0.0.94g is 0.45mmol) at 3mL acetonitrile/0.4M Na for the 1H-pyrazoles
2CO
3(50/50) adds Pd[(PPh in the de-gassed solution in
3)]
4(0.02mmol).Solution is shone under above-mentioned microwave condition.The separating acetonitrile layer, by
Layer filters.With the solution drying,, obtain the title compound (0.048mmol, 16% productive rate) of 20mg formate form by the preparation HPLC purified product.
C18H24F3N5O mass spectrum (calculated value) [383.42]; (measured value) [M+H
+]=384.21
Lc?Rt＝1.48(100％)
NMR(400MHz，dmso-d6)：1.31(4H，m)；2.43-2.30(2H，m)；2.57-2.55(2H，m)；2.75(2H，m)；3.05(2H，m)；3.81(3H，s)；6.17(1H，bs)；7.38-7.32(4H，m)；7.72(1H，s)；7.97(1H，s)；8.18(1H，s，HCOOH)；8.43(1H，s).
Embodiment 12
4 ＇-(5-azepan-1-base-pentanoyl amino)-2 ＇-chloro-biphenyl-3-benzoic acid amides
A) 5-azepan-1-base-valeric acid (4-bromo-3-chloro-phenyl)-acid amides
With 4-bromo-3-chloroaniline (0.72g, 3.5mmol), triethylamine (0.48mL, 3.35mmol) and 5-bromine valeryl chloride (0.44mL 3.32mmol) at room temperature reacted in DCE (12mL) in 2 hours; Add afterwards azepan (1.18mL, 10.3mmol) and new triethylamine (0.48mL, 3.35mmol) ,+55 ℃ of stirring reactions 4 hours.After reaction was finished and carried out aftertreatment, the purity of title compound enough was used for next step reaction (92% purity) (1.3g, quantitative yield).
C17H24BrClN2O mass spectrum (calculated value) [387.75]; (measured value) [M+H
+]=387.32/389.28
Lc?Rt＝2.83(92％)，10’
B) 4 ＇-(5-azepan-1-base-pentanoyl amino)-2 ＇-chloro-biphenyl-3-benzoic acid amides
Use the Pd[(PPh of catalytic amount
3)]
4(5mmol%), with 5-azepan-1-base-valeric acid (4-bromo-3-chloro-phenyl)-acid amides (0.07g, 0.18mmol) and benzamide-3-boric acid (0.044g, 0.27mmol) in acetonitrile/0.4M sodium carbonate solution 1/1 (3mL) reaction.
Behind the SCX column purification, obtain the title compound (0.045g, 0.11mmol, 60% productive rate) of free alkali form.
C24H30ClN3O2 mass spectrum (calculated value) [472.98]; (measured value) [M+H
+]=428.46
Lc?Rt＝2.04(100％)，10’
NMR(400MHz，CDCl
3)：1.68-1.55(8H，m)；1.77(4H，m)；2.41(2H，m；，2.58(2H，m)；2.67(2H，m)；2.72(2H，m)；7.27(1H，s)；7.49(2H，m)；7.59(1H，s)；7.8(2H，m)；7.85(1H，s)；8.16(1H，bs).
Embodiment 13
5-azepan-1-base-valeric acid (2-fluoro-2 ＇-methoxyl group-biphenyl-4-yl)-acid amides
A) 5-azepan-1-base-valeric acid (4-bromo-3-fluoro-phenyl)-acid amides
With 4-bromo-3-fluoroaniline (0.66g, 3.5mmol), triethylamine (0.48mL, 3.35mmol) and 5-bromine valeryl chloride (0.44mL 3.32mmol) at room temperature reacted in DCE (12mL) in 2 hours; Add afterwards azepan (1.18mL, 10.3mmol) and new triethylamine (0.48mL, 3.35mmol) ,+55 ℃ of stirring reactions 4 hours.After reaction was finished and carried out aftertreatment, the purity of title compound enough was used for next step reaction (90% purity) (1.29g, quantitative yield).
C17H24BrFN2O mass spectrum (calculated value) [371.30]; (measured value) [M+H
+]=371.33/373.35
Lc?Rt＝2.23(90％)，10’
B) 5-azepan-1-base-valeric acid (2-fluoro-2 ＇-methoxyl group-biphenyl-4-yl)-acid amides
Use the Pd[(PPh of catalytic amount
3)]
4(5mmol%), (0.093g is 0.25mmol) with 2-p-methoxy-phenyl-boric acid (0.057g, 0.37mmol) reaction in acetonitrile/0.4M sodium carbonate solution 1/1 (4mL) with 5-azepan-1-base-valeric acid (4-bromo-3-fluoro-phenyl)-acid amides.
Behind the preparation HPLC purifying, obtain the title compound (0.025g, 0.06mmol, 13% productive rate) of formate form.
C24H31FN2O2 mass spectrum (calculated value) [398.53]; (measured value) [M+H
+]=399.18
Lc?Rt＝2.98(98％)，10’
NMR(400MHz，CD
3OD)：1.83-1.72(8H，m)；1.9(4H，m)；2.5(2H，m)；3.18(2H，m)；3.37(4H，m)；3.77(3H，s)；6.99(1H，m)；7.06(1H，bs)；7.21(1H，m)；7.25(2H，m)；7.35(1H，m)；7.57(1H，m)；8.49(1H，s，HCOOH).
Embodiment 14
1-(2,2-two fluoro-4-piperidines-1-base-butyl)-3-(4 ＇-methoxyl group-biphenyl-4-yl)-urea
A) 1-(4-bromo-phenyl)-3-(2,2-two fluoro-4-piperidines-1-base-butyl)-urea
To 2, (0.149g 0.78mmol) slowly adds 4-bromophenyl isocyanic ester (0.153g, 0.78mmol) solution in CH2Cl2 (1mL) to 2-two fluoro-4-piperidines-1-base-butylamines in the solution of CH2Cl2 (4mL) under 0 ℃.Stirred the mixture 30 minutes at 0 ℃, then at room temperature stir, all consume up to reactant.Solution is by the SCX column purification.Gained oily matter uses (0.218g) without being further purified.
Productive rate: 72%
C16H22BrF2N3O calculated value 390; Measured value M+390/392
Lc Rt (5 minutes)=1.34
1H-NMR(400MHz，dmso-d6)：1.43-1.57(8H，m)；2.02-2.53(8H，m)；7.22-7.43(6H，m).
B) 1-(2,2-two fluoro-4-piperidines-1-base-butyl)-3-(4 ＇-methoxyl group-biphenyl-4-yl)-urea
To 1-(4-bromo-phenyl)-3-(2,2-two fluoro-4-piperidines-1-base-butyl)-urea (0.109g, 0.28mmol), 4-anisole ylboronic acid (0.051g, 0.34mmol) and Na2CO3 (0.042g, 0.40mmol) add three-neighbour-tolylphosphine (0.017g in the degassing mixture in DME (1.3mL) and water (0.2mL), 20mmol%) and Pd (OAc) 2 (0.003g, 5%mmol).Reaction mixture was heated 10 minutes in 90 ℃ under microwave condition.After adding ethyl acetate (1mL), separate organic layer, use the scx column purification, by SiO2 column purification (gradient is the 2N solution 9:1 in MeOH from 100%DCM to DCM-NH3), obtain the 0.010g product subsequently.
Productive rate: 9%
C23H29F2N3O2 calculated value 417; Measured value M+418/M-416
Lc Rt (10 minutes)=2.23,100%
NMR(400MHz，dmso-d6)：1.47-1.62(6H，m)；2.09-2.22(2H，m)；2.46-2.62(6H，m)；3.64(2H，t，J＝14)；3.81(3H，s)；6.96(2H，d，J＝8.8)；7.40(2H，d，J＝6.8)，7.47-7.51(4H，m).
19F-HNMR (400MHz, dmso-d6) :-118.90 (quintets)
Embodiment 15
5-piperidines-1-base-valeric acid [5-(4-methoxyl group-phenyl)-4-methyl-2H-pyrazole-3-yl]-acid amides
A) 3-(4-methoxyl group-phenyl)-2-methyl-3-oxo-propionitrile
According to amino-pyrazol synthetic universal method (route A1) preparation product.
Crude product with the gradient elution of 100% hexane to hexane-AcOEt 7:3, obtains 1.43g pure products (productive rate 31%) with SiO2 post (10g) purifying.
1H-NMR(400MHz，MeOH-d
4)：7.97(2H，d)，6.98(1H，d)，4.31(1H，q，J＝7.3Hz)，3.89(3H，s)，1.63(3H，d，J＝7.3Hz).
B) 5-(4-methoxyl group-phenyl)-4-methyl-2H-pyrazole-3-yl amine
According to amino-pyrazol synthetic universal method (route A2) preparation product.
Crude product with the gradient elution of 100%DCM to DCM-MeOH 8:2, obtains 1.0g pure products (productive rate 65%) with SiO2 post (10g) purifying.
1H-NMR(400MHz，CDCl3)：7.37(2H，d)，6.97(2H，d)，3.84(3H，s)，2.03(3H，s).
C) 5-piperidines-1-base-valeric acid [5-(4-methoxyl group-phenyl)-4-methyl-2H-pyrazole-3-yl]-acid amides
Universal synthesis method according to the synthetic omega-amino--paraffinic acid (1H-pyrazole-3-yl-5-aryl) of one kettle way-acid amides prepares product.
Crude product is with SiO2 post (2g) purifying, with the gradient elution of 100%DCM to DCM-NH3 (solution of 2N in MeOH) 95:5.
Then the gained crude product is passed through the preparation HPLC purifying again, obtain 54mg pure products (productive rate 7%).
C
21H
30N
4O
2
Mass spectrum (calculated value) [370]; (measured value) [M+H
+]=371
LC Rt=1.61,100% (10 fens clock methods)
1H-NMR (400MHz, dmso-d
6): 9.57 (1H, s), 8.12 (1H, s), 7.47 (2H, d), 7.02 (2H, d), 3.78 (3H, s), 2.41 (4H, broad peaks), 2.37 (2H, m), 2.29 (2H, t), 1.91 (3H, s), 1.57 (2H, m), 1.50 (6H, m), 1.38 (2H, m).
Embodiment 16
N-[5-(4-methoxyl group-phenyl)-2H-pyrazole-3-yl]-4-piperidines-1-base-butyramide
A) 4-piperidines-1-base-ethyl butyrate
To piperidines (5.4g, 65mmol) in the solution of toluene (15mL), add 4-bromo-butyric acid ethyl ester (3.8mL, 26mmol), with reaction mixture refluxed 10 hours.With the mixture cool to room temperature,, wash with ether with white solid (bromination piperidines) filtering that exists.Filtrate decompression concentrates, and obtains title compound, and it is used for next step without being further purified.
C
11H
21NO
2
Mass spectrum (calculated value) [199]; (measured value) [M+H
+]=200
LC Rt=0.2,100% (5 fens clock methods)
1H-NMR(400MHz，MeOH-d
4)：1.22-1.25(3H，m)，1.46-1.47(2H，m)，1.57-1.63(4H，m)，1.78-1.84(2H，m)，2.30-2.35(4H，m)，2.42(4H，m，broad)，4.08-4.14(2H，m).
B) 4-piperidines-1-base-butyric acid
(1.4g 25mmol), and refluxes mixture heating up 16 hours to add NaOH in the thick suspension of 4-piperidines-1-base-ethyl butyrate (about 25mmol) 15mL water that obtains from above-mentioned steps.Then cool to room temperature be will react, 6N HCl souring soln, concentrating under reduced pressure used down at 0 ℃.Resistates is handled with EtOH, and the sedimentary sodium-chlor of filtering.Solvent evaporated under reduced pressure obtains the title compound of 2.8g white solid, step a) and b) overall yield be 58%.
C
9H
17NO
2
Mass spectrum (calculated value) [171]; (measured value) [M+H
+]=172
LC Rt=0.23,100% (5 fens clock methods)
1H-NMR (400MHz, dmso-d
6): 1.44-1.51 (2H, m); 1.64-1.80 (6H, m); 2.22-2.25 (2H, m); (2.75-2.78 2H, m, broad peak); (2.91-2.94 2H, m, broad peak); 3.30-3.40 (2H, m).
C) N-[5-(4-methoxyl group-phenyl)-2H-pyrazole-3-yl]-4-piperidines-1-base-butyramide
(1.32g 7.93mmol) 2, adds N in the suspension of 2-ethylene dichloride (20mL) to 4-piperidines-1-base-butyric acid, N '-carbonyl dimidazoles (1.2g, 7.4mmol), and mixture at room temperature stirred 2 hours (after all amino acid are activated, observe suspension usually and dissolve fully).Then add 3-amino-5-(4-p-methoxy-phenyl) pyrazoles (1g, 5.29mmol), with reactant restir 10 hours.In case (by the LC-MS monitoring) finished in reaction, observe and form two kinds of isomer, mixture 50 ℃ of heating, till being converted into title compound, the isomer of observing less stable (is monitored by LC-MS).Use saturated Na
2CO
3The solution washing solvent, extraction and solvent removed by evaporation at reduced pressure.Crude product is crystallization from acetonitrile, obtains 1.2g title compound (productive rate: 70%).
C
19H
26N
4O
2
Mass spectrum (calculated value) [342]; (measured value) [M+H
+]=343
LC Rt=1.54,100% (10 fens clock methods)
1H-NMR(400MHz，dmso-d
6)：1.34-1.40(1H，m)；1.52-1.55(1H，m)；1.62-1.75(6H，m)；1.94-1.98(2H，m)；2.37-2.40(2H，m)；2.81-2.88(2H，m)；2.97-3.03(2H，m)；3.39-3.42(2H，m)；3.77(3H，s)；6.77(1H，s)；6.98(2H，d，J＝8.8Hz)；7.61(2H，d，J＝8.8Hz)；10.47(1H，s)，12.66(1H，s).
Embodiment 17
N-[5-(3-methoxyl group-phenyl)-1H-pyrazole-3-yl]-4-morpholine-4-base-butyramide
A) 3-(3-methoxyl group-phenyl)-3-oxo-propionitrile
At N
2Down to can from the 3-methoxyl group-ethyl benzoate of commercial purchase (3.2g, 18mmol) in the solution of dry toluene (25mL) careful add NaH (dispersion liquid of 50-60% in mineral oil, 1.44g, 36mmol).At 90 ℃ of heated mixt, and drip anhydrous CH
3CN (4.45mL, 85.2mmol).Reacting by heating 18 hours, product precipitates from reaction mixture with the Na salt form.Reaction is cooled to room temperature, filters formed solid and with ether washing, then that it is soluble in water again, solution is acidified to pH 3 with 2N HCl solution, observe title compound this moment and precipitate.From the aqueous solution, cross filter solid, obtain 1.57g title product (50% productive rate).
C
10H
9NO
2
Mass spectrum (calculated value) [175]; (measured value) [M+H
+]=176
LC Rt=1.69,94% (5 fens clock methods)
B) 5-(3-methoxyl group-phenyl)-2H-pyrazole-3-yl amine
To 3-(3-methoxyl group-phenyl)-3-oxo-propionitrile (8.96mmol) in the solution of pure EtOH (20mL), add the hydrazine monohydrate (0.52mL, 15mmol), with reactant reflux 18 hours.Then with reaction mixture cool to room temperature, solvent evaporated under reduced pressure.
Crude product is handled and is filtered with ether, obtains 1.4g title product (83% productive rate).
C
10H
11N
3O
Mass spectrum (calculated value) [189]; (measured value) [M+H
+]=190
LC Rt=1.13,100% (5 fens clock methods)
1H-NMR(400MHz，MeOH-d
4)：3.82(3H，s)；5.93(1H，s)；6.86-6.88(1H，m)；7.19-7.31(3H，m).
C) N-[5-(3-methoxyl group-phenyl)-1H-pyrazole-3-yl]-4-morpholine-4-base-butyramide
At N
2Down with the 4-bromobutanoylchloride (0.104mL, 0.9mmol) solution in anhydrous DMA (1mL) is cooled to-10 ℃ (ice/water-bath); With 5-(3-methoxyl group-phenyl)-2H-pyrazole-3-yl amine (170mg, 0.9mmol) and diisopropylethylamine (0.315mL, 1.8mmol) solution in anhydrous DMA (1mL) adds.Be converted into intermediate 4-bromo-N-[5-(3-methoxyl group-phenyl)-1H-pyrazole-3-yl fully]-butyramide (by LC-MS monitoring) after, add morpholine (0.079mL, 0.9mmol) and with mixture 60 ℃ of heating 16 hours.Resistates is dissolved in DCM (2mL), uses saturated Na
2CO
3Solution washing.The concentrating under reduced pressure organic phase is passed through SiO with crude product
2Column purification (from acetonitrile 100% to MeCN/MeOH, NH
390/10 gradient).Collection comprises the flow point of title compound, obtains 17mg (5.5% productive rate) title compound.
C
18H
24N
4O
3
Mass spectrum (calculated value) [344]; (measured value) [M+H
+]=345
LC Rt=1.36,95% (10 fens clock methods)
1H-NMR(400MHz，MeOH-d
4)：1.77-1.85(2H，m)；2.34-2.40(8H，m)；3.59-3.62(4H，m)；3.76(3H，s)；6.79-6.85(2H，m)；7.15-7.29(3H，m).
Embodiment 18
4-azepan-1-base-N-[5-(3-methoxyl group-phenyl)-1H-pyrazole-3-yl]-butyramide
At N
2Down with the 4-bromobutanoylchloride (0.104mL, 0.9mmol) solution in anhydrous DMA (1mL) is cooled to-10 ℃ (ice/water-bath); With 5-(3-methoxyl group-phenyl)-2H-pyrazole-3-yl amine (170mg, 0.9mmol) and diisopropylethylamine (0.315mL, 1.8mmol) solution in anhydrous DMA (1mL) adds.(by the LC-MS monitoring) adds the 0.101mL azepine after being converted into ω-bromo-acid amide intermediate fully
In solution, mixture was stirred 16 hours down at 60 ℃.
Resistates is dissolved in DCM (2mL), uses saturated Na
2CO
3Solution washing.The concentrating under reduced pressure organic phase, crude product passes through SiO
2Column purification (from acetonitrile 100% to MeCN/MeOH, NH
390/10 gradient).Collection comprises the flow point of title product, is further purified by preparation HPLC, obtains the title compound (5.5% productive rate) of its formate form of 20mg.
C
20H
28N
4O
2
Mass spectrum (calculated value) [356]; (measured value) [M+H
+]=357
LC Rt=1.71,99% (10 fens clock methods)
1H-NMR (400MHz, MeOH-d
4): 1.65-1.68 (4H, m); 1.80-1.90 (4H, m); 1.97-2.04 (2H, m); 2.49-2.52 (2H, m); 3.12-3.16 (2H, m); (3.24-3.30 4H, m, broad peak); 3.75 (3H, s); 6.76 (1H, s); 6.82-6.85 (1H, m); 6.13-6.15 (2H, m); 6.23-6.27 (1H, m); (8.37 1H, s, formate).
Embodiment 19
4-azepan-1-base-N-[5-(4-fluoro-phenyl)-2H-pyrazole-3-yl]-butyramide
Universal synthesis method preparation according to the synthetic omega-amino--paraffinic acid (1H-pyrazole-3-yl-5-aryl) of one kettle way-acid amides.From the commercial 5-that buys (4-fluoro-phenyl)-2H-pyrazole-3-yl amine,, behind the preparation HPLC purifying, be recovered to the title compound (7% productive rate) of its formate form of 25mg according to described method.
C
20H
28N
4O
2
Mass spectrum (calculated value) [344]; (measured value) [M+H
+]=345
LC Rt=1.69,100% (10 fens clock methods).
1H-NMR (400MHz, MeOH-d
4): 1.66-1.69 (4H, m); (1.80-1.90 4H, m, broad peak); 1.97-2.05 (2H, m); 2.52-2.54 (2H, m); 3.12-3.18 (2H, m); (3.25-3.30 4H, m, broad peak); (6.67 1H, s, broad peak); 7.08-7.12 (2H, m); 7.59-7.63 (2H, m); (8.43 1H, s, formate).
Embodiment 20
N-[5-(6-methyl-pyridin-3-yl)-1H-pyrazole-3-yl]-4-piperidines-1-base-butyramide
A) 3-(6-methyl-pyridin-3-yl)-3-oxo-propionitrile
According to synthetic this oxypropionitrile of the universal method (route A1) of 3-oxypropionitrile.
C
9H
8N
2O
Mass spectrum (calculated value) [160]; (measured value) [M+H
+]=161
LC Rt=0.63,100% (5 fens clock methods)
1H-NMR(400MHz，dmso-d
6)：2.55(3H，s)；4.65(2H，s)；7.43-7.45(m，1)；8.13-8.16(1H，m)；8.94-8.95(1H，m).
B) 5-(6-methyl-pyridin-3-yl)-1H-pyrazole-3-yl amine
According to the described universal method synthesizing amino of route A2 pyrazoles.
C
9H10N
4
Mass spectrum (calculated value) [174]; (measured value) [M+H
+]=175
LC Rt=0.23,100% (5 fens clock methods)
C) N-[5-(6-methyl-pyridin-3-yl)-1H-pyrazole-3-yl]-4-piperidines-1-base-butyramide
Universal synthesis method preparation according to the synthetic omega-amino--paraffinic acid (1H-pyrazole-3-yl-5-aryl) of one kettle way-acid amides behind the preparation HPLC purifying, obtains the title compound of its formate form of 19mg (6% productive rate).
C
18H
25N
5O
Mass spectrum (calculated value) [327]; (measured value) [M+H
+]=328
LC Rt=0.33,100% (10 fens clock methods)
1H-NMR (400MHz, MeOH-d
4): 1.40-1.90 (6H, m); 2.30-2.54 (5H, m); 3.05-3.09 (4H, m); 3.20-3.24 (2H, m); (6.72 1H, s, broad peak); (7.30 1H, d J=8.0Hz); 7.92-7.94 (1H, m); (8.35 1H, s, formate); 8.67 (1H, s).
Embodiment 21
N-[5-(5-methyl-pyridin-3-yl)-1H-pyrazole-3-yl]-4-piperidines-1-base-butyramide
A) 3-(5-methyl-pyridin-3-yl)-3-oxo-propionitrile
According to synthetic this oxypropionitrile of the universal method (route A1) of 3-oxypropionitrile.
C
9H
8N
2O
Mass spectrum (calculated value) [160]; (measured value) [M+H
+]=161
LC Rt=0.63,100% (5 fens clock methods)
1H-NMR(400MHz，MeOH-d
4)：2.55(3H，s)；4.65(2H，s)；7.43-7.45(m，1)；8.13-8.16(1H，m)；8.94-8.95(1H，m).
B) 5-(5-methyl-pyridin-3-yl)-1H-pyrazole-3-yl amine
According to the described universal method synthesizing amino of route A2 pyrazoles.
C
9H10N
4
Mass spectrum (calculated value) [174]; (measured value) [M+H
+]=175
LC Rt=0.23,100% (5 fens clock methods)
C) N-[5-(5-methyl-pyridin-3-yl)-1H-pyrazole-3-yl]-4-piperidines-1-base-butyramide
Universal synthesis method preparation according to the synthetic omega-amino--paraffinic acid (1H-pyrazole-3-yl-5-aryl) of one kettle way-acid amides behind the preparation HPLC purifying, obtains the title compound (7.4% productive rate) of its formate form of 25mg.
C
18H
25N
5O
Mass spectrum (calculated value) [327]; (measured value) [M+H
+]=328
LC Rt=0.33,100% (10 fens clock methods)
1H-NMR (400MHz, MeOH-d
4): 1.52-1.70 (2H, m, broad peak); (1.72-1.84 4H, m, broad peak); 1.98-2.06 (2H, m); 2.45 (3H, s); 2.48-2.54 (2H, m); 3.04-3.10 (4H, m); (3.20-3.24 2H, m, broad peak); (6.74 1H, s, broad peak); 7.88 (1H, s); 7.28 (1H, s); (8.37 1H, s, formate); 8.67 (1H, s).
Embodiment 22
4-(4-ethanoyl-[1,4] Diazesuberane-1-yl)-N-[5-(6-methoxyl group-naphthalene-2-yl)-1H-pyrazole-3-yl]-butyramide
A) 6-methoxyl group-naphthalene-2-methyl-formiate
To 6-methoxyl group-naphthalene-2-formic acid (1.01g, 5mmol) sulfuric acid of adding catalytic amount in the solution of methyl alcohol (10mL).Then mixture was heated 8 hours at 80 ℃.(by the LCMS monitoring) slowly cooled off solution after reaction was finished, and observed the product precipitation.Filter white solid, obtain 1.01g (94% productive rate) title compound.
C
13H
12O
3
Mass spectrum (calculated value) [216]; (measured value) [M+H+]=217
LC Rt=2.43,100% (5 fens clock methods)
B) 3-(6-methoxyl group-naphthalene-2-yl)-3-oxo-propionitrile
To 6-methoxyl group-naphthalene-2-methyl-formiate (1.0g, 4.7mmol) in the solution of dry toluene (8mL), add NaH (0.55mg, 9.4mmol), and with mixture 90 ℃ of heating.In this hot solution, drip acetonitrile (1.2mL).Then reacting by heating is 18 hours, and product precipitates from reaction mixture with its sodium-salt form.
To react cool to room temperature, and at first filter formed solid, with the ether washing, then that it is water-soluble, solution is acidified to pH3 with 2N HCl, observes the title compound precipitation subsequently.From the aqueous solution, cross filter solid, obtain 1.1g title compound (100% productive rate).
C
13H
12O
3
Mass spectrum (calculated value) [225]; (measured value) [M+H
+]=226
LC Rt=2.13,90% (5 fens clock methods)
C) 5-(6-methoxyl group-naphthalene-2-yl)-1H-pyrazole-3-yl amine
To 3-(6-methoxyl group-naphthalene-2-yl)-3-oxo-propionitrile (1.1g, 4.8mmol) add in the solution in pure EtOH (10mL) the hydrazine monohydrate (0.96mL, 19.2mmol), and with reactant reflux 18 hours.With reaction mixture cool to room temperature, solvent evaporated under reduced pressure.Crude product is handled and is filtered with ether, obtains 0.95g title compound (83% productive rate).
C
14H
13N
3O
Mass spectrum (calculated value) [239]; (measured value) [M+H
+]=240
LC Rt=1.49,90% (5 fens clock methods)
D) 4-(4-ethanoyl-[1,4] Diazesuberane-1-yl)-N-[5-(6-methoxyl group-naphthalene-2-yl)-1H-pyrazole-3-yl]-butyramide
According to the synthetic ω-universal method of bromo-paraffinic acid (1H-pyrazole-3-yl-5-aryl)-acid amides and universal method of synthetic omega-amino--paraffinic acid (1H-pyrazole-3-yl-5-aryl)-acid amides, by the preparation HPLC purifying, obtain the title compound of its formate form of 15mg (3% productive rate).
C
25H
31N
5O
3
Mass spectrum (calculated value) [449]; (measured value) [M+H+]=450
LC Rt=1.91,100% (10 fens clock methods)
1H-NMR (400MHz, MeOH-d
4): 1.88-2.0 (4H, m); 2.06 (3H, s); 2.48-2.52 (2H, m); 2.94-3.02 (2H, m); 3.08-3.18 (4H, m); 3.52-3.58 (2H, m); 3.64-3.72 (2H, m); 3.82 (3H, s); 6.78-6.82 (1H, m); 7.04-7.10 (1H, m); 7.16-7.18 (1H, m); 7.62-7.78 (3H, m); 7.98-8.02 (1H, m); (8.28 1H, s, formate).
Embodiment 23
6-(4-ethanoyl-[1,4] Diazesuberane-1-yl)-caproic acid [5-(4-methoxyl group-phenyl)-1H-pyrazole-3-yl]-acid amides
Universal synthesis method according to the synthetic omega-amino--paraffinic acid (1H-pyrazole-3-yl-5-aryl) of one kettle way-acid amides prepares product.At N
2Down with 5-bromine caproyl chloride (0.144mL, 0.94mmol) solution in anhydrous DMA (1mL) is cooled to-10 ℃ (ice/water-bath); With 5-(4-methoxyl group-phenyl)-1H-pyrazole-3-yl amine (178mg, 0.94mmol) and diisopropylethylamine (0.324mL, 1.88mmol) solution in anhydrous DMA (1mL) adds.
Reactant was stirred 1 hour at 0 ℃, then adds 1-[1,4] and Diazesuberane-1-base-ethyl ketone (0.310mL, 2.35mmol) and NaI (0.94mmol, 1 equivalent).
At 60 ℃ of reacting by heating mixtures, to analyze demonstration bromo-intermediate up to LC-MS and transform fully, this moment is with reactant cooling, solvent removed by evaporation at reduced pressure.Resistates is dissolved in DCM (2mL), uses saturated Na
2CO
3Solution washing.
The concentrating under reduced pressure organic phase is passed through SiO with half crude product
2Column purification (gradient is to DCM-NH3MeOH 2N solution 8:2 from 100%DCM).Collection comprises the flow point (35mg) of title compound.
C
23H
33N
5O
3
Mass spectrum (calculated value) [427]; (measured value) [M+H
+]=428
LC Rt=1.61,96% (10 fens clock methods)
1H-NMR(400MHz，dmso-d6)：1.24-1.29(2H，m)；1.36-1.44(2H，m)；1.54-1.58(2H，m)；1.62-1.76(2H，m)；1.94-1.96(3H，m)；2.25-2.28(2H，m)；2.35-2.41(2H，m)；2.51-2.54(2H，m)；2.60-2.62(1H，m)；3.38-3.44(5H，m)；3.77(3H，s)；6.73(1H，s)；6.98(2H，d，J＝8.8Hz)；7.61(2H，d，J＝8.8)；10.32(1H，s).
Embodiment 24
N-[5-(4-methoxyl group-phenyl)-2H-pyrazole-3-yl]-2-methyl-4-piperidines-1-base-butyramide
A) 4-bromo-2-methyl-methyl-butyrate
4-bromo-2-methyl-butyric acid (according to J.Am.Chem.Soc.1990,112,2755 described methods prepare for 2.16g, 1 equivalent) is dissolved in MeOH (10mL), adds several dense H
2SO
4To react stirring and refluxing 16 hours.After reaction is finished (by the LC-MS monitoring), reduction vaporization is removed MeOH, with the oily residue diluted with water, with 10%NaOH pH is transferred to 9, uses Et
2(2 * 20mL) extraction products are used Na to O
2SO
4Dry.Except that after desolvating, obtain the title compound (1.29g, 55% productive rate) of colorless oil.
NMR(400MHz，CDCl3)：1.19(3H，d)；1.94-1.89(2H，m)；2.29-2.23(2H，m)；3.43-3.40(1H，m)；3.69(3H，s).
B) 2-methyl-4-piperidines-1-base-butyrates hydrochlorate
4-bromo-2-methyl-methyl-butyrate (1.29g, 1 equivalent) is dissolved in toluene (15mL), adds piperidines (1.07mL, 3 equivalents); Stirring reaction 3 hours.After reaction is finished (by the LC-MS monitoring), reduction vaporization is removed toluene, and thick ester is dissolved among 1M NaOH (14mL, 1.1 equivalents) and the MeOH (2mL).To react stirring and refluxing 16 hours; After hydrolysis was finished, the concentrating under reduced pressure reactant transferred to 4 with 6N HCl with pH.Add EtOH and help the NaCl precipitation.Filter organic phase, reduction vaporization is removed EtOH.The gained oily matter Et of 2M HCl
2The O solution-treated obtains 2-methyl-4-piperidines-1-base-butyrates hydrochlorate (0.96g, 66% productive rate).
C
10H
19NO
2
Mass spectrum (calculated value) [185.27]; (measured value) [M+H
+]=186.27
LC Rt=0.23,95% (5 fens clock methods)
C) N-[5-(4-methoxyl group-phenyl)-2H-pyrazole-3-yl]-2-methyl-4-piperidines-1-base-butyramide
2-methyl-4-piperidines-1-base-butyrates hydrochlorate (0.45g, 1.2 equivalents) is suspended in 1, among the 2-DCE (15mL), adds triethylamine (0.29mL, 1.2 equivalents); Disposable adding 1,1 '-carbonyl dimidazoles (0.303g, 1.1 equivalents), at room temperature stirring reaction is 2 hours.Then add 5-(4-methoxyl group-phenyl)-2H-pyrazole-3-yl amine (0.325g, 1 equivalent), and at room temperature restir reacted 16 hours.After reaction is finished (by the LC-MS monitoring), solvent removed by evaporation at reduced pressure is passed through column chromatography (Flash-SI 10g with thick acid amides; CH
3CN:MeOH 9:1, CH
3CN:2N NH
3MeOH 9:1) purifying, obtain the heavy-gravity colorless oil title compound (0.120g, 0.33mmol).
C
20H
28N
4O
2
Mass spectrum (calculated value) [356.48]; (measured value) [M+H
+]=357.25
LC Rt=1.67,97% (10 fens clock methods)
NMR(400MHz，dmso-d6)；1.18(3H，d)；1.35-1.31(2H，m)；1.46-1.41(4H，m)；1.77-1.72(1H，m)；2.19-2.16(2H，m)；2.27-2.23(4H，m)；2.61-2.58(2H，m)；3.76(3H，s)；6.76(1H，s)；6.92(2H，d)；7.61(2H，d)；10.33(1H，s).
Embodiment 25
N-[4-(4-methoxyl group-phenyl)-1H-imidazoles-2-yl]-4-piperidines-1-base-butyramide
To 4-piperidines-1-base-butyric acid (200mg, 1.17mmol, 1.0 equivalent) 1, add N in the suspension of 2-ethylene dichloride (2mL), N '-carbonyl dimidazoles (179.9mg, 1.11mmol, 0.95 equivalent), and mixture at room temperature stirred 1 hour, up to amino acid activate fully and the suspension dissolving till.(according to JOC 1994,59,24,7299 reported method prepare to add the basic amine of 4-(4-methoxyl group-phenyl)-1H-imidazoles-2-; 110.5g, 0.58mmol, 0.50 equivalent), 50 ℃ of stirring reactions 1 day.This conversion reaction is slowly monitored by LC-MS.Another part activatory acid (the 4-piperidines-1-base-butyric acid of 200mg and the carbonyl dimidazoles of 179.9mg are at 1 of 2mL, in the 2-ethylene dichloride) is added, will be reflected at 50 ℃ of restir 2 days.
Solvent evaporated under reduced pressure by the preparation HPLC purifying, obtains the 9:1 mixture of product and unreacted 4-(4-methoxyl group-phenyl)-1H-imidazoles-2-base amine with crude mixture.Crude product is handled purifying with isocyanic ester resin and SCX post, obtain 78.0mg (productive rate: the title compound of white solid 39%).
C19H26N4O2 mass spectrum (calculated value) [342]; (measured value) [M+H
+]=343
LC Rt=1.00 (and solvent front), 99% (10 fens clock methods)
1H-NMR(400MHz，DMSO)：1.30-1.36(2H，m)；1.43-1.49(4H，m)；1.67-1.75(2H，m)；2.22-2.34(8H，m)；3.73(3H，s，-OCH3)；6.87(2H，d，J＝8.8Hz)；7.10(1H，s)；7.60(2H，d，J＝8.8Hz)；11.26(1H，s，NHCO)，11.52(1H，s，NH).
13C-NMR(400MHz，DMSO)：21.54(1C)；23.63(1C)；24.92(2C)；33.24(1C)；53.6(1C，-OCH3)；55.02(2C)；57.46(1C)；113.88(2C)；125.18(2C)，141.13(1C)；157.67(1C)；162.33(2C)；163.66(1C)；171.15(1C，CO).
Table 1-embodiment 26-171
Table 1 has shown selected synthetic compound, they according to the described method in last hurdle in the table and in experimental technique the synthetic method that describes in detail by embodiment 1-25 prepare.
When compound was illustrated as HCl salt, this salt was by free alkali being dissolved in methyl alcohol and adding the diethyl ether solution of 1 normal 1M HCl, and evaporating solvent forms subsequently.When compound was illustrated as HCOOH (formic acid) salt, this compound was by the preparation HPLC purifying.
Biologic activity
The clone of the clone of alpha 7 nicotinic acetylcholine receptors and stably express recombinant alpha 7nAChR
Produce
The Protocols in Molecular Biology of employing standard, from the rat brain cdna library clone coding alpha 7 nicotinic acetylcholine receptors full-length cDNA.With this rat receptor transfection rat GH4C1 cell, the clone also utilizes the FLIPR test of measuring the intracellular calcium concentration variation that its functional alpha 7 nicotinic receptor is expressed and analyzes then.Show the further subclone of cell clone that the highest calcium mediates fluorescent signal after will using agonist (nicotine), use the α-bungatotoxin (BgTX) of texas Red-mark to dye subsequently, use Laser Scanning Confocal Microscope that alpha 7 nicotinic acetylcholine receptors expression levels and homogeneity are analyzed.Then three clones are increased and a clone is carried out pharmacological characteristic identify (referring to following table 2), use it for screening compound subsequently.
Table 2-adopts functional FLIPR test that the pharmacology that the α 7nAChR of stably express in the GH4C1 cell carries out is identified
| Compound | EC 50[μM] |
| Vagusstoff | 3.05±0.08(n＝4) |
| Choline | 24.22±8.30(n＝2) |
| Cytisine | 1.21±0.13(n＝5) |
| DMPP | 0.98±0.47(n＝6) |
| Epibatidine | 0.012±0.002(n＝7) |
| Nicotine | 1.03±0.26(n＝22) |
Be used for the exploitation of the functional FLIPR measuring method of primary dcreening operation and concentration-effect analysis
Use stable reorganization GH4C1 clone, set up stable functional FLIPR test (Z ＇=0.68) with the screening alpha 7 nicotinic acetylcholine receptors.This FLIPR system allows to use Ca
2+Fluorescent dye sensitive (as Fluo4) is measured the real-time Ca in the viable cell
2+-change in concentration.These means can be screened the agonist and the antagonist of the α 7 nAChR passages of stably express in the GH4C1 cell.
Cell cultures
Use the GH4C1 cell (on seeing) of stable transfection rat-α 7-nAChR.These cell adhesions are poor, therefore carry out pre-treatment with poly--D-Methionin pair cell culturing bottle and plank.Make cell at the 150cm that the 30mL substratum is housed
2In the T-culturing bottle at 37 ℃ and 5%CO
2Under grow.
Data analysis
Use IDBS Xlfit4.1 software package, utilize S shape concentration-effect (variable slope) Equation for Calculating EC
50And IC
50Value:
At the bottom of the Y=+((top-end)/(1+ ((EC
50/ X) ^Hill slope))
Checking to test
With alpha 7 nAChR agonists nicotine, Cytisine, DMPP, epibatidine, choline and vagusstoff functional FLIPR is verified.In the concentration range of 0.001 to 30 μ M, obtained concentration-effect curve.In table 2, listed the EC of gained
50Value, the peci-order of the agonist that is obtained and public data people such as (, 1997) Quik (22) unanimity.
With the concentration of 1 μ M to 0.01nM, use the competitive nicotinic density of specific α 7nAChR antagonist MLA (methyllycaconitine) and 10 μ M further this test to be verified together.Independently calculate IC in the experiment at 9
50Value is 1.31 ± 0.43nM.
Be used for the foundation of the functional FLIPR assay method of selectivity check
Set up functional FLIPR assay method with the selectivity of check compound to 5-HT3 acceptor relevant on α 1 (muscle) and α 3 (neuroganglion) nACh acceptor and the structure.In order to measure activity to α 1 acceptor of natural expression in TE 671 clones that come from rhabdosarcoma, use a kind of assay method of utilizing membrane potential susceptibility dyestuff, and the selectivity of α 3 is measured by the calcium monitoring test that uses natural SH-SY5Y clone.In order to check selectivity, the recombinant cell lines of construction expression people 5-HT3A acceptor in the HEK293 cell, and the FLIPR assay method of use monitoring calcium to the 5-HT3 acceptor.
The screening of compound
In the functional FLIPR primary dcreening operation test that the stable reorganization GH4C1 clone of utilizing express alpha 7nAChR is carried out, the compound of described embodiment 1-171 shows agonist activity.The strongest determined lead compound (Hits) is further verified by obtaining concentration-effect curve.The compound usefulness of the embodiment 1-153 that records in functional FLIPR shaker test is 10nM to 30 μ M, and wherein most compounds show the usefulness of 10nM to 10 μ M.
Proved that also the best compound that exemplifies has selectivity to α 1nACh, α 3nACh acceptor and 5HT3 acceptor.
Reference
1.Prendergast，M.A.，Harris，B.R.，Mayer，S.，Holley，R.C.，Pauly，J.R.，Littleton，J.M.(2001)Nicotine?exposure?reduces?N-methyl-D-aspartatetoxicity?in?the?hippocampus：relation?to?distribution?of?the?alpha7?nicotinicacetylcholine?receptor?subunit.Med.Sci.Monit.7，1153-1160.
2.Garrido，R.，Mattson，M.P.，Hennig，B.，Toborek，M.(2001)Nicotine?protects?against?arachidonic-acid-induced?caspase?activation，cytochrome?c?release?and?apoptosis?of?cultured?spinal?cord?neurons.J.Neurochem.76，1395-1403.
3.Semba，J.，Miyoshi，R.，Kito，S.(1996)Nicotine?protects?against?thedexamethasone?potentiation?of?kainic?acid-?induced?neurotoxicity?incultured?hippocampal?neurons.Brain?Res.735，335-338.
4.Shimohama，S.，Akaike，A.，Kimura，J.(1996)Nicotine-inducedprotection?against?glutamate?cytotoxicity.Nicotinic?cholinergicreceptor-mediated?inhibition?of?nitric?oxide?formation.Ann.N.Y.Acad.Sci.777，356-361.
5.Akaike，A.，Tamura，Y.，Yokota，T.，Shimohama，S.，Kimura，J.(1994)Nicotine-induced?protection?of?cultured?cortical?neurons?against?N-methyl-D-aspartate?receptor-mediated?glutamate?cytotoxicity.Brain?Res.644，181-187.
6.Yamashita，H.，Nakamura，S.(1996)Nicotine?rescues?PC12?cellsfrom?death?induced?by?nerve?growth?factor?deprivation.Neurosci.Lett.213，145-147.
7.Shimohama，S.，Greenwald，D.L.，Shafron，D.H.，Akaika，A.，Maeda，T.，Kaneko，S.，Kimura，J.，Simpkins，C.E.，Day，A.L.，Meyer，E.M.(1998)Nicotinic?alpha?7?receptors?protect?against?glutamateneurotoxicity?and?neuronal?ischemic?damage.Brain?Res.779，359-363.
8.Socci，D.J.，Arendash，G.W.(1996)Chronic?nicotine?treatmentprevents?neuronal?loss?in?neocortex?resulting?from?nucleus?basalis?lesionsin?young?adult?and?aged?rats.Mol.Chem.Neuropathol.27，285-305.
9.Rusted，J.M.，Newhouse，P.A.，Levin，E.D.(2000)Nicotinictreatment?for?degenerative?neuropsychiatric?disorders?such?as?Alzheimer＇sdisease?and?Parkinson＇s?disease.Behav.Brain?Res.113，121-129.
10.Kihara，T.，Shimohama，S.，Sawada，H.，Kimura，J.，Kume，T.，Kochiyama，H.，Maeda，T.，Akaike，A.(1997)Nicotinic?receptorstimulation?protects?neurons?against?beta-amyloid?toxicity.Ann.Neurol.42，159-163
11.Kihara，T.，Shimohama，S.，Sawada，H.，Honda，K.，Nakamizo，T.，Shibasaki，H.，Kume，T.，Akaike，A.(2001)alpha?7?nicotinic?receptortransduces?signals?to?phosphatidylinositol?3-?kinase?to?block?Abeta-amyloid-induced?neurotoxicity.J.Biol.Chem.276，13541-13546.
12.Kelton，M.C.，Kahn，H.J.，Conrath，C.L.，Newhouse，P.A.(2000)The?effects?of?nicotine?on?Parkinson＇s?disease.Brain?Cogn?43，274-282.
13.Kem，W.R.(2000)The?brain?alpha?7?nicotinic?receptor?may?bean?important?therapeutic?target?for?the?treatment?of?Alzheimer＇s?disease：studies?with?DMXBA(GTS-21).Behav.Brain?Res.113，169-181.
14.Daj?as-Bailador，F.A.，Lima，P.A.，Wonnacott，S.(2000)Thealpha7?nicotinic?acetylcholine?receptor?subtype?mediates?nicotineprotection?against?NMDA?excitotoxicity?in?primary?hippocampal?culturesthrough?a?Ca(2+)?dependent?mechanism.Neuropharmacology?39，2799-2807.
15.Strahlendorf，J.C.，Acosta，S.，Miles，R.，Strahlendorf，H.K.(2001)Choline?blocks?AMPA-induced?dark?cell?degeneration?of?Purkinjeneurons：potential?role?of?the?alpha?7?nicotinic?receptor.Brain?Res.901，71-78.
16.Jonnala，R.R.，Terry，A.V.，Jr.，Buccafusco，J.J.(2002)Nicotineincreases?the?expression?of?high?affinity?nerve?growth?factor?receptors?inboth?in?vitro?and?in?vivo.Life?Sci.70，1543-1554.
17.Bencherif, M., Bane, A.J., Miller, C.H., Dull, G.M., Gatto, G.J. (2000) TC-2559:a novel orally active ligand selective at neuronalacetylcholine recepto rs.Eur.J.Pharmacol.409,45-55 reference type: periodical.
18.Donnelly-Roberts，D.L.，Xue，I.C.，Arneric，S.P.，Sullivan，J.P.(1996)In?vitro?neuroprotective?properties?of?the?novel?cholinergic?channelactivator(ChCA)，ABT-418.Brain?Res.719，36-44.
19.Meyer，E.M.，Tay，E.T.，Zoltewicz，J.A.，Meyers，C.，King，M.A.，Papke，R.L.，De?Fiebre，C.M.(1998)Neuroprotective?andm?emory-related?actions?of?novel?alpha-7?nicotinic?agents?with?differentmixed?agonist/antagonist?properties.J.Pharmacol.Exp.Ther.284，1026-1032.
20.Stevens，T.R.，Krueger，S.K.，Fizsimonds，R.M.and?Picciotto，M.R.(2003)Neuroprotection?by?nicotine?in?mouse?primary?corticalcultures?involves?activation?of?calcineurin?and?L-type?calcium?channelinactivation.J.Neuroscience?23，10093-10099.
21.Wang?H，Yu?M，Ochani?M，Amella?CA，Tanovic?M，Susarla?S，LiJH，Wang?H，Yang?H，Ulloa?L，Al-Abed?Y，Czura?CJ，Tracey?KJ(2003)Nicotinic?acetylcholine?receptor?alpha7?subunit?is?an?essential?regulator?ofinflammation.Nature?421：384-388.
22.Quik?M，Philie?J.and?Choremis?J.(1997).Modulation?of?alpha?7nicotinic?receptor-mediated?calcium?influx?by?nicotinic?agonists.Mol.Pharmacol.，51，499-506.
Claims (18)
1. the compound of formula (I)
Wherein
W, h and k are 0,1,2 or 3 independently of one another, and condition is 3≤w+h+k≤5;
At k〉1 o'clock, K1 and K2 are connected on the identical or different carbon atom, represent hydrogen independently of one another; Halogen; (C
1-C
5) alkyl, alkoxyl group, fluoro-alkyl, alkylidene group, fluoro alkylidene group; Hydroxyalkyl; Or K1 and K2 form alkylidene group or fluoro alkylidene group together; Or K1 forms (C with K2 with the carbon atom that they were connected
3-C
6) group of naphthene base; Perhaps when k 〉=2, two O
kCarbon atom can form unsaturated link(age); Perhaps when w be 1,2 or 3 and k when being 1, K1 can form oxo group with the carbon atom that they were connected with K2;
J is 0,1 or 2;
X is a following radicals
Z is CH
2, N, O, S, S (=O) or S (=O)
2
P is 0,1,2 or 3;
N is 0,1 or 2;
S is 1 or 2;
Q and q ' are 1 to 4 integer independently of one another;
T ' is representation hydroxy independently of one another; Sulfydryl; Amino; Cyano group; Nitro; Straight chain, side chain or cyclic (C
1-C
6) alkyl, three alkylhalide groups, hydroxyalkyl, aminoalkyl group, mercaptoalkyl, alkoxyl group, alkylthio, alkyl-carbonyl, alkoxy carbonyl, alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
6) alkylamino; Straight chain, side chain or cyclic (C
1-C
6) alkoxyl group-(C
1-C
6) alkyl, list-or two-(C
1-C
6) alkylamino-(C
1-C
6) alkyl, or (C
1-C
6) alkylthio-(C
1-C
6) alkyl; (C
1-C
3) alkyl sulfonyl-amino; Single-or two-(C
1-C
3) alkyl amino sulfonyl; Sulfamyl; Straight chain, side chain or cyclic (C
1-C
6) alkyl amino-carbonyl; Carbamyl; Perhaps, when p was 2 or 3, two T ' substituting groups formed 5 to 8 yuan of volutions or condensed ring;
U and U ' represent independently of one another
Hydrogen; Cyano group; Hydroxyl; Amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
6) alkylamino group; (the C of straight or branched
1-C
6) alkoxy base; Straight chain, side chain or cyclic (C
1-C
6) alkyl, azepine alkyl, oxa alkyl chain, it is randomly replaced by following radicals: hydroxyl, sulfydryl, amino, cyano group, nitro, oxo, trihalogenmethyl, three halogen methoxyl groups, carbamyl, sulfamyl, straight chain, side chain or cyclic (C
1-C
6) alkyl, hydroxyalkyl, aminoalkyl group, mercaptoalkyl, alkoxyl group, alkylthio, alkyl-carbonyl, alkoxy carbonyl, alkyl-carbonyl-amino, list-or two-straight chain, side chain or cyclic (C
1-C
6) alkyl amino-carbonyl, list-or two-(C
5-C
10) aryl-or heteroaryl amino carbonyl, (C
5-C
10) aryl-or heteroarylsulfonyl amino, (C
1-C
3) alkyl sulfonyl-amino, (C
5-C
10) aryl-or heteroarylsulfonyl, (C
1-C
3) alkyl sulphonyl, list-or two-(C
5-C
10) aryl-or heteroaryl sulfamyl, list-or two-(C
1-C
3) alkylsulfamoyl group, list-or two-straight chain, side chain or cyclic (C
1-C
6) alkylamino;
Randomly be independently selected from the following straight chain, side chain or the cyclic (C that are connecting 5 to 10 yuan of aryl or heteroaryl groups that group replaced by one or more
1-C
6) alkyl, azepine alkyl, oxa alkyl chain: hydroxyl, sulfydryl, amino, cyano group, nitro, trihalogenmethyl, three halogen methoxyl groups, straight chain, side chain or cyclic (C
1-C
6) alkyl, hydroxyalkyl, aminoalkyl group, mercaptoalkyl, alkoxyl group, alkylthio, alkyl-carbonyl, alkoxy carbonyl, alkyl-carbonyl-amino, list-or two-, straight chain, side chain or cyclic (C
1-C
6) alkylamino, straight chain, side chain or cyclic (C
1-C
6) alkoxyl group-(C
1-C
6) alkyl, list-or two-(C
1-C
6) alkylamino-(C
1-C
6) alkyl or (C
1-C
6) alkylthio-(C
1-C
6) alkyl, carbamyl, (C
5-C
10) aryl-or heteroarylsulfonyl amino, (C
1-C
3) alkyl sulfonyl-amino, list-or two-(C
5-C
10) aryl-or heteroaryl sulfamyl, (C
1-C
3) alkylsulfamoyl group, sulfamyl, list-or two-straight chain, side chain or cyclic (C
1-C
6) alkyl amino-carbonyl, list-or two-(C
5-C
10) aryl-or the heteroaryl amino carbonyl;
Randomly be independently selected from following 5 to 10 yuan of aromatic rings or hetero-aromatic rings that group replaced: hydroxyl by one or more; Halogen; Sulfydryl; Amino; Cyano group; Nitro; Trihalogenmethyl; Three halogen methoxyl groups; Straight chain, side chain or cyclic (C
1-C
6) alkyl, hydroxyalkyl, aminoalkyl group, mercaptoalkyl, alkoxyl group, alkylthio, alkyl-carbonyl-, alkoxy carbonyl, alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
6) alkylamino; Straight chain, side chain or cyclic (C
1-C
6) alkoxyl group-(C
1-C
6) alkyl, single-or two-(C
1-C
6) alkylamino-(C
1-C
6) alkyl, or (C
1-C
6) alkylthio-(C
1-C
6) alkyl; Carbamyl; (C
5-C
10) aryl-or heteroarylsulfonyl amino; (C
1-C
3) alkyl sulfonyl-amino; Single-or two-(C
5-C
10) aryl-or the heteroaryl sulfamyl; Single-or two-(C
1-C
3) alkylsulfamoyl group; Sulfamyl; Single-or two-(C
5-C
10) aryl-or the heteroaryl amino carbonyl; Single-or two-, straight chain, side chain or cyclic (C
1-C
6) alkyl amino-carbonyl;
-Y-Q-is-C (=O) NH-Q-or-NH-C (=O)-NH-Q;
Q is 5 to 10 yuan of aromatic rings or hetero-aromatic rings;
R represents 5 to 10 yuan of aromatic rings or hetero-aromatic rings, and it randomly is independently selected from following group and replaces by one or more: halogen; Hydroxyl; Sulfydryl; Cyano group; Nitro; Amino; Straight chain, side chain or cyclic (C
1-C
6) alkyl, three alkylhalide groups, alkoxyl group or alkyl-carbonyl; Straight chain, side chain or cyclic (C
1-C
6) alkyl-carbonyl-amino, single-or two-(C
5-C
10) aryl-or the heteroaryl amino carbonyl; Single-or two, straight chain, side chain or cyclic (C
1-C
6) alkyl amino-carbonyl; Carbamyl; Straight chain, side chain or cyclic (C
1-C
6) alkyl sulfonyl-amino; Straight chain, side chain or cyclic (C
1-C
6) alkyl sulphonyl; Single-or two-(C
5-C
10) aryl-or the heteroaryl sulfamyl; Single-or two-straight chain, side chain or cyclic (C
1-C
6) alkylsulfamoyl group; Straight chain, side chain or cyclic (C
1-C
6) alkoxyl group-(C
1-C
6) alkyl, single-or two-(C
1-C
6) alkylamino-(C
1-C
6) alkyl, (C
1-C
6) alkylthio-(C
1-C
6) alkyl;
When j=2, R ' represents halogen independently of one another; Hydroxyl; Sulfydryl; Cyano group; Nitro; Trihalogenmethyl; Three halogen methoxyl groups; Straight chain, side chain or cyclic (C
1-C
6) alkyl, three alkylhalide groups, alkoxyl group, hydroxyalkyl, mercaptoalkyl, alkoxy carbonyl, alkyl-carbonyl, alkyl sulphonyl; Straight chain, side chain or cyclic (C
1-C
6) alkyl-carbonyl-amino; Single-or two, straight chain, side chain or cyclic (C
1-C
6) alkyl amino-carbonyl; Carbamyl; Straight chain, side chain or cyclic (C
1-C
6) alkylsulfamoyl group; Straight chain, side chain or cyclic (C
1-C
6) alkoxyl group-(C
1-C
6) alkyl, single-or two-(C
1-C
6) alkylamino-(C
1-C
6) alkyl, (C
1-C
6) alkylthio-(C
1-C
6) alkyl.
Condition be when k be 0 and the summation of w and h when being 4, T ' is a sulfydryl; Amino; Three alkylhalide groups; Hydroxyalkyl; (C
1-C
6) aminoalkyl group; Mercaptoalkyl; Alkylthio; Alkoxy carbonyl; Alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
6) alkylamino; Straight chain, side chain or cyclic (C
1-C
6) alkoxyl group-(C
1-C
6) alkyl, single-or two-(C
1-C
6) alkylamino-(C
1-C
6) alkyl, or (C
1-C
6) alkylthio-(C
1-C
6) alkyl; Single-or two-(C
1-C
3) alkyl amino sulfonyl, or j ≠ 0; And when j is 0 and the summation of w, h and k when being 4, K1 and K2 not all are hydrogen;
And get rid of following compound:
1-[4-(2-amino-thiazolyl--5-yl)-phenyl]-3-(3-imidazoles-1-base-propyl group)-urea; 1-(biphenyl-4-yl)-3-(5-(spiral shell (indane-1,4 '-piperidines-10-yl)-amyl group)-urea; 1-(biphenyl-4-yl)-3-(4-(spiral shell (indane-1,4 '-piperidines-10-yl)-butyl)-urea; 3-{4-[3-(3-morpholine-4-base-propyl group)-urea groups]-phenyl }-1H-indazole-5-benzoic acid amides; 3-{4-[3-(3-piperidines-1-base-propyl group)-urea groups]-phenyl }-1H-indazole-5-benzoic acid amides; 1-[4-(8-methylamino-imidazo [1,2-a] pyrazine-3-yl)-phenyl]-3-(3-morpholine-4-base-propyl group)-urea;
1-[4-(8-cyclopropyl amino-imidazo [1,2-a] pyrazine-3-yl)-phenyl]-3-(3-tetramethyleneimine-1-base-propyl group)-urea; 1-(2-hydroxyl-3-morpholine-4-base-propyl group)-3-[4-(8-methylamino-imidazo [1,2-a] pyrazine-3-yl)-phenyl]-urea; 1-[4-(8-cyclopropyl amino-imidazo [1,2-a] pyrazine-3-yl)-phenyl]-3-(3-morpholine-4-base-propyl group)-urea; 1-[4-(8-methylamino-imidazo [1,2-a] pyrazine-3-yl)-phenyl]-3-(3-tetramethyleneimine-1-base-propyl group)-urea; N-biphenyl-4-base-4-piperazine-1-base-butyramide.
2. compound as claimed in claim 1, wherein:
W, h, k, K1, K2, j, p, q, q ' and Y according to claim 1,
X is
Z is selected from CH
2, N, O;
When p greater than 1 the time, T ' is representation hydroxy independently of one another; Amino; Cyano group; Nitro; Straight chain, side chain or cyclic (C
1-C
6) alkyl, three alkylhalide groups, hydroxyalkyl, aminoalkyl group, mercaptoalkyl, alkoxyl group, alkylthio, alkyl-carbonyl, alkoxy carbonyl, alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
6) alkylamino; Straight chain, side chain or cyclic (C
1-C
6) alkoxyl group-(C
1-C
6) alkyl, list-or two-(C
1-C
6) alkylamino-(C
1-C
6) alkyl or (C
1-C
6) alkylthio-(C
1-C
6) alkyl; (C
1-C
3) alkyl sulfonyl-amino; Single-or two-(C
1-C
3) alkyl amino sulfonyl; Sulfamyl; Straight chain, side chain or cyclic (C
1-C
6) alkyl amino-carbonyl; Carbamyl; Perhaps when p was 2 or 3, two T ' substituting groups formed 5 to 8 yuan of volutions or condensed ring;
U and U ' represent hydrogen independently of one another; Straight chain, side chain or cyclic (C
1-C
6) alkyl, azepine alkyl, oxa alkyl chain, it is randomly by hydroxyl, oxo, trihalogenmethyl, three halogen methoxyl groups, carbamyl, sulfamyl, pyridyl, straight chain, side chain or cyclic (C
1-C
3) alkyl-carbonyl, alkoxy carbonyl, alkyl-carbonyl-amino, list-or two-, straight chain, side chain or cyclic (C
1-C
3) alkyl amino-carbonyl, (C
1-C
3) alkyl sulfonyl-amino, (C
1-C
3) alkyl sulphonyl, list-or two-(C
1-C
3) alkylsulfamoyl group, list-or two-straight chain, side chain or cyclic (C
1-C
6) alkylamino;
Q is 6 to 10 yuan of aromatic rings or hetero-aromatic rings;
R represents 5 to 10 yuan of aromatic rings or hetero-aromatic rings, and it randomly is independently selected from following group and replaces by one or more: halogen; Hydroxyl; Sulfydryl; Cyano group; Nitro; Amino; Straight chain, side chain or cyclic (C
1-C
6) alkyl, three alkylhalide groups, alkoxyl group or alkyl-carbonyl; Straight chain, side chain or cyclic (C
1-C
6) alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
6) alkyl amino-carbonyl; Carbamyl; Straight chain, side chain or cyclic (C
1-C
6) alkyl sulfonyl-amino; Straight chain, side chain or cyclic (C
1-C
6) alkyl sulphonyl; Single-or two-straight chain, side chain or cyclic (C
1-C
6) alkylsulfamoyl group; Straight chain, side chain or cyclic (C
1-C
6) alkoxyl group-(C
1-C
6) alkyl, list-or two-(C
1-C
6) alkylamino-(C
1-C
6) alkyl;
When j=2, R ' represents halogen independently of one another; Hydroxyl; Trihalogenmethyl; Three halogen methoxyl groups; Straight chain, side chain or cyclic (C
1-C
3) alkyl, three alkylhalide groups, alkoxyl group, hydroxyalkyl, alkoxy carbonyl, alkyl-carbonyl, alkyl sulphonyl; Straight chain, side chain or cyclic (C
1-C
3) alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
3) alkyl amino-carbonyl; Carbamyl; (C
1-C
3) alkyl sulfonyl-amino; Straight chain, side chain or cyclic (C
1-C
3) alkylsulfamoyl group; Straight chain, side chain or cyclic (C
1-C
3) alkoxyl group-(C
1-C
3) alkyl, list-or two-(C
1-C
3) alkylamino-(C
1-C
3) alkyl, (C
1-C
3) alkylthio-(C
1-C
3) alkyl;
3. compound as claimed in claim 2, wherein:
K1, K2, j, p, q, q ', T ', U, U ', Q, R, R ' and Y such as claim 2 definition,
W, h and k are 0,1,2 or 3 independently of one another, and condition is w+h+k=4;
X is
Z is selected from CH
2, N, O.
4. compound as claimed in claim 3, wherein:
H, w, Q and Y such as claim 3 definition
K is 0
X is the group of following formula:
U and U ' represent hydrogen independently of one another; Straight chain, side chain or cyclic (C
1-C
6) alkyl, azepine alkyl, oxa alkyl chain, it is randomly replaced by trihalogenmethyl, three halogen methoxyl groups, carbamyl, sulfamyl, pyridyl;
J is 0 or 1;
R represents 5 to 10 yuan of aromatic rings or hetero-aromatic rings, and it randomly is independently selected from following group and replaces by one or more: halogen; Hydroxyl; Straight chain, side chain or cyclic (C
1-C
6) alkyl, three alkylhalide groups, alkoxyl group; Straight chain, side chain or cyclic (C
1-C
3) alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
3) alkyl amino-carbonyl; Carbamyl;
R ' represents halogen; Trihalogenmethyl; Three halogen methoxyl groups; Straight chain, side chain or cyclic (C
1-C
3) alkyl, alkoxyl group.
5. compound as claimed in claim 3, wherein:
J, q, q ', Q and Y such as claim 3 definition;
K1 and K2 represent hydrogen independently of one another; Halogen; (C
1-C
3) alkyl, alkoxyl group;
X is the group of following formula:
Z is CH
2, N, O;
P is 0 or 1;
T ' represents straight chain, side chain or cyclic (C
1-C
3) alkyl, three alkylhalide groups, alkyl-carbonyl, alkoxy carbonyl, alkyl-carbonyl-amino; Straight chain, side chain or cyclic (C
1-C
3) alkyl amino-carbonyl; Carbamyl;
R represents 5 to 10 yuan of aromatic rings or hetero-aromatic rings, and it randomly is independently selected from following group and replaces by one or more: halogen; Hydroxyl; Straight chain, side chain or cyclic (C
1-C
3) alkyl, three alkylhalide groups, alkoxyl group or alkyl-carbonyl; Straight chain, side chain or cyclic (C
1-C
3) alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
3) alkyl amino-carbonyl; Carbamyl; Straight chain, side chain or cyclic (C
1-C
3) alkyl sulfonyl-amino; Straight chain, side chain or cyclic (C
1-C
6) alkyl sulphonyl; Single-or two-straight chain, side chain or cyclic (C
1-C
6) alkylsulfamoyl group; Straight chain, side chain or cyclic (C
1-C
6) alkoxyl group-(C
1-C
6) alkyl, list-or two-(C
1-C
6) alkylamino-(C
1-C
6) alkyl;
When j=2, R ' represents halogen independently of one another; Hydroxyl; Trihalogenmethyl; Three halogen methoxyl groups; Straight chain, side chain or cyclic (C
1-C
3) alkyl, three alkylhalide groups, alkoxyl group; Straight chain, side chain or cyclic (C
1-C
3) alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
3) alkyl amino-carbonyl; Carbamyl; (C
1-C
3) alkyl sulfonyl-amino; Straight chain, side chain or cyclic (C
1-C
3) alkylsulfamoyl group; Straight chain, side chain or cyclic (C
1-C
3) alkoxyl group-(C
1-C
3) alkyl, single-or two-(C
1-C
3) alkylamino-(C
1-C
3) alkyl, (C
1-C
3) alkylthio-(C
1-C
3) alkyl.
6. compound as claimed in claim 5, wherein:
J, Q and Y such as claim 5 definition;
K1 and K2 represent hydrogen independently of one another; Halogen; (C
1-C
3) alkyl;
X is the group of following formula:
Z is CH
2, N;
Q and q ' are 1 to 3 integer independently of one another;
T ' represents straight chain, side chain or cyclic (C
1-C
3) alkyl, alkyl-carbonyl;
R represents 5 to 10 yuan of aromatic rings or hetero-aromatic rings, and it randomly is independently selected from following group and replaces by one or more: halogen; Straight chain, side chain or cyclic (C
1-C
3) alkyl, three alkylhalide groups, alkoxyl group; Straight chain, side chain or cyclic (C
1-C
3) alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
3) alkyl amino-carbonyl; Carbamyl;
When j=2, R ' represents halogen independently of one another; Trihalogenmethyl; Straight chain, side chain or cyclic (C
1-C
3) alkyl, alkoxyl group.
7. compound as claimed in claim 6, wherein:
Q, j and R such as claim 6 definition
Y is-C (=O) NH-.
8. compound as claimed in claim 7, wherein:
Q is phenyl or pyridyl ring;
J is 1 or 2;
R represents phenyl, pyridyl, pyrazoles basic ring, and it randomly is independently selected from following group and replaces by one or more: halogen; Straight chain, side chain or cyclic (C
1-C
3) alkyl, three alkylhalide groups, alkoxyl group; Straight chain, side chain or cyclic (C
1-C
3) alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
3) alkyl amino-carbonyl; Carbamyl.
9. compound as claimed in claim 6, wherein:
Q and R such as claim 6 definition
Y is-NH-C (=O)-NH-.
10. compound as claimed in claim 9, wherein:
Q is phenyl or pyridyl;
R represents phenyl, pyridyl or pyrazoles ring, and it randomly is independently selected from following group and replaces by one or more: halogen; Straight chain, side chain or cyclic (C
1-C
3) alkyl, three alkylhalide groups, alkoxyl group; Straight chain, side chain or cyclic (C
1-C
3) alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
3) alkyl amino-carbonyl; Carbamyl.
11. compound as claimed in claim 2, wherein:
J, T ', q, q ', p, R, R ', Q and Y such as claim 2 definition;
W, h and k are 0,1,2 or 3 independently of one another, and condition is w+h+k=3
X is
12. compound as claimed in claim 11, wherein:
W, h, k, j, p and Q such as claim 11 definition;
Q and q ' are 1 to 3 integer independently of one another;
As p〉1 the time, T ' is representation hydroxy independently of one another; Cyano group; Oxo; Straight chain, side chain or cyclic (C
1-C
6) alkyl, three alkylhalide groups, hydroxyalkyl, alkoxyl group, alkyl-carbonyl, alkoxy carbonyl, alkyl-carbonyl-amino; Straight chain, side chain or cyclic (C
1-C
6) alkoxyl group-(C
1-C
6) alkyl; (C
1-C
3) alkyl sulfonyl-amino; Single-or two-(C
1-C
3) alkyl amino sulfonyl; Sulfamyl; Straight chain, side chain or cyclic (C
1-C
6) alkyl amino-carbonyl; Carbamyl; Straight chain, side chain or cyclic (C
1-C
3) alkoxyl group-(C
1-C
3) alkyl; (C
1-C
3) alkyl sulfonyl-amino; Single-or two-(C
1-C
3) alkylsulfamoyl group; (C
1-C
3) alkylsulfonyl;
-Y-is-NH-C (=O)-NH-;
R represents 5 to 6 yuan of aromatic rings or hetero-aromatic rings, and it randomly is independently selected from following group and replaces by one or more: halogen; Hydroxyl; Cyano group; Straight chain, side chain or cyclic (C
1-C
3) alkyl, three alkylhalide groups, alkoxyl group; Straight chain, side chain or cyclic (C
1-C
3) alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
3) alkyl amino-carbonyl; Carbamyl; Straight chain, side chain or cyclic (C
1-C
3) alkyl sulfonyl-amino; Straight chain, side chain or cyclic (C
1-C
3) alkyl sulphonyl; Single-or two-straight chain, side chain or cyclic (C
1-C
3) alkylsulfamoyl group; Straight chain, side chain or cyclic (C
1-C
3) alkoxyl group-(C
1-C
3) alkyl;
When j=2, R ' represents halogen independently of one another; Trihalogenmethyl; Three halogen methoxyl groups; Straight chain, side chain or cyclic (C
1-C
3) alkyl, alkoxyl group;
13. compound as claimed in claim 12, wherein:
K is 0
P is 0 or 1;
When p greater than 1 the time, T ' represents straight chain, side chain or cyclic (C independently of one another
1-C
3) alkyl, alkyl-carbonyl, alkoxy carbonyl, alkyl-carbonyl-amino; Straight chain, side chain or cyclic (C
1-C
3) alkyl amino-carbonyl; Carbamyl;
Q is phenyl or pyridyl;
J is 0 or 1;
R represents phenyl or pyridyl ring, and it randomly is independently selected from following group and replaces by one or more: halogen; Hydroxyl; Straight chain, side chain or cyclic (C
1-C
6) alkyl, alkoxyl group; Straight chain, side chain or cyclic (C
1-C
3) alkyl-carbonyl-amino; Single-or two-, straight chain, side chain or cyclic (C
1-C
3) alkyl amino-carbonyl; Carbamyl;
R ' represents halogen.
14. comprise pharmaceutical composition as the described compound of claim 1-13 and pharmaceutically useful carrier or vehicle.
15. as the purposes of the described compound of claim 1-13 in the medicine of preparation treatment nervous system disease, mental disorder, cognitive disorder, immunological disease and inflammatory diseases.
16. purposes as claimed in claim 15, it is used for the treatment of neurodegenerative disease, particularly alzheimer's disease.
17. treatment or prevention relate to disease, illness or the handicapped method of α 7 nAChR, this method comprise to its individuality of needs use significant quantity as the described compound of claim 1-13.
18. method as claimed in claim 17, it is used for prevention or treatment mental disorder or neurodegenerative disease, particularly senile dementia, attention deficit disorder, alzheimer's disease and schizophrenia.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US74314106P | 2006-01-18 | 2006-01-18 | |
| US60/743,141 | 2006-01-18 | ||
| US60/743,144 | 2006-01-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101374810A true CN101374810A (en) | 2009-02-25 |
Family
ID=40448285
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800032922A Pending CN101374810A (en) | 2006-01-18 | 2007-01-17 | Modulators of alpha7 nicotinic acetylcholine receptors and therapeutic uses thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101374810A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102639530A (en) * | 2009-11-27 | 2012-08-15 | 詹森药业有限公司 | Morpholinothiazoles as alpha 7 positive allosteric modulators |
| CN103288684A (en) * | 2013-05-03 | 2013-09-11 | 西安交通大学 | Biphenyl carbamide compound with antineoplastic activity and preparation method thereof |
| CN104837820A (en) * | 2012-10-02 | 2015-08-12 | 大日本住友制药株式会社 | Imidazole derivative |
| CN105360131A (en) * | 2010-11-03 | 2016-03-02 | 陶氏益农公司 | Pesticidal Compositions and Processes Related Thereto |
| CN105384692A (en) * | 2015-10-26 | 2016-03-09 | 深圳大学 | Glutaminyl cyclase inhibitor |
| CN111205236A (en) * | 2020-02-10 | 2020-05-29 | 贵州医科大学 | Naphthalene ring-isoxazole type compound and preparation method and application thereof |
| CN111233766A (en) * | 2020-02-10 | 2020-06-05 | 贵州医科大学 | Naphthalene ring-pyrazole compound and preparation method and application thereof |
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2007
- 2007-01-17 CN CNA2007800032922A patent/CN101374810A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102639530A (en) * | 2009-11-27 | 2012-08-15 | 詹森药业有限公司 | Morpholinothiazoles as alpha 7 positive allosteric modulators |
| CN102639530B (en) * | 2009-11-27 | 2014-08-06 | 詹森药业有限公司 | Morpholinothiazoles as alpha 7 positive allosteric modulators |
| CN105360131A (en) * | 2010-11-03 | 2016-03-02 | 陶氏益农公司 | Pesticidal Compositions and Processes Related Thereto |
| CN104837820A (en) * | 2012-10-02 | 2015-08-12 | 大日本住友制药株式会社 | Imidazole derivative |
| CN103288684A (en) * | 2013-05-03 | 2013-09-11 | 西安交通大学 | Biphenyl carbamide compound with antineoplastic activity and preparation method thereof |
| CN105384692A (en) * | 2015-10-26 | 2016-03-09 | 深圳大学 | Glutaminyl cyclase inhibitor |
| CN111205236A (en) * | 2020-02-10 | 2020-05-29 | 贵州医科大学 | Naphthalene ring-isoxazole type compound and preparation method and application thereof |
| CN111233766A (en) * | 2020-02-10 | 2020-06-05 | 贵州医科大学 | Naphthalene ring-pyrazole compound and preparation method and application thereof |
| CN111233766B (en) * | 2020-02-10 | 2022-07-01 | 贵州医科大学 | Naphthalene ring-pyrazole compound and preparation method and application thereof |
| CN111205236B (en) * | 2020-02-10 | 2022-07-01 | 贵州医科大学 | Naphthalene ring-isoxazole type compound and preparation method and application thereof |
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