CN101155817A - Dihydroimidazothiazole derivatives - Google Patents

Dihydroimidazothiazole derivatives Download PDF

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Publication number
CN101155817A
CN101155817A CNA2006800113959A CN200680011395A CN101155817A CN 101155817 A CN101155817 A CN 101155817A CN A2006800113959 A CNA2006800113959 A CN A2006800113959A CN 200680011395 A CN200680011395 A CN 200680011395A CN 101155817 A CN101155817 A CN 101155817A
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glyoxalidine
thiazole
phenyl
compound
hydroxyl
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O·巴尔巴
G·J·道森
T·M·克鲁勒
R·J·罗利
D·史密斯
G·H·托马斯
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Prosidion Ltd
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Abstract

Compounds of formula (I) or pharmaceutically acceptable salts thereof, exhibit 5-HT1A agonism in addition to noradrenaline reuptake inhibition and optionally also 5-HT reuptake inhibition are useful for the treatment of obesity.

Description

Glyoxalidine and thiazole derivative
Technical field
The present invention relates to show 5-HT 1AAgonism and norepinephrine reuptake restraining effect and glyoxalidine [2,1-b] thiazole derivative also of 5-HT reuptake inhibition randomly, it can for example be used for the treatment of obesity as the conditioning agent of ingesting and/or satiate.
Background technology
Fat excessive with respect to body size with the quality of fatty tissue is feature.Clinically, body lipid amount is by body-mass index (BMI, weight (kg)/height (m) 2) or waistline assess.When BMI individuality greater than 30 time is considered to fat, and has definite overweight medical consequences that is derived from.The weight increase that weight increase is especially caused by belly body fat with suffer from diabetes, hypertension, heart trouble and multiple other health complications for example sacroiliitis, apoplexy, gallbladder disease, muscle and breathing problem, backache and even the risk of some tumour increase relevantly, this has become generally acknowledged medical science viewpoint for a long period.
The balance that the fat pharmacological method of treatment relates generally to by changing between energy intake and the consumption reduces fat mass.Big quantity research has clearly been determined fat and has been related to having between the gyrus road of regulating homeostasis energy and get in touch.Direct and indirect evidence shows that serotonin passage, dopaminergic passage, adrenergic passage, cholinergic passage, interior cannaboid (endocannabinoid) passage, opium passage and histamine passage and numerous neuropeptide passage (as neuropeptide tyrosine and melanocortin (nelanocortins)) are relevant with the maincenter control of energy intake and consumption.Hypothalamic cells can also perception peripheral hormone such as Regular Insulin and the leptin (leptin) relevant with keeping body weight and bluntness, and the peptide that is derived from fatty tissue.
There are many potential side effects and in Most patients, can not fully solve the problem of dyslipidaemia and hyperglycemia at the medicine of the physiopathology relevant with insulin-dependent type i diabetes and non-insulin-dependent type ii diabetes.Utilize the methods of treatment of diet, exercise, hypoglycemic drug and Regular Insulin to concentrate on the needs of individual patient usually, but need novel antidiabetic medicine always, especially those can tolerate and have the antidiabetic thing of still less side effect preferably.
Similarly, comprise that with hypertension and relevant pathology thereof atherosclerosis, lipidemia, hyperlipidemia and hypercholesterolemia are that the metabolism syndrome (syndrome X) of feature is considered to can cause the susceptibility of the unusual Regular Insulin of glucose level to reduce relevant when being stimulated.It is to cross with untreated or the relevant morbid state of metabolism syndrome of control not yet in effect that myocardial ischemia and microvascular disease are confirmed to be.
It is believed that (compounds of SNRI ' s) can reduce ingestion of food and energization consumption by enhancing maincenter 5-HT and norepinephrine (NA) function to be known as serotonin/NRI.Sibutramine (1-(4-chloro-phenyl-)-N, (+) and (-) enantiomer of N-dimethyl-α-(2-methyl-propyl) tetramethylene methylamine) is a member in this compounds, thereby proved that it is by strengthening the nature satiety and descending by stimulating living hot energization consumption can obtain persistent dose-dependently weight in the obese patient.The common adverse effect relevant with sibutramine-treated comprises headache, dry, constipation and mistake eye.Yet it is also relevant with the dosage correlation increase of heart rate and blood pressure, and this has limited attainable body weight reduction, and is taboo in the patient that the cardiovascular diseases history is arranged.
Compare with independent SNRI, have 5-HT 1AThe SNRI of agonist activity is considered to by postsynaptic 5-HT 1AThe activation of acceptor has reduced that sympathetic nerve drives and cardiovascular performance (van den Buuse, M.﹠amp with improvement; Wegener, N., 2005, Eur.J.Pharmacol., Vol.507(1-3)PP187-98；Chamienia，A.L.&Johns，E.J.1996.Brit.J.Pharmacol.，Vol.118(8)PP?1891-1898)。By through 5-HT 1AThe 5-HT neurone that autoreceptor activation reduces in kind of the ridge (raphe) triggers, remove the tetanic property of the active 5-HT of norepinephrine inhibition (tonic inhibition) in the decerebration (
Figure A20068001139500121
J-C, de Montigny, C, Blier, P.﹠amp; DeBonnel, G.1999; Synapse, Vol.32, PP 198-211; Haddjeri, N., de Montigny, C.﹠amp; Blier, Brit.J.Pharmacol. P.1997, Vol.120, PP865-875), 5-HT 1AAgonist has also strengthened norepinephrine neuron activity (Szabo, the S.T.﹠amp in the nucleus ceruleus; Blier, P., 2001; Eur.J.Neuroscience, Vol.13, PP2077-2087).It is confirmed that, repeating to give 5-HT 1AAfter the agonist, postsynaptic 5-HT 1AAcceptor is downward modulation not obviously, and this shows long-term treatment effect can not descend (Anxiety and theSerotoninlA Receptor, Jeremy D.Coplan, Susan I.WoIk and Donald F.Klein; Mochizuki, D., Hokonohara, T., Kawasaki, K. ， ﹠amp; Miki, N.2002.J.PsychopharmacoL, Vol.16 (3) PP 253-260).
WO97/02269 and WO00/71549 disclose the Condesned thiazole derivatives with 5-HT receptor affinity.
WO98/41528 discloses and has shown the compound that monoamine-reuptake suppresses.
WO02/26747 discloses and has been used for the treatment of the fat dual 5-HT that has 1AAgonist/monoamine-reuptake suppresses active compound.
WO01/62341 discloses a kind of fat method for the treatment of, and comprises giving monoamine re-uptake inhibitor and 5-HT 1AAgonist.
WO01/68653 discloses the 5-HT that has that is used for the treatment of dysthymia disorders, obesity and other illnesss 1AAgonist/monoamine-reuptake suppresses also [2,1-b] thiazole and dihydro-5H-thiazole [3,2-a] pyrimidine also of active glyoxalidine.
People such as Sharpe, J.Med.Chem., 1971,14 (10), 977 disclose phenacyl (phenacyl) thiocarbamoyl imidazole quinoline and the 3-aryl-5 with antidepressant activity, the 6-glyoxalidine is [2,1-b] thiazole also, comprises compound 3-naphthalene-1-base-5,6-glyoxalidine also [2,1-b] thiazole hydrobromide salt and 3-naphthalene-2-base-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also.There is not to disclose or point out the mechanism of action of these compounds.
USSR patent application No.910637 discloses the 3-(3-chloro-4-propoxy-phenyl)-5 with mutagenesis, and the 6-glyoxalidine is [2,1-b] thiazole and 3-(3-chloro-4-butyl oxygen base phenyl)-5 also, and the 6-glyoxalidine is [2,1-b] thiazole also.
US patent No.3,671,533 and 3,806,515 disclose 5,6-glyoxalidine also [2,1-b] thiazole derivative 3-(4-chloro-phenyl-)-2-ethyl-5, the 6-glyoxalidine is [2,1-b] thiazole and 3-(4-chloro-phenyl-)-2-methyl-5 also, 6-glyoxalidine also [2,1-b] thiazole and some 2,3,5, the 6-imidazolidine is [2,1-b] thiazole derivative also.It is said 2,3,5,6-imidazolidine also [2,1-b] thiazole derivative is preferred.It is said that these compounds have the CNS stimulating activity, and can be used as antidepressive, anoretic and diuretic(s).
US patent No.3,715,367 disclose and have had the active compound 3-(3 of antidepressive, the 4-dichlorophenyl)-5, also [2,1-b] thiazole, 3-(2-hydroxy-5-methyl base phenyl)-5 of 6-glyoxalidine, 6-glyoxalidine also [2,1-b] thiazole and 3-(4-aminophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also.
People need the fat and antidiabetic medicine of novel anti always, especially to those novel anti obesity and antidiabetic medicines that has well tolerable property and have still less side effect.
Summary of the invention
The compound of formula (I) or the acceptable salt of its pharmacology:
Figure A20068001139500141
They show 5-HT 1AAgonism and norepinephrine reuptake restraining effect and 5-HT reuptake inhibition randomly can for example be used for the treatment of obesity as the conditioning agent of ingesting and/or satiate.
Detailed Description Of The Invention
The present invention relates to the compound or the acceptable salt of its pharmacology of formula (I):
Figure A20068001139500142
(I)
Wherein
R 1The C that is hydrogen, halogen, is randomly replaced by one or more halogen atoms or hydroxyl 1-6Alkyl, the C that is randomly replaced by one or more halogen atoms or hydroxyl 3-6Cycloalkyl, the C that is randomly replaced by one or more halogen atoms or hydroxyl 1-2Alkyl C 3-6Cycloalkyl, C 1-6Alkoxy carbonyl, cyano group ,-C=N-OR 7, randomly replaced and wherein hydroxyl is not and the direct-connected C of the either carbon of two keys by one or more halogen atoms or hydroxyl 2-6Thiazolinyl, randomly replaced and wherein hydroxyl is not and the direct-connected C of the either carbon of three key by one or more halogen atoms or hydroxyl 2-6Alkynyl, (CH 2) mNR 5R 6, C 1-3Alkoxyl group, C 1-3Alkylthio, C 1-3Alkoxy C 1-3Alkyl or C 1-3Alkylthio C 1-3Alkyl;
R 2Be randomly to contain maximum 3 first bicyclic aryls of heteroatomic 8-to 10-that are selected from N and S, or phenyl, condition is R 2It or not benzo [b] thiophene;
R 2Can randomly be selected from halogen, cyano group, hydroxyl, NR 5R 6, CONR 5R 6, or COOR 7, or C 1-3Alkyl, C 2-3Thiazolinyl, C 1-3Alkynyl, C 3-6Cycloalkyl, C 1-3Alkoxyl group, C 1-3Hydroxyalkyl, C 2-3Alkoxyalkyl or C 1-3Alkyl S (O) nOne or more groups replace, arbitrary above-mentioned substituting group can randomly be replaced by one or more halogen atoms; Or work as R 2When being phenyl, two substituting groups on the phenyl can be connected to form and condense C 5-6Carbocyclic ring;
R 3And R 4Be hydrogen or C independently 1-3Alkyl;
R 5And R 6Be hydrogen or C independently 1-3Alkyl, or form 5-or 6-unit heterocyclic radical with the nitrogen that they connected;
R 7Be hydrogen or C 1-3Alkyl;
M is 1,2 or 3; And
N is 0,1 or 2;
Condition is that described compound is not:
A) 3-naphthalene-1-base-5,6-glyoxalidine be [2,1-b] thiazole hydrobromide salt also,
B) 3-naphthalene-2-base-5,6-glyoxalidine be [2,1-b] thiazole hydrobromide salt also,
C) 3-(3-chloro-4-propoxy-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
D) 3-(4-chloro-phenyl-)-2-ethyl-5, the 6-glyoxalidine is [2,1-b] thiazole also,
E) 3-(4-chloro-phenyl-)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole also,
F) 3-(3, the 4-dichlorophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
G) 3-(2-hydroxy-5-methyl base phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
H) 3-(4-aminophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
I) 3-(2-chloro-phenyl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
J) 3-(3-chloro-phenyl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
K) 3-(4-chloro-phenyl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
1) 3-(2,4 dichloro benzene base)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
M) 3-(2, the 5-dichlorophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
N) 3-(4-bromophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
O) 3-(2,4 difluorobenzene base)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
P) 3-(2-aminomethyl phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Q) 3-(3-aminomethyl phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
R) 3-(4-aminomethyl phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
S) 3-(2, the 4-3,5-dimethylphenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
T) 3-(3, the 4-3,5-dimethylphenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
U) 3-(4-cyano-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
V) 3-(4-carboxyl phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
W) 3-(2-p-methoxy-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
X) 3-(3-p-methoxy-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Y) 3-(4-p-methoxy-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Z) 3-(2-hydroxy phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Aa) 3-(3-hydroxy phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Ab) 3-(4-hydroxy phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Ac) 3-(3, the 4-dihydroxy phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Ad) 3-(2-hydroxyl-4-p-methoxy-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Ae) 3-(3-hydroxyl-4-p-methoxy-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Af) 3-(4-hydroxy 3-methoxybenzene base)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Ag) 3-(4-hydroxyl-3-chloro-phenyl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Ah) 3-(4-hydroxy-3-methyl phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also, or
Ai) 3-(3, the 4-dichlorophenyl)-2-phenyl-5, the 6-glyoxalidine is [2,1-b] thiazole also.
Compound that preferred one group of The compounds of this invention is a formula (Ia) or the acceptable salt of its pharmacology:
Figure A20068001139500171
Wherein
R 1The C that is hydrogen, halogen, is randomly replaced by one or more halogen atoms or hydroxyl 1-6Alkyl, the C that is randomly replaced by one or more halogen atoms or hydroxyl 3-6Cycloalkyl, the C that is randomly replaced by one or more halogen atoms or hydroxyl 1-2Alkyl C 3-6Cycloalkyl, C 1-6Alkoxy carbonyl, cyano group ,-C=N-OR 7, randomly replaced and wherein hydroxyl is not and the direct-connected C of the either carbon of two keys by one or more halogen atoms or hydroxyl 2-6Thiazolinyl, randomly replaced and wherein hydroxyl is not and the direct-connected C of the either carbon of three key by one or more halogen atoms or hydroxyl 2-6Alkynyl, (CH 2) mNR 5R 6, C 1-3Alkoxyl group, C 1-3Alkylthio, C 1-3Alkoxy C 1-3Alkyl or C 1-3Alkylthio C 1-3Alkyl;
R 2Be randomly to contain maximum 3 first bicyclic aryls of heteroatomic 8-to 10-that are selected from N and S, condition is R 2It or not benzo [b] thiophene;
R 2Can randomly be selected from halogen, cyano group, hydroxyl, NR 5R 6, CONR 5R 6, or COOR 7, or C 1-3Alkyl, C 1-3Alkoxyl group, C 1-3Hydroxyalkyl, C 2-3Alkoxyalkyl or C 1-3Alkyl S (O) nOne or more groups replace, arbitrary above-mentioned substituting group can randomly be replaced by one or more halogen atoms;
R 3And R 4Be hydrogen or C independently 1-3Alkyl;
R 5And R 6Be hydrogen or C independently 1-3Alkyl, or form 5-or 6-unit heterocyclic radical with the nitrogen that they connected;
R 7Be hydrogen or C 1-3Alkyl;
M is 1,2 or 3; And
N is 0,1 or 2;
Condition is that described compound is not:
A) 3-naphthalene-1-base-5,6-glyoxalidine be [2,1-b] thiazole hydrobromide salt also, or
B) 3-naphthalene-2-base-5,6-glyoxalidine be [2,1-b] thiazole hydrobromide salt also.
Another group compound that can mention is the compound or the acceptable salt of its pharmacology of formula (Ib):
Figure A20068001139500181
Wherein
R 1The C that is hydrogen, halogen, is randomly replaced by one or more halogen atoms or hydroxyl 1-6Alkyl, the C that is randomly replaced by one or more halogen atoms or hydroxyl 3-6Cycloalkyl, the C that is randomly replaced by one or more halogen atoms or hydroxyl 1-2Alkyl C 3-6Cycloalkyl, C 1-6Alkoxy carbonyl, cyano group ,-C=N-OR 7, randomly replaced and wherein hydroxyl is not and the direct-connected C of the either carbon of two keys by one or more halogen atoms or hydroxyl 2-6Thiazolinyl, randomly replaced and wherein hydroxyl is not and the direct-connected C of the either carbon of three key by one or more halogen atoms or hydroxyl 2-6Alkynyl, (CH 2) mNR 5R 6, C 1-3Alkoxyl group, C 1-3Alkylthio, C 1-3Alkoxy C 1-3Alkyl or C 1-3Alkylthio C 1-3Alkyl;
R 2Be selected from halogen, cyano group, hydroxyl, NR 5R 6, CONR 5R 6, or COOR 7, or C 1-3Alkyl, C 2-3Thiazolinyl, C 2-3Alkynyl, C 3-6Cycloalkyl, C 1-3Alkoxyl group, C 1-3Hydroxyalkyl, C 2-3Alkoxyalkyl or C 1-3Alkyl S (O) nThe phenyl that replaces of one or more groups, arbitrary above-mentioned substituting group can randomly be replaced by one or more halogen atoms;
R 3And R 4Be hydrogen or C independently 1-3Alkyl;
R 5And R 6Be hydrogen or C independently 1-3Alkyl, or form 5-or 6-unit heterocyclic radical with the nitrogen that they connected;
R 7Be hydrogen or C 1-3Alkyl;
M is 1,2 or 3; And
N is 0,1 or 2;
Condition is that described compound is not:
C) 3-(3-chloro-4-propoxy-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
D) 3-(4-chloro-phenyl-)-2-ethyl-5, the 6-glyoxalidine is [2,1-b] thiazole also,
E) 3-(4-chloro-phenyl-)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole also,
F) 3-(3, the 4-dichlorophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
G) 3-(2-hydroxy-5-methyl base phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
H) 3-(4-aminophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
I) 3-(2-chloro-phenyl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
J) 3-(3-chloro-phenyl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
K) 3-(4-chloro-phenyl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
L) 3-(2,4 dichloro benzene base)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
M) 3-(2, the 5-dichlorophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
N) 3-(4-bromophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
O) 3-(2,4 difluorobenzene base)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
P) 3-(2-aminomethyl phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Q) 3-(3-aminomethyl phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
R) 3-(4-aminomethyl phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
S) 3-(2, the 4-3,5-dimethylphenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
T) 3-(3, the 4-3,5-dimethylphenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
U) 3-(4-cyano-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
V) 3-(4-carboxyl phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
W) 3-(2-p-methoxy-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
X) 3-(3-p-methoxy-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Y) 3-(4-p-methoxy-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Z) 3-(2-hydroxy phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Aa) 3-(3-hydroxy phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Ab) 3-(4-hydroxy phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Ac) 3-(3, the 4-dihydroxy phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Ad) 3-(2-hydroxyl-4-p-methoxy-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Ae) 3-(3-hydroxyl-4-p-methoxy-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Af) 3-(4-hydroxy 3-methoxybenzene base)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Ag) 3-(4-hydroxyl-3-chloro-phenyl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Ah) 3-(4-hydroxy-3-methyl phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also, or
Ai) 3-(3, the 4-dichlorophenyl)-2-phenyl-5, the 6-glyoxalidine is [2,1-b] thiazole also.
In formula (I), (Ia) and compound (Ib):
R 1Hydrogen preferably, the randomly C that is replaced by one or more halogen atoms or hydroxyl 1-6Alkyl is randomly by the C of one or more halogen atoms or hydroxyl replacement 3-6Cycloalkyl, or randomly by the C of one or more halogen atoms or hydroxyl replacement 1-2Alkyl C 3-6Cycloalkyl.R 1Be more preferably C 1-6Alkyl, particularly methyl.
Another group particular compound that can mention is R wherein 1Not those of hydrogen.
Work as R 1Be the C that is randomly replaced by one or more halogen atoms 1-6During alkyl, it can be a fluoroalkyl.
R 2The example of 8-to the 10-unit bicyclic aryl that can represent can comprise naphthyl, naphthalene-1-base or naphthalene-2-base for example, the thienothiophene base, thieno-[2,3-b] thiophene-2-base for example, indyl, quinolyl, quinoline-2-base for example, isoquinolyl and benzisothiazole, for example benzisothiazole (benzoisothiaxol)-3-base.R 2Naphthyl, particularly naphthalene-1-base preferably.
Work as R 2Be 8-to the 10-unit bicyclic aryl that replaces for example during naphthyl, it preferably is preferably selected from halogen for example fluorine or chlorine and C 1-3Alkyl for example one or two substituting group of methyl replaces.Work as R 2When being naphthalene-1-base, it is preferably unsubstituted or at 4-, a place of 5-or 7-position or two places by halogen for example fluorine or chlorine replace.
Work as R 2When being phenyl, it preferably is substituted at 3-, 4-and/or 5-position.
Work as R 2When being phenyl, it is preferably by the C that is selected from halogen and is randomly replaced by one or more halogen atoms 1-3One or two group of alkyl replaces.
Work as R 2When being phenyl, one group of concrete The compounds of this invention can mentioning can be following compound: wherein work as R 1Be the unsubstituted C of straight chain 1-4Alkyl and R 3And R 4When being hydrogen, R 2Not by one, two or three phenyl that the fluorine or chlorine atom replaces in 3-, 4-and/or 5-position.
R 3And R 4Preferably be hydrogen or methyl, more preferably R independently 3And R 4All be hydrogen.
Formula (I), the molecular weight of compound (Ia) and (Ib) is preferably less than 800, is more preferably less than 600, is more preferably less than 500 again.
Those compounds that the particular compound of the present invention that can mention is among the embodiment to be comprised and the acceptable salt of its pharmacology.
Except as otherwise noted, when being used for herein, " alkyl " and other groups with prefix " alk ", for example thiazolinyl, alkynyl etc. all refer to be the carbochain of straight or branched or its combination.The example of alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl and the tertiary butyl, amyl group, hexyl, heptyl etc." thiazolinyl ", " alkynyl " and other similar terms comprise the carbochain that contains at least one unsaturated carbon carbon bond.
Term " fluoroalkyl " comprises the alkyl that is replaced by one or more fluorine atoms, as CH 2F, CHF 2And CF 3
Term " cycloalkyl " and " carbocylic radical " are meant and do not contain heteroatomic carbocyclic ring, and comprise the monocycle saturated carbon ring.The example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Term " halogen " comprises fluorine, chlorine, bromine and iodine atom.
Term " aryl " comprises phenyl and naphthyl, especially phenyl.
Term " heterocyclic radical " comprises 5-and the 6-unit saturated rings that contains one or two nitrogen-atoms.
The example of heterocyclic radical comprises azetidine, tetramethyleneimine, piperidines and piperazine.Heterocyclic radical also can contain other heteroatomss, for example morpholine.
Compound described herein can contain one or more asymmetric centers and therefore have enantiomer, diastereomer and optical isomer.The present invention includes all these possible enantiomers, diastereomer and racemic mixture thereof, it is pure substantially through resolved enantiomers, all possible geometrical isomer and the acceptable salt of pharmacology thereof.Following formula (I) is not presented at the stereochemistry of determining of certain position.The present invention includes all steric isomers and the acceptable salt of pharmacology thereof of formula (I).In addition, in the particular stereoisomer that obtains of the mixture of steric isomer and separation is also included within.In the building-up process of these compounds of preparation, perhaps in the process of utilizing racemization well known to those skilled in the art or epimerization, the product of these methods can be the mixture of steric isomer.
Compound of the present invention also can show steric hindrance isomery (atropisomerism), the present invention includes all steric hindrance isomer and its mixture of formula (I).
When formula (I) when there is tautomer in compound, unless indicate especially or explanation arranged in addition, the present invention includes all possible tautomer and the acceptable salt of its pharmacology with and composition thereof.
When formula (I) compound and the acceptable salt of pharmacology thereof are when existing with solvate or polymorphic forms, the present invention includes all possible solvate and polymorphic forms.The solvent types that forms solvate is not particularly limited, as long as this solvent is that pharmacology is acceptable.For example can make water, ethanol, propyl alcohol, acetone etc.
Term " the acceptable salt of pharmacology " is meant by the acceptable nontoxic alkali of pharmacology or the salt of acid preparation.When compound of the present invention was acidity, its corresponding salt can be prepared by the acceptable nontoxic alkali of pharmacology (comprising mineral alkali and organic bases) easily.Comprise aluminium salt, ammonium salt, calcium salt, copper (monovalence and divalence) salt, molysite, ferrous salt, lithium salts, magnesium salts, sylvite, sodium salt and zinc salt etc. by this mineral alkali deutero-salt.Preferred especially ammonium salt, calcium salt, magnesium salts, sylvite and sodium salt.The salt that comprises the amine that the amine of primary amine, secondary amine and tertiary amine and cyclammonium and replacement such as natural existence and synthetic replace by the acceptable organic nontoxic alkali deutero-of pharmacology salt.Can by the salifiable other drug of shape learn acceptable organic nontoxic alkali and comprise arginine, trimethyl-glycine, caffeine, choline, N ', N '-dibenzyl-ethylenediamin, diethylamine, 2-DEAE diethylaminoethanol, 2-dimethylaminoethanol, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, glycosamine, glucosamine, Histidine, Kazakhstan amine (hydrabamine), Isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, polyamines resin, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, Trometamol etc.
When compound of the present invention was alkalescence, its corresponding salt can be prepared by the acceptable non-toxic acid of pharmacology (comprising mineral acid and organic acid) easily.This acid comprises for example acetate, Phenylsulfonic acid, phenylformic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, fumaric acid, gluconic acid, L-glutamic acid, Hydrogen bromide, hydrochloric acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, methylsulfonic acid, glactaric acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, succsinic acid, sulfuric acid, tartrate, tosic acid etc.
Because formula (I) compound is intended to be used for pharmaceutical use, so they preferably adopt pure substantially form, for example at least 60% purity is more suitable for the purity at least 75%, especially at least 98% purity (% is a weight ratio).
The compound of formula (I) can be as preparing of summing up in the following route 1, wherein R 1, R 2, R 3And R 4As defined above, R xBe hydrogen or C 1-6Alkyl, and G is leavings group or hydrogen.
Route 1
Figure A20068001139500241
Can be by randomly in acid for example in the presence of acetate or the sulfuric acid, 0-200 ℃, preferably under 20-150 ℃ temperature, the compound of formula (II) is dewatered comes the compound of preparation formula (I):
Figure A20068001139500242
Can be by under 0-150 ℃ temperature, in the presence of solvent such as ethanol or acetone, preferred alcohol, acid as acetate in the presence of, preferably by under 20-120 ℃ temperature, heating, make the compound of the compound of formula (III) and formula (IV) react the compound of preparation formula (II):
Figure A20068001139500251
Wherein G is a leavings group, for example halogen such as bromine or chlorine.
Can also by 0-200 ℃, preferably under 20-120 ℃ temperature, randomly in acid for example in the presence of the acetate, randomly at solvent for example in the presence of the ethanol, the intermediate of separate type (II) not makes the compound of the compound of formula (IV) and formula (III) react the compound of preparation formula (I).
Can also be by in for example acetate and acid for example in the presence of sulfuric acid or the hydrochloric acid of solvent, randomly at second dewatering agent for example in the presence of the diacetyl oxide, under 0-200 ℃, preferred 20-150 ℃ temperature, making the compound of formula (III) and G wherein is the compound that the compound of the formula (IV) of H reacts preparation formula (I).
According to a further aspect in the invention, provide the method for a kind of preparation formula (I) compound, described method comprises the step of the compound reaction of the compound that makes formula (III) and formula (IV):
Figure A20068001139500252
R wherein 1～R 4Define suc as formula (I) is middle, and G is hydrogen or leavings group.
R wherein 1Formula (I) compound that is bromine or chlorine can be by under-50-150 ℃ temperature, randomly for example in the presence of methylene dichloride, tetrahydrofuran (THF) or the acetone, makes wherein R at solvent 1Be that for example bromine or benzyl trimethyl tetrachloro ammonium iodate react and prepare for formula (I) compound of H and halogenating agent.
R wherein 1Formula (I) compound that is ethoxy carbonyl can be by making wherein R 1Be that ethoxy carbonyl and G are that the compound of formula (IV) compound of bromine and above-mentioned formula (III) reacts and prepares.R wherein 1Be that ethoxy carbonyl and G are that formula (IV) compound of bromine can be by following halogenation method from R wherein 1The compound that is the formula V of ethoxy carbonyl prepares.R wherein 1Be that for example the compound of the formula V of ethoxy carbonyl can be by for example reacting from R wherein with diethyl carbonate in the presence of alkali such as sodium hydride for alkoxy carbonyl 1The formula V compound that is H prepares.The compound of formula (III) is normally commercially available.
Wherein G is that formula (IV) compound of halogen can be by under 0-200 ℃, at solvent for example in the presence of the tetrahydrofuran (THF), preferably by under 20-120 ℃ temperature, heating, make the compound of formula V and halogenating agent for example bromizating agent such as phenyl trimethylammonium tribromide ammonium (PTAT), sodium bromate, bromine or cupric bromide (II) reaction prepare:
Figure A20068001139500261
Selectively, wherein G is bromine and R 2Contain for example R of alkaline atom 2Formula (IV) compound that is quinoline or isoquinolyl can under 20-120 ℃ temperature, prepare the compound of formula V and the reaction of tribromide pyridine by in solvent such as acetate preferablyly.
In addition, wherein G is halogen and R 2Contain for example R of alkaline atom 2Formula (IV) compound that is quinolyl can followingly prepare preferablyly: at solvent as in as the methylene dichloride in the solvent of acetate, under 0-120 ℃ temperature, the compound of formula V and t-butyldimethylsilyl trifluoroacetate and alkali such as triethylamine are reacted, obtain the compound of formula (VI):
Figure A20068001139500271
Then under 0-200 ℃ temperature, at solvent for example in the presence of the tetrahydrofuran (THF); Preferably by under 20-120 ℃ temperature, heating, make itself and halogenating agent for example bromizating agent such as phenyl trimethylammonium tribromide ammonium (PTAT) react, use mineral acid for example the mixture of Hydrogen bromide and acetate after-78 ℃ of following acidic treatment, obtain the compound of formula (IV).
Wherein G is bromine and R 1Formula (IV) compound that is hydrogen can also be by in solvent such as tetrahydrofuran (THF), at-78 ℃ to the temperature of selected solvent boiling point, the compound of formula (VII) and methylene bromide and organolithium reagent such as lithium methide are reacted, or, to the temperature of selected solvent boiling point, prepare at-78 ℃ by using methylene bromide and alkali such as N-Lithiodiisopropylamide (LDA) in solvent such as tetrahydrofuran (THF):
R wherein xBe C 1-6Alkyl.
The compound of formula (VII) is normally commercially available.
The compound of formula V can be by at solvent for example in the presence of tetrahydrofuran (THF) or the ether, at-50 ℃ extremely under the temperature of selected solvent boiling point, make the compound of formula (VIII) and organometallic reagent for example wherein X be the formula R of halogen such as chlorine 1CH 2The reaction of the compound of MgX, then randomly acid for example in the presence of the hydrochloric acid hydrolysis intermediate inferior amine salt directly prepare:
Figure A20068001139500273
The compound of formula (VIII) can be by method known to those skilled in the art preparation or commercially available.
In addition, R wherein 1The formula V compound that is H can also be by in solvent such as tetrahydrofuran (THF) ,-50 ℃ to the temperature of selected solvent boiling point, make wherein R xBe that formula (VII) compound of hydrogen and methylene bromide and organolithium reagent such as lithium methide react and prepare.
The compound of formula V can also be by at solvent for example in the presence of tetrahydrofuran (THF) or the ether, at-50 ℃ extremely under the temperature of selected solvent boiling point, make formula (IX) compound that is commonly referred to as the Weinreb acid amides and organometallic reagent for example wherein X be the formula R of halogen such as chlorine 1CH 2The reaction of the compound of MgX, then randomly acid for example in the presence of the hydrochloric acid hydrolysis intermediate inferior amine salt prepare:
In addition, the compound of formula V also can following compound from formula (VII) (R wherein x=H) directly preparation: at first with containing N, oxalyl chloride reaction in the methylene dichloride of dinethylformamide (DMF), obtain the intermediate acyl chlorides, then at solvent for example in the presence of the tetrahydrofuran (THF), in the presence of ferric acetyl acetonade (III), again with organometallic reagent for example wherein X be the formula R of halogen such as chlorine 1CH 2The compound of MgX reacts and prepares.
The compound of formula (IX) can be by making wherein R under standard amide coupling condition well known by persons skilled in the art xBe that formula (VII) compound of hydrogen and methoxymethyl amine react and prepares.
The embodiment part is seen in being described in further detail of the preparation of formula (I) compound.
The compound of formula (I) can prepare separately or as comprising 2 at least, 5～1,000 compound for example, and more preferably the compound library of the compound of 10～100 formulas (I) prepares.Compound library can utilize method well-known to those skilled in the art, prepares by combination " division and mixing " mode or by how parallel synthetic (the multiple parallelsynthesis) that adopts solution or solid state chemistry.
In the building-up process of formula (I) compound, unstable functional group such as hydroxyl, carboxyl and amino in the midbody compound can be protected.Protecting group can be removed in arbitrary stage of synthesis type (I) compound, perhaps may reside in the final compound of formula (I).About various unstable functional groups can protected method and comprehensive argumentation of the method for the protected derivative of fracture gained for example be found in Protective Groups in Organic Chemistry; T.W.Greene and P.G.M.Wuts; (1991); Wiley-Interscience; New York, second edition.
Any new intermediate as defined above is also included within the scope of the present invention, suc as formula the compound of (II).
The intermediate that other that are included in the scope of the present invention are new is the compound of formula (X):
R wherein 2, R 3And R 4As defined above.The compound of formula (X) is to be used to prepare wherein R 1For example be cyano group or the C that replaced by hydroxyl 1-6The useful intermediates of the formula of alkyl (I) compound.
For formula (I), (Ia) and (Ib) the above-mentioned preference of compound also be applicable to any midbody compound, suc as formula (II) and (X) those.
As mentioned, the compound of formula (I) can be used as norepinephrine and serotonin reuptake inhibitor randomly, for example is used for the treatment of obesity.For this application, the compound of formula (I) adopts the form administration of pharmaceutical composition usually.
The present invention also comprises pharmaceutical composition, and described pharmaceutical composition comprises compound or the acceptable salt of its pharmacology and the pharmacology acceptable carrier of formula (I).
Preferably, described composition comprises formula (I) compound or the acceptable salt of its pharmacology of pharmacology acceptable carrier and nontoxic treatment significant quantity.
In addition, the present invention also provide can be used for by---for example cause treat fat ground---suppress norepinephrine and randomly serotonin reuptake transporter treat the pharmaceutical composition of disease, described composition comprise pharmacology acceptable carrier and nontoxic treatment significant quantity comprise restrictive clause a) and b) formula (I) compound or the acceptable salt of its pharmacology of compound.
Described pharmaceutical composition can randomly comprise other treatment composition or adjuvant.Described composition comprises the composition that is suitable for oral, rectum, part and parenteral (comprising subcutaneous, intramuscular and intravenously) administration, but under any specific situation, character and severity that only approach will depend on specific main body and give the disease that activeconstituents is used for.Described pharmaceutical composition can adopt the form of unit dosage and the method preparation of knowing by any pharmaceutical field expediently.
In the practice, can formula (I) compound or the acceptable salt of its pharmacology be mixed into closely (intimate) mixture as activeconstituents and pharmaceutical carrier according to the conventional medicine compounding process.According to the dosage form difference of required administration, as oral or parenteral (comprising intravenously), carrier can be taked multiple different form.
Therefore, described pharmaceutical composition can adopt the form of the discrete unit that is suitable for oral administration, for example the capsule of the activeconstituents of each self-contained predetermined amount, cachet or tablet.In addition, described composition can adopt the form of powder, granule, solution, suspensoid, anhydrous liq, oil-in-water emulsion or water-in-oil-type liquid emulsion in liquid, aqueous.Except the common formulation of listing above, formula (I) compound or the acceptable salt of its pharmacology also can pass through controlled release means and/or transfer device administration.Described composition can be by any method of pharmacy preparation.Usually, this method comprise with activeconstituents with constitute the contacted step of carrier that one or more must composition.Usually, by both evenly, closely mix and prepare described composition with activeconstituents and liquid vehicle or finely divided solid carrier or its.Then, product can be made required form expediently.
Formula (I) compound or the acceptable salt of its pharmacology can also together be comprised in the pharmaceutical composition with one or more other treatment active compounds.
The pharmaceutical carrier that is adopted can be for example solid, liquid or gas.The example of solid carrier comprises lactose, kaolin, sucrose, talcum, gelatin, agar, pectin, gum arabic, Magnesium Stearate and stearic acid.The example of liquid vehicle is syrup, peanut oil, sweet oil and water.The example of carrier gas comprises carbonic acid gas and nitrogen.
When the preparation oral dosage form composition, can use any drug media easily.For example, water, glycols, oil, alcohol, seasonings, sanitas, tinting material etc. can be used to form oral liquid, for example suspensoid, elixir and solution; And carrier such as starch, carbohydrate, Microcrystalline Cellulose, thinner, granulation agent, lubricant, tackiness agent, disintegrating agent etc. can be used for forming oral solid formulation, for example powder, capsule and tablet.When using solid pharmaceutical carriers, because tablet and capsule are convenient to administration, so tablet and capsule are preferred oral dosage units.Randomly, tablet can carry out dressing by the moisture or anhydrous technology of standard.
The tablet that comprises the present composition can randomly prepare by compacting or molding with one or more additional compositions or adjuvant.Compressed tablets can be by in suitable machine, and compacting randomly prepares with the free-flowing form of tackiness agent, lubricant, inert diluent, tensio-active agent or dispersant such as the activeconstituents of powder or particle form.The molding tablet can will carry out molding and prepare by in suitable machine through the mixture of the moistening powdered compounds of inert liquid diluent.Various tablets all preferably comprise the activeconstituents of about 0.05mg～about 5g, and various cachets or capsule preferably comprise the activeconstituents of about 0.05mg～about 5g.
For example, be intended to can comprise to the preparation of human oral administration the active substance of about 0.5mg～about 5g, described active substance mixes mutually with the solid support material suitable and convenient quantity that can account for total composition about 5%～about 95%.Unit dosage will comprise the activeconstituents of about 1mg～about 2g usually, be generally 25mg, 50mg,, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or 1000mg.
The pharmaceutical composition of the present invention that is suitable for administered parenterally can be prepared as the solution of active compound in water or the form of suspensoid.Can comprise suitable tensio-active agent, for example hydroxypropylcellulose.Also can in glycerine, liquid macrogol and its mixture in oil, prepare dispersion.In addition, can comprise sanitas to prevent the obnoxious growth of microorganism.
The pharmaceutical composition of the present invention that is suitable for injecting application comprises aseptic aqueous solution or dispersion.In addition, described composition can be for can be used for preparing the form of the sterilized powder of this sterile injectable solution or dispersion temporarily.In all cases, final injectable forms must be aseptic and must be that effective fluid is so that injection.Described pharmaceutical composition must be stable under production and condition of storage; Therefore, preferably should under antimicrobial condition, preserve as bacterium and fungal contamination.Carrier can be for containing for example solvent or the dispersion medium of water, ethanol, polyvalent alcohol (as glycerine, propylene glycol and liquid macrogol), vegetables oil and suitable mixture thereof.
Pharmaceutical composition of the present invention can adopt and be suitable for the local form of using, and for example is aerosol, emulsifiable paste, ointment, lotion, epipasxtic etc.In addition, described composition can adopt the form that is applicable to transdermal device.These preparations can prepare by conventional working method with formula (I) compound or the acceptable salt of its pharmacology.For example, emulsifiable paste or ointment can prepare by the compound that mixes hydrophilic material and water and about 5 weight %～10 weight %, thereby make emulsifiable paste or the ointment with required denseness (consistency).
Pharmaceutical composition of the present invention can adopt wherein, and carrier is the form that solid is suitable for rectal administration.Mixture is preferably formed unitary dose suppository.Appropriate carriers comprises other materials commonly used in theobroma oil and this area.By at first composition being mixed with carrier softening or fusing, cool off then and can form suppository easily in die for molding.
Except above-mentioned carrier components, if it is suitable, the said medicine preparation can comprise one or more other carrier components, for example thinner, buffer reagent, seasonings, tackiness agent, tensio-active agent, thickening material, lubricant, sanitas (comprising antioxidant) etc.In addition, can also comprise other adjuvants so that preparation and target recipient's blood etc. ooze.
The composition that comprises formula (I) compound or the acceptable salt of its pharmacology also can be prepared into the form of powder or liquid concentrates.
Usually, every day about 0.01mg/kg～150mg/kg body weight dosage level can be used for treating above-mentioned illness, perhaps about 0.5mg～7g/ patient/sky.For example, by with the about 0.01～50mg of per kilogram of body weight every day or every patient's every day about 0.5mg～3.5g compound administration can treat obesity effectively.
Yet, should understand for any particular patient, concrete dosage level will depend on various factors, comprise age, body weight, whole body health situation, sex, diet, administration time, route of administration, excretion rate, drug regimen and the seriousness of the specified disease of receiving treatment.
Comprise restrictive clause a), b) and f)～ai) described in formula (I) compound of compound can be used for treating norepinephrine wherein and the disease or the illness that work of serotonin reuptake transporter randomly.The 5-HT that formula (I) compound shows 1AAgonist activity refers to and treats these diseases with SNRI separately or illness is compared that this compound should provide more large effect and lower side effect.
Therefore, the present invention also provides a kind of norepinephrine wherein and the randomly disease that works of serotonin reuptake transporter or method of illness of being used for the treatment of, it comprise to the patient that these needs are arranged give significant quantity comprise restrictive clause a), b) and f)～ai) described in formula (I) compound of compound or the step of the acceptable salt of its pharmacology.
The present invention also provide a kind of be used for the treatment of wherein norepinephrine and randomly serotonin reuptake transporter work and wherein need 5-HT 1AThe disease of agonism or the method for illness, it comprise to the patient that these needs are arranged give significant quantity comprise restrictive clause a), b) and f)～ai) described in formula (I) compound of compound or the step of the acceptable salt of its pharmacology.
Wherein norepinephrine and randomly the disease or the illness that work of serotonin reuptake transporter comprise obesity.In the application's context, fat treatment for example is used to contain by reducing appetite and body weight, keep alleviating and preventing that bounce-back from treating disease or illness of weight, such as fat with too much other the relevant drinking and eating irregularly of ingestion of food.
Compound of the present invention also can be used for treating wherein, and obesity is a kind of other diseases of factor, comprise metabolic trouble, as type ii diabetes, metabolism syndrome (syndrome X), glucose tolerance reduction, dyslipidaemia, hyperlipidaemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels and hypertension.
Norepinephrine the and randomly other diseases that works of serotonin reuptake transporter or illness comprise and be documented among the WO01/68653 those wherein, for example depressed, anxiety, psychosis (for example schizophrenia), tardive dyskinesia, drug habit, drug abuse, cognitive dissonance, alzheimer's disease, obsession, panic attack, social anxiety, drinking and eating irregularly such as bulimia, appetite stimulator, snacks and gluttony (snacking and binge eating), anxiety, auxiliary agent as smoking cessation, epileptics, nervous disorder such as falling sickness and/or the illness such as the apoplexy of nerve injury are wherein arranged, cerebral trauma, cerebral ischemia, head damage and hemorrhage.Other indications comprise stress incontinence, neurodynia and the chronic pain relevant with pharmacological agent or radiotherapy.
The method that the present invention also provides a kind of adjusting to ingest and/or satiate, it comprise to the patient that these needs are arranged give significant quantity comprise restrictive clause a), b) and f)～ai) described in formula (I) compound of compound or the step of the acceptable salt of its pharmacology.
The present invention also provides a kind of fat method for the treatment of, it comprise to the patient that these needs are arranged give significant quantity comprise restrictive clause a), b) and f)～ai) described in formula (I) compound of compound or the step of the acceptable salt of its pharmacology.
The present invention also provides a kind of method that is reduced in the cardiovascular side effects possibility in treatment above-mentioned disease or the illness, it comprise to the patient that these needs are arranged give significant quantity comprise restrictive clause a), b) and f)～ai) described in formula (I) compound of compound or the step of the acceptable salt of its pharmacology.
The method that the present invention also provides a kind of treatment to be selected from type ii diabetes, metabolism syndrome (syndrome X), glucose tolerance reduction, dyslipidaemia, hyperlipidaemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels and hypertensive metabolic trouble, it comprise to the patient that these needs are arranged give significant quantity comprise restrictive clause a), b) and f)～ai) described in formula (I) compound of compound or the step of the acceptable salt of its pharmacology.
The present invention also provide comprise restrictive clause a), b) and f)～ai) described in formula (I) compound of compound or the purposes of the acceptable salt of its pharmacology in the above-mentioned illness of treatment.
The present invention also provide comprise restrictive clause a), b) and f)～ai) described in formula (I) compound of compound or the acceptable salt of its pharmacology be used for the treatment of purposes in the medicine of above-mentioned illness in preparation.
In the method for the invention, term " treatment " comprises therapeutic and prophylactic treatment.
Formula (I) compound or the acceptable salt of its pharmacology can be individually dosed or with one or more other treatment active compound Combined Preparation.Described other treatment active compound can be used for the treatment of identical disease or the illness or the different disease or the illnesss for the treatment of with formula (I) compound.The administration simultaneously of described therapeutical active compound, sequential administration or individually dosed.
The compound of formula (I) can be with other active compound administrations that are used for the treatment of obesity and/or diabetes, for example Regular Insulin and insulin analog, the gastric lipase enzyme inhibitor, pancreatic lipase inhibitor, sulfonylurea and analogue, biguanides, α 2 agonists, lattice row ketone, the PPAR-gamma agonist, rxr agonist, fatty acid oxidation inhibitors, alpha-glucosidase inhibitor, beta-2-agonists, phosphodiesterase inhibitor, fat-reducing medicament, glycogen phosphorylase inhibitors, MCH-1 antagonist and CB-1 antagonist, pancreas opsonin (amylin) antagonist, lipoxidase inhibitor, somatostatin analogue, glucokinase activators, glucagon antagonist, insulin signaling conduction agonist, the PTP1B inhibitor, the glyconeogenesis inhibitor, antilypolitic agent, the GSK inhibitor, galanin (galanin) receptor stimulant, appetite suppressant, the cck receptor agonist, leptin, serotonin energy/dopaminergic anti-obesity medicine, the CRF antagonist, CRF is conjugated protein, the Protirelin compound, aldose reductase inhibitor, glucocorticoid receptor antagonists, NHE-1 inhibitor or sorbitol dehydrogenase inhibitors.
When being used for combination therapy, if peripheral effect, the compound of formula (I) preferably gives with uniting at other non-maincenter methods of obesity, for example (GPR119 is at WO00/50562 that discloses people and rat receptor and the US 6 that also discloses the mouse acceptor with orlistat (Xenical ) or with the GPR119 agonist, be known as SNORF25 in 468,756) unite and give.
The patent that includes but not limited in this specification sheets to be quoted and all publications of patent application are all introduced herein as a reference, just introduce herein as a reference as specifically describing each publication respectively.
Describe the present invention referring now to following embodiment, these embodiment are not considered to limit the scope of the invention in order to play illustration.
Embodiment
Material and method
Except as otherwise noted, column chromatography is at SiO 2Carry out on (40-63 order).The following acquisition of LCMS data: Atlantis 3 μ C 18Post (3.0 * 30.0mm, flow velocity=0.85mL/ minute) is to contain 0.1%HCO 2The H of H 2O-CH 3CN eluant solution 6 minutes, UV detects wavelength: 220nm.Gradient information: 0.0-0.3 minute 100%H 2O; 0.3-4.25 minute: gradient is to 10%H 2O-90%CH 3CN; 4.25 minutes-4.4 minutes: gradient was to 100%CH 3CN; 4.4-4.9 minute: remain 100%CH 3CN; 4.9-5.0 minute: be back to 100%H 2O; 5.0-6.0 minute: remain on 100%H 2O.Mass spectrum is with positive ion (ES by the electro-spray ionization source +) or negative ion (ES -) the pattern acquisition.NMR spectrum be under 27 ℃, on Varian Mercury 400 spectrographs in obtaining under the 400MHz or on Bruker AMX2500 spectrograph, under 500MHz, obtaining.
Abbreviation and initial curtail word
Ac: ethanoyl; AIBN; 2,2 '-the azo-group bis-isobutyronitrile; DCM: methylene dichloride; DIPEA:N, N '-diisopropyl ethyl amine; DMF:N, dinethylformamide; DMSO: dimethyl sulfoxide (DMSO); EDCI:1-ethyl-3-(3 '-dimethylaminopropyl) carbodiimide; Et: ethyl; The HOBt:1-hydroxybenzotriazole; Me: methyl; iPr: sec.-propyl; PTAT: phenyl trimethylammonium tribromide ammonium; RT: retention time; Rt: room temperature; TFA; Trifluoroacetic acid; THF: tetrahydrofuran (THF).
Preparation example 1:2-bromo-1-naphthalene-1-base ethyl ketone
Figure A20068001139500361
(0.452g, (1.10g, 2.92mmol), reaction was at room temperature stirred 16 hours to add PTAT in THF 2.66mmol) (20mL) stirred solution to 1 '-acetonaphthone.Filter reaction mixture, (2 * 20mL) wash solid with THF.Vacuum concentrated filtrate, residue (distributes between 2 * 30mL) at water (30mL) and DCM.Merge organism, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use EtOAc: hexane (1: 9) wash-out obtains target compound, δ H(CDCl 3): 4.56 (2H, s), 7.50 (1H, m), 7.55 (1H, m), 7.63 (1H, m), 7.88 (1H, m), 7.92 (1H, m), 8.01 (1H, m), 8.63 (1H, m).
Preparation example 2:1-naphthalene-2-base third-1-ketone
Figure A20068001139500371
(3g 19.6mmol) is dissolved in Et to the 2-naphthyl cyanide 2Among the O (20mL), (2.0M is at Et to add ethylmagnesium chloride then 2Among the O, 9.8mL, 19.6mmol), reaction reflux 5 hours at room temperature stirred 16 hours then.Reaction extracts DCM (3 * 40mL) then with 2N HCl (20mL) and water (20mL) quencher.Merge organic fraction, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use EtOAc: hexane (1: 9) wash-out obtains target compound, δ H(CDCl 3): 1.30 (3H, t), 3.13 (2H, q), 7.57 (2H, m), 7.88 (2H, m), 7.96 (1H, d), 8.05 (1H, dd), 8.47 (1H, s).
Preparation example 3:2-bromo-1-naphthalene-2-base third-1-ketone
Figure A20068001139500372
(preparation example 2,3.5g 19.0mmol) are dissolved among the THF (50mL) 1-naphthalene-2-base third-1-ketone, and (7.1g, 19.0mmol), reaction was at room temperature stirred 16 hours to add PTAT then.Cross filter solid, vacuum concentrated filtrate, purifying on silica gel, use EtOAc: hexane (1: 9) wash-out obtains target compound, δ H(CDCl 3): 1.98 (3H, d), 5.47 (1H, q), 7.57 (1H, m), 7.63 (1H, m), 7.91 (2H, m), 7.99 (1H, d), 8.08 (1H, dd), 8.57 (1H, s).
Preparation example 4: thieno-[2,3-b] thiophene-2-carboxylic acid methoxymethyl acid amides
With thieno-[2,3-b] thiophene-2-carboxylic acid (1g, 5.43mmol), N, O-dimethyl hydroxyl amine hydrochlorate (0.53g, 5.43mmol) and HOBt (0.73g, 5.43mmol) be dissolved in DMF (20mL) and DIPEA (2.9mL, 16.8mmol) in.After 5 minutes, (1.35g, 7.1mmol), reaction was at room temperature stirred 24 hours to add EDCI.Solvent removed in vacuo, residue (distributes between 3 * 30mL) at water (30mL) and EtOAc.Merge organic fraction, (2 * 20mL), (2 * 20mL), salt solution (20mL) washs 1N HCl, dry (MgSO with 1N NaOH 4), vacuum concentration.Residue is chromatogram purification on silica gel, uses EtOAc: hexane (2: 3) wash-out obtains target compound, δ H(CDCl 3): 3.40 (3H, s), 3.82 (3H, s), 7.28 (1H, d), 7.39 (1H, d), 8.13 (1H, s).
Preparation example 5:1-thieno-[2,3-b] thiophene-2-base ethyl ketone
(preparation example 4,0.958g 4.21mmol) are dissolved among the THF (20mL) and are cooled to 0 ℃ with thieno-[2,3-b] thiophene-2-carboxylic acid methoxymethyl acid amides in argon gas atmosphere.(1.4M, in toluene: THF, 6.3mL 8.85mmol), is reflected at 0 ℃ and stirred 2 hours down, at room temperature stirs then 16 hours to drip methyl-magnesium-bromide.The 5%HCl quencher of reaction among the MeOH, solvent removed in vacuo then.Residue is at 10%NaHCO 3Solution (50mL) and EtOAc (distribute between 3 * 40mL).Merge organic fraction, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use EtOAc: hexane (1: 3) wash-out obtains target compound, δ H(CDCl 3): 2.60 (3H, s), 7.28 (1H, d), 7.41 (1H, d), 7.83 (1H, s).
Preparation example 6:2-bromo-1-thieno-[2,3-b] thiophene-2-base ethyl ketone
Figure A20068001139500391
With 1-thieno-[2,3-b] thiophene-2-base ethyl ketone (preparation example 5,400mg 2.2mmol) are dissolved among the THF (20mL), add then PTAT (825mg, 2.2mmol).Reaction was at room temperature stirred 16 hours, filtered the solid of separating out, with THF (2 * 20mL) washings.Vacuum concentrated filtrate, residue (distributes between 3 * 30mL) at water (30mL) and EtOAc.Merge organic fraction, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use EtOAc: hexane (1: 4) wash-out obtains target compound.δ H(CDCl 3)：4.39(2H，s)，7.32(1H，d)，7.45(1H，d)，7.96(1H，s)。
Preparation example 7:2-bromo-1-(4-methylnaphthalene-1-yl) ethyl ketone
Figure A20068001139500392
In argon gas with 4-methyl isophthalic acid-methyl phenyl ketone (0.5g, 2.7mmol) and PTAT (1.1g, anhydrous THF (20mL) mixture 3.0mmol) at room temperature stirred 3 hours.Filter reaction mixture, with the THF washing several times.Vacuum concentrated filtrate, residue (distributes between 3 * 30mL) at water (30mL) and EtOAc.Merge organic phase, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use EtOAc: hexane (1: 10) wash-out obtains target compound, δ H(CDCl 3): 2.77 (3H, s), 4.57 (2H, s), 7.37 (1H, d), 7.63 (2H, m), 7.86 (1H, d), 8.07 (1H, d), 8.71 (1H, d).
Preparation example 8: quinaldic acid's methoxymethyl acid amides
Figure A20068001139500393
To the quinaldic acid (2.5g, 14.4mmol), O, N-dimethyl-hydroxy amine hydrochloric acid salt (2.9g, 29.7mmol), EDCI (3.4g, 17.7mmol) and the HOBt monohydrate (2.25g, add in DMF 14.7mmol) (55mL) suspension DIPEA (10.5mL, 61.3mmol).The solution that obtains at room temperature stirred 12 hours, and reaction mixture is at EtOAc (100mL) and water then: distribute between the salt solution (200mL, 1: 1).Separate each layer, (3 * 50mL) extract water with EtOAc.(1M 50mL) and after salt solution (50mL) washing, merges organic extract, dry (MgSO with dilute NaOH solution 4), filter vacuum concentration.By (the eluent: EtOAc), obtain target compound, δ of purification by flash chromatography residue on silica gel H(DMSO): 3.34,3.36 (6H, 2s), 7.71 (2H, m), 7.86 (1H, m), 8.08 (2H, m), 8.52 (1H, d); M/z (ES +)=217.09[M+H] +RT=2.79 minute.
Preparation example 9:1-quinoline-2-base ethyl ketone
Figure A20068001139500401
(1.4M solution, the toluene at 3: 1: among the THF, (preparation example 8,2.0g is in THF solution 9.25mmol) 8mL) to be added to quinaldic acid's methoxymethyl acid amides with methyl-magnesium-bromide in the method A:0 ℃ of following argon gas atmosphere.After stirring 2 hours under the cooling, reaction mixture is added to dense NH 4In the Cl solution (400mL).With EtOAc (4 * 100mL) extractions, the extract of using salt solution (150mL) washing to merge then, dry (MgSO 4), vacuum concentration by purification by flash chromatography residue on silica gel (eluent, hexane: EtOAc, 2: 1), obtains target compound.
(1.6M solution, in the ether, (1.40g is in THF 8.1mmol) (40mL) solution 10mL) to be added to the quinaldic acid with lithium methide in the method B:0 ℃ of following argon gas atmosphere.After 2 hours, under vigorous stirring, add the chlorine trimethyl silane (10mL, 79mmol), after 10 minutes, add then dilute hydrochloric acid (1M, 30mL).Separate water layer, solid NaHCO is used in water (200mL) dilution 3Neutralization.Carry out processing similar and purifying, obtain target compound, δ to method A H(DMSO): 2.80 (3H, s), 7.78 (1H, m), 7.90 (1H, m), 8.07 (1H, d), 8.81 (1H, d), 8.20 (1H, d), 8.57 (1H, d); M/z (ES +)=172.10[M+H] +RT=3.34 minute.
Preparation example 10:2-[2-bromo-1-(sec.-propyl dimethylsilyl oxygen base) vinyl] quinoline
Figure A20068001139500411
(0.40mL, 2.85mmol) (0.35mL, (preparation example 9,240mg is in anhydrous DCM (10mL) solution 1.40mol) 1.52mmol) to be added to the basic ethyl ketone of 1-quinoline-2-with the tert-butyldimethylsilyl chloride thing with triethylamine in 0 ℃ of following argon gas atmosphere.After 1 hour, (535mg 1.42mmol), removes ice bath, the mixture restir that obtains 2 hours to add PTAT.At EtOAc (100mL) and rare Na 2S 2O 3Solution (10%, 50mL) and NaHCO 3Distribute between the mixture of solution (50mL), use EtOAc (3 * 50mL) further aqueous phase extracted then.After salt solution (50mL) washing, merge organic extract, dry (MgSO 4), filter vacuum concentration.By purification by flash chromatography residue on silica gel (eluent, hexane: EtOAc, 4: 1), obtain target compound, δ H(DMSO): 0.19 (6H, s), 1.01 (9H, s), 6.91 (1H, s), 7.42 (1H, m), 7.60 (1H, m), 7.63 (1H, d), 7.78 (1H, d), 7.80 (1H, d), 8.38 (1H, d); M/z (ES +)=364.09,364.09[M+H] +RT=4.95 minute.
Preparation example 11:2-bromo-1-quinoline-2-base ethyl ketone
Figure A20068001139500412
Method A: (30%, among the AcOH, (420mg, AcOH suspension (10mL) 1.31mmol) at room temperature stirred 30 minutes then 0.26mL) to handle the tribromide pyridine with Hydrogen bromide.Quinoline-(preparation example 9,200mg, solution 1.08mmol), mixture at room temperature stirred 12 hours 2-base-ethyl ketone to add 1-.Except that after desolvating, residue is at EtOAc (100mL) and dense NaHCO 3Distribute between the solution (100mL).Separate each layer, (3 * 50mL) extract water with EtOAc.With the extract that salt solution (100mL) washing merges, dry (MgSO 4), vacuum concentration is used the hexane recrystallization then, obtains target compound.
Method B: with Hydrogen bromide (30%, among the AcOH, 0.46mL) be added to-78 ℃ of 2-[2-bromo-1-(sec.-propyl dimethylsilyl oxygen base) vinyl in the following argon gas atmosphere] (preparation example 10,420mg is in THF 1.15mmol) (20mL) solution for quinoline.Remove IPA/ the dry ice bath, mixture at room temperature stirred 12 hours.Carry out processing similar and purifying, obtain target compound, δ to method A H(DMSO): 5.24 (2H, s), 7.82 (1H, m), 7.94 (1H, m), 8.14 (2H, m), 8.21 (1H, d), 8.63 (1H, d); M/z (ES +)=249.98,251.98[M+H] +RT=3.65 minute.
Preparation example 12:2-bromo-1-(4-fluoronaphthalene-1-yl) ethyl ketone
Figure A20068001139500421
With 4-fluoro-1-acetonaphthone (500mg 2.66mmol) is dissolved among the THF (20mL), add then PTAT (1.1g, 2.92mmol).Reaction was at room temperature stirred 16 hours, filtered the solid of separating out then, with THF (2 * 20mL) washings.Vacuum concentrated filtrate, chromatogram purification on silica gel, use EtOAc: hexane (1: 9) wash-out obtains target compound, δ H(CDCl 3): 4.55 (2H, s), 7.19 (1H, m), 7.64 (1H, m), 7.72 (1H, m), 7.99 (1H, m), 8.19 (1H, d), 8.79 (1H, d).
Preparation example 13:3-naphthalene-2-base-3-oxo ethyl propionate
Figure A20068001139500422
In argon gas atmosphere, with methyl betanaphthyl ketone (5g 29.4mmol) is dissolved in the diethyl carbonate (50mL), add in 10 minutes in batches sodium hydride (60%, in the mineral oil, 2.35g, 58.8mmol).Reaction mixture is heated to 100 ℃ and kept 4 hours, at room temperature stirs then 16 hours.Solvent removed in vacuo, residue AcOH (5mL) and the Et in water (200mL) 2O (distributes between 3 * 100mL).Merge organic fraction, with salt solution (50mL) washing, dry (MgSO 4), vacuum concentration.Residue is chromatogram purification on silica gel, uses EtOAc: hexane (1: 9～1: 4) wash-out obtains target compound.δ H(CDCl 3)：1.27(3H，t)，4.12(2H，s)，4.24(2H，q)，7.58(2H，m)，7.88(2H，m)，7.96(1H，d)，8.02(1H，m)，8.45(1H，s)。
Preparation example 14:2-bromo-3-naphthalene-2-base-3-oxo ethyl propionate
(preparation example 13,6.33g 26.1mmol) are dissolved among the THF (100mL) and are cooled to 0 ℃ with 3-naphthalene-2-base-3-oxo ethyl propionate.(9.82g 26.1mmol), is reflected at 0 ℃ and stirred 2 hours down, at room temperature stirs then 16 hours to add PTAT.The solid that filtration is separated out is with THF (2 * 30mL) washings.Vacuum concentrated filtrate, chromatogram purification on silica gel, use EtOAc: hexane (1: 9) wash-out obtains target compound.δ H(CDCl 3)：1.25(3H，t)，4.30(2H，q)，5.84(1H，s)，7.58(1H，m)，7.64(1H，m)，7.90(2H，m)，7.97(1H，d)，8.02(1H，dd)，8.53(1H，s)。
Preparation example 15:1-naphthalene-1-benzylacetone
Figure A20068001139500432
(4.6g 30mmol) is dissolved in Et with 1-cyano group naphthalene 2Among the O (15mL), add ethylmagnesium chloride (2.0M, Et then 2Among the O, 15mL), reaction reflux 17 hours.(mixture reheat 1 hour adds entry (20mL) then for 2N, 20mL) quencher, and separating mixture is with DCM (3 * 40mL) extractions with rare HCl in reaction.Merge organic fraction, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel is used Et 2O: isohexane (1: 19) wash-out obtains target compound.δ H(CDCl 3): 1.27 (3H, t), 3.12 (2H, q), 7.58 (3H, m), 7.90 (2H, m), 8.02 (1H, d), 8.61 (1H, d); M/z (ES +)=184.09[M+H] +RT=2.37 minute.
Preparation example 16:2-bromo-1-naphthalene-1-benzylacetone
((6.3g, 16.3mmol), reaction was at room temperature stirred 16 hours to add PTAT in THF 16.3mmol) (20mL) stirred solution for preparation example 15,3.0g to 1-naphthalene-1-benzylacetone.Filter reaction mixture, (2 * 20mL) wash solid with THF.Vacuum concentrated filtrate, residue distribute between EtOAc (50mL) and saturated sodium bicarbonate solution (50mL).Merge organism, dry (MgSO 4), vacuum concentration obtains target compound.δ H(CDCl 3)：2.0(3H，d)，5.4(1H，q)，7.60(3H，m)，7.90(2H，m)，8.06(1H，d)，8.49(1H，d)。
Preparation example 17:3-naphthalene-1-base-5,6-glyoxalidine be [2,1-b] thiazole-2-formaldehyde also
Figure A20068001139500442
In 10 minutes in batches to the ethylmagnesium chloride (2.0M, the Et that are cooled to 0 ℃ 2Among the O, 3.6mL adds 2-bromo-3-naphthalene-1-base-5 in THF 7.28mmol) (20mL) solution, the 6-glyoxalidine also [2,1-b] thiazole hydrobromide salt (embodiment 4, and 1g 2.43mmol), is reflected at 0 ℃ and stirred 2 hours down.(0.75mL 9.71mmol), is reflected at 0 ℃ and stirred 30 minutes down, at room temperature stirs then 16 hours to add DMF in 5 minutes.The saturated NH of reaction 4Cl solution (40mL) and water (20mL) quencher, EtOAc (3 * 40mL) is advanced in extraction then.Merge organic fraction, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use MeOH: DCM (1: 19) wash-out obtains target compound.δ H(CDCl 3)：3.55(2H，m)，4.31(2H，t)，7.63(4H，m)，7.79(1H，m)，7.99(1H，m)，8.07(1H，m)，9.13(1H，s)。
Preparation example 18:1-(7-chloronaphthalene-1-yl) third-1-ketone
Figure A20068001139500451
(12.5g, (5.0g is in DCM 30.7mmol) (50mL) solution 93.7mmol) to be added to-10 ℃ 2-chloronaphthalene with aluminum chloride.Stir after 20 minutes, mixture is cooled to-78 ℃, and the dropping propionyl chloride (5.5mL, 63.3mmol).The suspension that obtains kept 4 hours down at-78 ℃, be added to then rare HCl (0.3M, 300mL) in.Separate each layer, (2 * 100mL) further extract water layer with EtOAc.Merge extract, with salt solution (100mL) washing, dry (MgSO 4).Concentrate, by purification by flash chromatography residue (eluent, hexane: EtOAc, 10: 1) on silica gel, obtain target compound, δ then H(DMSO): 1.16 (3H, t), 3.15 (2H, q), 7.62-7.67 (2H, m), 8.07 (1H, d), 8.19-8.21 (2H, m), 8.62 (1H, s); M/z (ES +)=219.01[M+H] +RT=4.02 minute.
Preparation example 19:2-bromo-1-(7-chloronaphthalene-1-yl) third-1-ketone
Figure A20068001139500452
(2.21g, (preparation example 18,1.28g is in THF 5.85mmol) (50mL) solution 5.88mmol) to be added to 1-(7-chloronaphthalene-1-yl) third-1-ketone with PTAT.When at room temperature stirring 2 hours, bright orange solution almost completely decolours, and forms precipitation.By the diatomite filtration mixture, filtrate is used rare Na with EtOAc (300mL) dilution 2S 2O 3Solution (10%, 100mL) and salt solution (100mL) washing.Dry (MgSO 4), vacuum concentration is used the EtOH recrystallization then, obtains target compound, δ H(DMSO): 1.98 (3H, d), 5.94 (1H, q), 7.67-7.71 (2H, m), 8.12 (1H, d), 8.26 (1H, d), 8.31 (1H, d), 8.42 (1H, s); M/z (ES +)=298.94[M+H] +RT=4.12 minute.
Preparation example 20:3-naphthalene-2-base-5,6-glyoxalidine be [2,1-b] thiazole-2-formaldehyde also
Figure A20068001139500461
In argon gas atmosphere with 2-bromo-3-naphthalene-2-base-5, the 6-glyoxalidine also [2,1-b] thiazole hydrobromide salt (embodiment 11, and 4.0g 9.7mmol) is suspended among the THF (50mL) and is cooled to 0 ℃.Add ethylmagnesium chloride (2.0M, Et 2Among the O, 14.6mL 29.1mmol), is reflected at 0 ℃ and stirred 1 hour down, at room temperature stirs then 1 hour.Reaction is cooled to 0 ℃, and adding DMF (3.0mL, 38.8mmol).Be reflected at 0 ℃ and stirred 1 hour down, at room temperature stirred then 16 hours.The saturated NH of reaction 4Cl solution (50mL) and water (25mL) quencher, EtOAc (3 * 50mL) is advanced in extraction then.Merge organic fraction, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use MeOH: DCM (1: 19) wash-out obtains target compound.δ H(CDCl 3)：3.87(2H，m)，4.35(2H，m)，7.54(1H，dd)，7.64(2H，m)，7.94(2H，m)，8.02(2H，m)，9.36(1H，s)。
Preparation example 21:1-(4-fluoronaphthalene-1-yl) third-1-ketone
(1g 5.8mmol) is dissolved in Et to 1-cyano group-4-fluoronaphthalene 2Among the O (10mL), add ethylmagnesium chloride (2.0M, Et then 2Among the O, 2.9mL, 5.8mmol), reaction reflux 16 hours.Reaction extracts DCM (3 * 40mL) then with 2N HCl (20mL) quencher.Merge organic fraction, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use EtOAc: hexane (1: 9) wash-out obtains target compound.δ H(CDCl 3)：1.29(3H，t)，3.08(2H，q)，7.16(1H，m)，7.60(1H，m)，7.66(1H，m)，7.89(1H，m)，8.16(1H，d)，8.74(1H，d)。
Preparation example 22:2-bromo-1-(4-fluoronaphthalene-1-yl) third-1-ketone
Figure A20068001139500471
(preparation example 21,3.30g 16.3mmol) are dissolved among the THF (50mL) and are cooled to 0 ℃ with 1-(4-fluoronaphthalene-1-yl) third-1-ketone.(6.14g, 16.3mmol), reaction mixture at room temperature stirred 16 hours to add PTAT.Cross filter solid, with THF (2 * 20mL) washings.Vacuum concentrated filtrate, residue (distributes between 2 * 50mL) at water (30mL) and EtOAc.Merge organic fraction, with salt solution (3 * 20mL) washings, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel is used the DCM wash-out, obtains target compound, δ H(CDCl 3): 1.98 (3H, d), 5.36 (1H, q), 7.18 (1H, m), 7.63 (1H, m), 7.70 (1H, m), 7.92 (1H, m), 8.18 (1H, d), 8.59 (1H, d).
Preparation example 23:1-naphthalene-1-Ji Ding-1-ketone
Figure A20068001139500472
(1g 6.5mmol) is dissolved among the THF (20mL) and is cooled to 0 ℃ with 1-cyano group naphthalene in argon gas atmosphere.Add ethylmagnesium chloride (2.0M, Et 2Among the O, 9.8mL 19.6mmol), is reflected at 0 ℃ and stirred 1 hour down, at room temperature stirs then 16 hours.Reaction is advanced DCM (3 * 30mL) with 1N HCl (40mL) quencher, extraction.Merge organic fraction, dry (MgSO 4), vacuum concentration, purifying on silica gel, use EtOAc: hexane (1: 4) wash-out obtains target compound, δ H(CDCl 3): 1.05 (3H, t), 1.84 (2H, m), 3.04 (2H, t), 7.48-7.71 (3H, m), 7.87 (2H, m), 7.98 (1H, d), 8.57 (1H, d).
Preparation example 24:2-bromo-1-naphthalene-1-Ji Ding-1-ketone
Figure A20068001139500481
(preparation example 23,0.99g 5.0mmol) are dissolved among the THF (20mL) and are cooled to 0 ℃ with 1-naphthalene-1-Ji Ding-1-ketone.(1.88g, 5.0mmol), reaction was at room temperature stirred 16 hours to add PTAT.The solid that filtration is separated out is with THF (2 * 10mL) washings.Vacuum concentrated filtrate, residue (distributes between 2 * 40mL) at water (40mL) and EtOAc.Merge organic fraction, with salt solution (20mL) washing, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use EtOAc: hexane (1: 9) wash-out obtains target compound, δ H(CDCl 3): 1.15 (3H, t), 2.20 (1H, m), 2.33 (1H, m), 5.16 (1H, t), 7.50-7.65 (3H, m), 7.89 (2H, m), 8.03 (1H, d), 8.47 (1H, d).
Preparation example 25:3-methyl isophthalic acid-naphthalene-1-Ji Ding-1-ketone
Figure A20068001139500482
(1g 6.5mmol) is dissolved among the THF (20mL) and is cooled to 0 ℃ with 1-cyano group naphthalene in argon gas atmosphere.Add isobutyl-bromination magnesium (2.0M, Et 2Among the O, 9.8mL 19.6mmol), is reflected at 0 ℃ and stirred 1 hour down, at room temperature stirs then 16 hours.Reaction extracts DCM (3 * 30mL) then with 1N HCl (30mL) quencher.Merge organic fraction, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use EtOAc: hexane (1: 9) wash-out obtains target compound, δ H(CDCl 3): 1.04 (6H, d), 2.35 (1H, m), 2.95 (2H, d), 7.48-7.62 (3H, m), 7.83 (1H, d), 7.89 (1H, d), 7.98 (1H, d), 8.56 (1H, d).
Preparation example 26:2-bromo-3-methyl isophthalic acid-naphthalene-1-Ji Ding-1-ketone
Figure A20068001139500491
(preparation example 25,0.36g 1.7mmol) are dissolved among the THF (10mL) and are cooled to 0 ℃ with 3-methyl isophthalic acid-naphthalene-1-Ji Ding-1-ketone.(0.64g, 1.7mmol), reaction was at room temperature stirred 72 hours to add PTAT.Cross filter solid, with THF (2 * 20mL) washings.Vacuum concentrated filtrate, residue (distributes between 2 * 40mL) at water (40mL) and EtOAc.Merge organic fraction, with salt solution (2 * 20mL) washings, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use EtOAc: hexane (1: 9) wash-out obtains target compound, δ H(CDCl 3): 1.13 (3H, d), 1.24 (3H, d), 2.53 (1H, m), 5.03 (1H, d), 7.52 (1H, m), 7.57 (1H, m), 7.63 (1H, m), 7.89 (2H, m), 8.03 (1H, d), 8.46 (1H, d).
Preparation example 27:5-chloronaphthalene-1-carboxylic acid methoxymethyl acid amides
Figure A20068001139500492
To 5-chloro-1-naphthoic acid (1.12g adds N in DMF 5.4mmol) (10mL) solution, O-dimethyl hydroxyl amine (0.53g, 5.4mmol), HOBt (0.73g, 5.4mmol) and DIPEA (2.9mL, 17.0mmol).After 5 minutes, (1.35g, 7.0mmol), reaction mixture at room temperature stirred 96 hours in argon gas to add EDCI.Solvent removed in vacuo, oil (distributes between 3 * 100mL) at water (100mL) and EtOAc.Merge organic phase, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use EtOAc: hexane (1: 1) wash-out obtains target compound, δ H(CD 3OD): 3.42 (6H, br s), 7.51 (1H, m), 7.62 (1H, d), 7.68 (2H, m), 7.79 (1H, d), 8.37 (1H, d).
Preparation example 28:1-(5-chloronaphthalene-1-yl) third-1-ketone
Figure A20068001139500501
In argon gas atmosphere with 5-chloronaphthalene-1-carboxylic acid methoxymethyl acid amides (preparation example 27,0.89g, 3.6mmol) and the stirred solution of THF (50mL) be cooled to 0 ℃.Drip ethylmagnesium bromide (2.0M, Et 2Among the O, 1.2mL 3.6mmol), at room temperature stirred 24 hours.(1.2mL 3.6mmol), reacted at room temperature restir 24 hours to add ethylmagnesium bromide again.With dense HCl (5mL) acidification reaction in the methyl alcohol (40mL), vacuum concentration.Residue (distributes between 3 * 100mL) at water (100mL) and EtOAc.Merge organic phase, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use EtOAc: hexane (1: 9) wash-out obtains target compound, δ H(CDCl 3): 1.29 (3H, t), 3.08 (2H, q), 7.48 (1H, m), 7.63 (2H, m), 7.88 (1H, d), 8.44 (1H, d), 8.48 (1H, d).
Preparation example 29:2-bromo-1-(5-chloronaphthalene-1-yl) third-1-ketone
With 1-(5-chloronaphthalene-1-yl) third-1-ketone (preparation example 28,0.13g, 0.6mmol) and PTAT (0.25g, 0.66mmol) mixture in anhydrous THF (10mL) at room temperature stirred in argon gas 48 hours.Filter reaction mixture, with the THF washing several times.Vacuum concentrated filtrate obtains oil, (distributes between 3 * 100mL) at water (100mL) and EtOAc.Merge organic phase, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use EtOAc: hexane (1: 19) wash-out obtains target compound.δ H(CDCl 3)：1.99(3H，d)，5.35(1H，q)，7.53(1H，m)，7.65(2H，m)，7.89(1H，d)，8.31(1H，d)，8.53(1H，d)。
Preparation example 30:6-fluoronaphthalene-2-carboxylic acid methoxymethyl acid amides
To 6-fluoro-2-naphthoic acid (1.13g adds N in DMF 5.9mmol) (10mL) solution, O-dimethyl hydroxyl amine (0.58g 5.9mmol), HOBt (0.80g, 5.9mmol) and DIPEA (3.2mL, 18.2mmol).After 5 minutes, (1.47g, 7.7mmol), reaction mixture at room temperature stirred 24 hours in argon gas to add EDCI.Solvent removed in vacuo, residue EtOAc (3 * 50mL) and water (50mL) between distribute.Merge organic phase, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use EtOAc: hexane (1: 1) wash-out obtains target compound, δ H(CDCl 3): 3.42 (3H, s), 3.57 (3H, s), 7.31 (1H, m), 7.48 (1H, dd), 7.80 (2H, s), 7.91 (1H, m), 8.24 (1H, s).
Preparation example 31:1-(6-fluoronaphthalene-2-yl) third-1-ketone
Figure A20068001139500512
With ethylmagnesium chloride (2.0M, Et 2Among the O, 5.5mL, (preparation example 30,0.18g is in the solution of THF 5.0mmol) (50mL) 11mmol) to be added drop-wise to 0 ℃ of 6-fluoronaphthalene-2-carboxylic acid methoxymethyl acid amides in the following argon gas atmosphere.Reaction mixture rises to room temperature and stirred 24 hours.Reaction is with dense HCl (5mL) acidifying in methyl alcohol (40mL), vacuum concentration, the solid that obtains EtOAc (3 * 100mL) and water (100mL) between distribution.Merge organic phase, dry (MgSO 4), vacuum concentration obtains target compound, δ H(CDCl 3): 1.30 (3H, t), 3.14 (2H, q), 7.33 (1H, td), 7.50 (1H, dd), 7.84 (1H, d), 7.97 (1H, m), 8.08 (1H, d), 8.48 (1H, s).
Preparation example 32:2-bromo-1-(6-fluoronaphthalene-2-yl) third-1-ketone
Figure A20068001139500513
With 1-(6-fluoronaphthalene-2-yl) third-1-ketone (preparation example 31,0.84g, 4.0mmol) and PTAT (1.72g, 4.6mmol) mixture in anhydrous THF (10mL) at room temperature stirred 24 hours.Filter reaction mixture, with the THF washing several times.Vacuum concentrated filtrate obtains target compound, δ H(CDCl 3): 1.98 (3H, d), 5.44 (1H, q), 7.36 (1H, td), 7.51 (1H, dd), 7.88 (1H, d), 8.00 (1H, m), 8.10 (1H, d), 8.57 (1H, s).
Preparation example 33:6-chloronaphthalene-2-carboxylic acid
Figure A20068001139500521
(3.14g, 17.0mmol) stirred solution in water (10mL) and dense HCl (20mL) is cooled to 0 ℃, drips water (10mL) solution of Sodium Nitrite (1.17g.17.0mmol) with 6-amino-2-naphthoic acid.After 1 hour, add cuprous chloride (I) (3.36g, dense HCl (10mL) solution 34.0mmol) under 0 ℃ in batches.Reaction mixture water (400mL) dilution was stirred 30 minutes.Filter and collect the solid of separating out, wash with water several times, drying obtains target compound.δ H(DMSO)：7.63(1H，dd)，8.03(2H，m)，8.17(2H，m)，8.64(1H，s)。
Preparation example 34:6-chloronaphthalene-2-carboxylic acid methoxymethyl acid amides
Figure A20068001139500522
To 6-chloronaphthalene-2-carboxylic acid (preparation example 33,1.65g add N in DMF 8.0mmol) (10mL) solution, O-dimethyl hydroxyl amine (0.78g 8mmol), HOBt (1.08g, 8mmol) and DIPEA (4.3mL, 25mmol).After 5 minutes, (2.0g, 10.0mmol), reaction mixture at room temperature stirred 24 hours in argon gas to add EDCI.Solvent removed in vacuo, residue EtOAc (3 * 100mL) and water (100mL) between distribute.Merge organic phase, dry (MgSO 4), vacuum concentration.Residue is dissolved among the EtOAc (100mL), with HCl (2M, 50mL) washing.(2M 50mL) washs organic layer, dry (MgSO with sodium hydroxide 4), vacuum concentration obtains target compound.δ H(CDCl 3)：3.42(3H，s)，3.56(3H，s)，7.48(1H，dd)，7.83，(4H，m)，8.21(1H，s)。
Preparation example 35:1-(6-chloronaphthalene-2-yl) third-1-ketone
Figure A20068001139500531
In argon gas atmosphere with 6-chloronaphthalene-2-carboxylic acid methoxymethyl acid amides (preparation example 34,1.84g, 7.4mmol) and the stirred solution of THF (50mL) be cooled to 0 ℃.Drip ethylmagnesium chloride (2M, Et 2Among the O, 7.7mL 15.4mmol), at room temperature stirred 24 hours.Dense HCl (5mL) acidifying of reaction mixture in the methyl alcohol (40mL), vacuum concentration.Residue EtOAc (3 * 100mL) and sodium bicarbonate (100mL) between distribute.Merge organic phase, dry (MgSO 4), vacuum concentration obtains target compound, δ H(CDCl 3): 1.30 (3H, t), 3.14 (2H, q), 7.51 (1H, dd), 7.82 (1H, d), 7.90 (2H, m), 8.08 (1H, dd), 8.46 (1H, s).
Preparation example 36:2-bromo-1-(6-chloronaphthalene-2-yl) third-1-ketone
Figure A20068001139500532
With 1-(6-chloronaphthalene-2-yl) third-1-ketone (preparation example 35,1.39g, 6.4mmol) and PTAT (2.64g, 7.0mmol) mixture in anhydrous THF (40mL) at room temperature stirred in argon gas 24 hours.Filter reaction mixture, solid are with the THF washing several times.Vacuum concentrated filtrate then.Residue is chromatogram purification on silica gel, uses EtOAc: hexane (8: 92) wash-out obtains target compound, δ H(CDCl 3): 1.98 (3H, d), 5.43 (1H, q), 7.53 (1H, dd), 7.89 (3H, m), 8.11 (1H, dd), 8.55 (1H, s).
Preparation example 37:1-naphthalene-2-Ji Ding-1-ketone
With propyl group magnesium chloride (2.0M, Et 2Among the O, 3.3mL 6.5mmol) is added drop-wise to 0 ℃ of 2-naphthyl cyanide (1.0g, Et 6.5mmol) in the following argon gas atmosphere 2In O (20mL) stirred solution.Reaction rises to room temperature and stirred 48 hours.(vacuum concentration obtains target compound, δ for 2M, 15mL) acidifying with HCl in reaction H(CDCl 3): 1.06 (3H, t), 1.85 (2H, m), 3.09 (2H, t), 7.61 (2H, m), 7.90 (2H, m), 7.98 (1H, d), 8.05 (1H, d), 8.48 (1H, s).
Preparation example 38:2-bromo-1-naphthalene-2-Ji Ding-1-ketone
Figure A20068001139500541
With 1-naphthalene-2-Ji Ding-1-ketone (preparation example 37,1.26g, 6.4mmol) and PTAT (2.65g, 7.0mmol) mixture in anhydrous THF (20mL) at room temperature stirred in argon gas 48 hours.Filter reaction mixture, solid are with the THF washing several times.Vacuum concentrated filtrate obtains solid, and chromatogram purification on silica gel is used EtOAc: hexane (1: 19) wash-out obtains target compound, δ H(CDCl 3): 1.14 (3H, t), 2.23 (1H, m), 2.30 (1H, m), 5.25 (1H, t), 7.61 (2H, m), 7.92 (2H, m), 8.00 (1H, d), 8.08 (1H, dd), 8.56 (1H, s).
Preparation example 39: benzo [b] thiophene-2,3-diketone
(3.8mL 43.0mmol) is added drop-wise to thiophenol (3g, Et 27.0mmol) with oxalyl chloride 2In O (20mL) stirred solution, mixture heating up refluxed 1.5 hours.Solution cool to room temperature, vacuum concentration then.Residue is dissolved among the DCM (50mL) and is cooled to 0 ℃.(2.3g 32.0mmol) is added in the reaction mixture in batches, vlil 1 hour with aluminum chloride.The solution cool to room temperature is poured on ice.Separate organic layer, use saturated sodium bicarbonate aqueous solution (100mL) in succession, water (100mL) and salt solution (100mL) washing.Dry organic layer (MgSO 4), vacuum concentration.Add hexane, form precipitation, filter and collect, obtain target compound, δ H(CDCl 3): 7.38 (1H, t), 7.43 (1H, d), 7.70 (1H, t), 7.84 (1H, d).
Preparation example 40: benzo [d] isothiazole-3-carboxylic acid amide
Figure A20068001139500551
In 5 minutes to benzo [b] thiophene-2, the 3-diketone (preparation example 39,0.73g, ammonium hydroxide 4.4mmol) (28%, at H 2Among the O, (30 volume % 1.4mL), and stirred 96 hours 14mL) to drip hydrogen peroxide in the stirred solution.Filter collecting precipitation, obtain target compound, δ H(CDCl 3): 5.62 (1H, br s) 7.27 (1H, br s), 7.57 (2H, m), 7.97 (1H, d), 8.98 (1H, d).
Preparation example 41: benzo [d] isothiazole-3-nitrile
(preparation example 40,0.52g 3.0mmol) are dissolved in 0 ℃ the middle phosphorus oxychloride (10mL), rise to room temperature, and reflux is 3 hours then with benzo [d] isothiazole-3-carboxylic acid amide.Solvent removed in vacuo, residue (distributes between 3 * 100mL) at frozen water (100mL) and EtOAc.Merge organic phase, dry (MgSO 4), vacuum concentration obtains target compound, δ H(CDCl 3): 7.67 (2H, m), 8.06 (1H, d), 8.26 (1H, d).
Preparation example 42:1-benzo [d] isothiazole-3-base third-1-ketone
Figure A20068001139500553
(3.0M is at Et with ethylmagnesium bromide 2Among the O, 0.83mL 2.5mmol) is added drop-wise to benzo [d] isothiazole-3-nitrile (preparation example 41,0.39g, Et 2.5mmol) under 0 ℃ 2In O (20mL) stirred solution, in argon gas atmosphere, stirred 24 hours.Reaction HCl (2M, 15mL) acidifying, vacuum concentration, the solid that obtains (distributes between 3 * 100mL) at water (100mL) and EtOAc.Merge organic phase, dry (MgSO 4), vacuum concentration obtains target compound, δ H(CDCl 3): 1.29 (3H, t), 3.33 (2H, q), 7.56 (2H, m), 7.98 (1H, d), 8.88 (1H, d).
Preparation example 43:1-benzo [d] isothiazole-3-base-2-bromine third-1-ketone
Figure A20068001139500561
With 1-benzo [d] isothiazole-3-base third-1-ketone (preparation example 42,0.35g, 1.8mmol) and PTAT (0.74g, 2.0mmol) mixture in anhydrous THF (10mL) at room temperature stirred in argon gas 72 hours.Filter reaction mixture, with the THF washing several times.Vacuum concentrated filtrate obtains oil, EtOAc (3 * 100mL), distribute between water (100mL) and the salt solution (50mL).Merge organic phase, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use EtOAc: hexane (1: 19) wash-out obtains target compound, δ H(CDCl 3): 1.97 (3H, d), 5.99 (1H, q), 7.60 (2H, m), 8.00 (1H, dd), 8.85 (1H, dd); M/z (ES +)=274[M+H] +RT=2.12 minute.
Preparation example 44:2-bromo-1-(3, the 4-dichlorophenyl) third-1-ketone
Figure A20068001139500562
(1.0g, (1.94g, 5.170mmol), reaction was at room temperature stirred 16 hours to add PTAT in THF 4.924mmol) (30mL) stirred solution to 1-(3, the 4-dichlorophenyl) third-1-ketone.Filter reaction mixture, (2 * 20mL) wash solid with THF.Vacuum concentrated filtrate, residue is at saturated NaHCO 3(30mL) solution and DCM (distribute between 2 * 30mL).Merge organism, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use ethyl acetate: hexane (1: 4) wash-out, obtain target compound, be light yellow oil.δ H(CDCl 3)：8.20(1H，s)，7.90(1H，d)，7.60(1H，d)，5.20(1H，q)，1.95(3H，m)。
Preparation example 45:4-bromo-N-methoxyl group-3, the N-dimethyl benzamide
Figure A20068001139500571
With diisopropyl ethyl amine (7.3mL, 0.042mol) be added to the 4-bromo-3-tolyl acid (3g under the room temperature, 0.014mol), N, O-dimethyl hydroxyl amine hydrochlorate (1.36g, 0.014mol), EDCI (4.01g, 0.021mol) and HOBt (1.94g is in DMF 0.01395mol) (20ml) solution.After 24 hours, solvent removed in vacuo, residue is purifying on silica gel, uses the DCM wash-out, obtains target compound, m/z (ES +)=257.93[M+H] +RT=3.31 minute.
Preparation example 46:1-(4-bromo-3-aminomethyl phenyl) ethyl ketone
(3.7mL 5.93mmol) is added to-70 ℃ 4-bromo-N-methoxyl group-3, and (preparation example 45,1.53g is in THF solution 5.93mmol) for the N-dimethyl benzamide with lithium methide.After rising to ambient temperature overnight, partly remove and desolvate, residue distributes between methylene dichloride (50mL) and saturated ammonium chloride (50mL).Dry organic layer (MgSO 4), filter vacuum concentration.Residue is purifying on silica gel, uses hexane: DCM (4: 1) wash-out obtains target compound, δ H(CDCl 3): 7.90 (1H, br s), 7.70 (2H, br s), 2.65 (3H, s), 2.45 (3H, s).
Preparation example 47:2-bromo-1-(4-bromo-3-aminomethyl phenyl) ethyl ketone
Figure A20068001139500573
Add together among the THF at room temperature (30ml) 1-(4-bromo-3-aminomethyl phenyl) ethyl ketone (preparation example 46,0.58g, 2.732mmol) and PTAT (1.027g, 2.732mmol).After reaction is spent the night, filter out solid, concentrated filtrate stays brown oil.Purifying on the silica gel, use hexane: EtOAc (25: 1) wash-out obtains target compound, m/z (ES +)=292.97[M+H] +RT=2.60 minute.
Preparation example 48:5-chloronaphthalene-1-carboxylic acid methoxymethyl acid amides
Figure A20068001139500581
With 5-chloro-1-naphthoic acid (1.12g, 5.4mmol), N, O-dimethyl hydroxyl amine hydrochlorate (0.53g, 5.4mmol) and HOBt (0.73g, 5.4mmol) be dissolved in DMF (15mL) and DIPEA (2.9mL, 17.0mmol) in.After 5 minutes, (1.35g, 7mmol), reaction was at room temperature stirred 96 hours to add EDCI.Solvent removed in vacuo, residue (distributes between 3 * 100mL) at water (100mL) and EtOAc.Merge organic fraction, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use EtOAc: 1: 1 wash-out of hexane obtains target compound, δ H(CDCl 3): 3.41 (6H, br s), 7.44 (1H, t), 7.61 (3H, m), 7.83 (1H, d), 8.37 (1H, m).
Preparation example 49:1-(4-chloronaphthalene-1-yl) third-1-ketone
Figure A20068001139500582
(10g, add aluminum chloride in DCM 61.5mmol) (150mL) stirred solution (24.6g, 184.5mmol), reaction mixture is cooled to-78 ℃ to the 1-chloronaphthalene of 5 minutes introversions-10 ℃ in batches.(10.7mL 123.0mmol), is reflected at-78 ℃ and stirred 16 hours down to drip propionyl chloride in 10 minutes.Reaction mixture rises to 0 ℃, with 1M HCl quencher, adds entry (200mL) then.Separate organic layer, water layer extracts into DCM (2 * 125mL).Merge organic fraction, (2 * 50mL), salt solution (50mL) washs, dry (MgSO with 1M NaOH solution 4), vacuum concentration obtains target compound, δ H(CDCl 3): 1.28 (3H, t), 3.04 (2H, q), 7.58 (1H, d), 7.64 (2H, m), 7.73 (1H, d), 8.34 (1H, m), 8.59 (1H, m).
Preparation example 50:5-chloronaphthalene-1-nitrile
Figure A20068001139500591
(2.08g, thionyl chloride 10.1mmol) (10mL) solution refluxed 3 hours, cool to room temperature then, vacuum concentration with 5-chloro-1-naphthoic acid.Carefully concentrated ammonia solution (10mL) is added in 0 ℃ the residue, reaction mixture rises to room temperature and stirred 30 minutes.Filter solid is crossed in reaction mixture water (50mL) dilution, washes vacuum-drying with water.Solid is dissolved in the phosphorus oxychloride (10mL), reflux 4 hours, and cool to room temperature is slowly poured in the warm water (50mL) then.The solid that filtration is separated out, (2 * 20mL) washings, vacuum-drying obtains target compound to water, δ H(CDCl 3): 7.64 (2H, m), 7.73 (1H, m), 8.00 (1H, m), 8.20 (1H, d), 8.56 (1H, d).
Preparation example 51: cyclopropyl methyl acetate
Figure A20068001139500592
(2g adds dense H in MeOH 20.0mmol) (10mL) solution to cyclopropyl acetate 2SO 4(5), reaction mixture reflux 16 hours.The reaction mixture cool to room temperature, vacuum concentration.Residue is at saturated NaHCO 3Solution (30mL) and Et 2O (distributes between 2 * 30mL).Merge organic fraction, with salt solution (2 * 20mL) washings, dry (MgSO 4), vacuum concentration obtains target compound, δ H(CDCl 3): 0.15 (2H, m), 0.54 (2H, m), 1.04 (1H, m), 2.21 (2H, d), 3.68 (3H, s).
Preparation example 52:2-cyclopropyl-3-naphthalene-1-base-3-oxo methyl propionate
Figure A20068001139500601
((2.9mL is in THF 20.9mmol) (20mL) solution 20.9mmol) to be added to 0 ℃ of Diisopropylamine in the following argon gas atmosphere for 2.5M, 8.3mL with n-Butyl Lithium.Reaction mixture stirred 1 hour down at 0 ℃, was cooled to-78 ℃ then.(THF 10.4mmol) (15mL) solution is reflected at-78 ℃ and stirred 20 minutes down for preparation example 51,1.19g to drip the cyclopropyl methyl acetate.(reaction rises to room temperature and stirred 16 hours for 1.56mL, THF 11.5mmol) (15mL) solution to add the 1-naphthaldehyde then.Add entry (50mL), reaction mixture extracts into Et 2O (3 * 50mL).Merge organic fraction, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel is used EtOAc: 1: 9 wash-out of hexane.The product that wash-out goes out is dissolved among the DCM (50mL), and adding DMP reagent (Dess-Martin periodinane) (3.30g, 7.8mmol).Reaction was at room temperature stirred 16 hours.Reaction mixture adds entry (100mL) with DCM (50mL) dilution.Filtering-depositing separates each layer.Water layer extract into DCM (2 * 50mL), merge organic fraction, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use EtOAc: 1: 9 wash-out of hexane obtains target compound, δ H(CDCl 3): 0.17 (1H, m), 0.40 (1H, m), 0.63 (1H, m), 0.73 (1H, m), 1.58 (1H, m), 3.60 (1H, d), 3.72 (3H, s), 7.50 (1H, m), 7.56 (1H, m), 7.61 (1H, m), 7.82 (1H, d), 7.89 (1H, d), 8.00 (1H, d), 8.55 (1H, d).
Preparation example 53:2-cyclopropyl-1-naphthalene-1-base ethyl ketone
Figure A20068001139500602
With cyclopropyl-3-naphthalene-1-base-3-oxo methyl propionate (preparation example 52,0.61g, 2.3mmol) and NaCl (0.13g, 2.3mmol) suspension in DMSO (15mL) and water (0.5mL) is heated to 160 ℃ and kept 24 hours.The reaction mixture cool to room temperature (distributes between 3 * 40mL) at water (50mL) and EtOAc.Merge organic fraction, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use EtOAc: 1: 9 wash-out of hexane obtains target compound, δ H(CDCl 3): 0.23 (2H, m), 0.61 (2H, m), 1.19 (1H, m), 2.97 (2H, d), 7.50 (1H, m), 7.54 (1H, m), 7.60 (1H, m), 7.82 (1H, m), 7.89 (1H, d), 7.98 (1H, d), 8.60 (1H, d).
Preparation example 54:1-bromo-5-chloronaphthalene
Figure A20068001139500611
According to people such as Robert F.O ' Malley, J.Org.Chem., 1994,59, the method for 7335-7340 has prepared target compound.
Preparation example 55:5-chloronaphthalene-1-formaldehyde
Figure A20068001139500612
(THF 4.14mmol) (20mL) solution is cooled to-78 ℃ for preparation example 54,1g with 1-bromo-5-chloronaphthalene in argon gas atmosphere.(2.5M, 1.8mL 4.55mmol), are reflected at-78 ℃ and stirred 1 hour down to drip n-Butyl Lithium.(0.96mL 12.4mmol), is reflected at-78 ℃ and stirred 2 hours down, rises to room temperature then, with 1M HCl (30mL) quencher to add DMF.Reaction mixture extract into EtOAc (3 * 30mL), merge organic fraction, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use EtOAc: 1: 9 wash-out of hexane obtains target compound, δ H(CDCl 3): 7.60 (1H, m), 7.70 (1H, d), 7.75 (1H, m), 8.05 (1H, d), 8.61 (1H, d), 9.22 (1H, d), 10.41 (1H, s).
Preparation example 56:3-(5-chloronaphthalene-1-yl)-2-cyclopropyl-3-oxo methyl propionate
Figure A20068001139500621
Use the method identical, begin to prepare target compound from 5-chloronaphthalene-1-formaldehyde (preparation example 55) with preparation example 52.δ H(CDCl 3)：0.15(1H，m)，0.40(1H，m)，0.62(1H，m)，0.73(1H，m)，1.54(1H，m)，3.56(1H，d)，7.51(1H，m)，7.62(1H，m)，7.66(1H，m)，7.84(1H，d)，8.40(1H，d)，8.50(1H，d)。
Preparation example 57:1-(5-chloronaphthalene-1-yl)-2-cyclopropyl ethyl ketone
Figure A20068001139500622
Use the method identical, begin to prepare target compound from 3-(5-chloronaphthalene-1-yl)-2-cyclopropyl-3-oxo methyl propionate (preparation example 56) with preparation example 53.δ H(CDCl 3)：0.22(2H，m)，0.60(2H，m)，1.16(1H，m)，2.95(2H，d)，7.49(1H，m)，7.62(2H，m)，7.83(1H，m)，8.47(2H，m)。
Preparation example 58:(3,3-diethoxy-1-methyl-propyl) three phenyl phosphonium bromides
Figure A20068001139500623
According to people such as Henri Brunner, Synthesis, 1997, the method for 79-86 prepares target compound.
Preparation example 59:1-chloro-7-methylnaphthalene
Figure A20068001139500631
(30g 61.6mmol) is suspended among the THF (90mL), and is cooled to-78 ℃ with (3,3-diethoxy-1-methyl-propyl) three phenyl phosphonium bromides in argon gas atmosphere.(2.5M, 27mL 67.7mmol), are reflected at-78 ℃ and stirred 1.5 hours down to drip n-Butyl Lithium in 15 minutes.(reaction rises to room temperature and stirred 16 hours for 6.9mL, THF 61.6mmol) (10mL) solution to add the 2-chlorobenzaldehyde.Add EtOH (20mL) and triethylamine (2mL), reaction mixture is at water (100mL) and Et 2O (distributes between 3 * 100mL).Merge organic fraction, dry (MgSO 4), vacuum concentration.Residue is dissolved among the 48%HBr in glacial acetic acid (100mL) and the water (100mL), is heated to 100 ℃ and keeps 16 hours.The reaction cool to room temperature is at water (150mL) and Et 2O (distributes between 3 * 100mL).Merge organic fraction, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel is used the hexane wash-out, obtains target compound, δ H(CDCl 3): 2.59 (3H, s), 7.33 (1H, m), 7.39 (1H, m), 7.56 (1H, m), 7.73 (1H, d), 7.77 (1H, d), 8.07 (1H, s).
Preparation example 60:8-chloronaphthalene-2-formaldehyde
Figure A20068001139500632
To N-bromine succinimide (1.20g, 6.7mmol) and AIBN (84mg is 0.5mmol) at CCl 4Add 1-chloro-7-methylnaphthalene (preparation example 59,1.13g, CCl 6.4mmol) in the reflux solution (25mL) 4(25mL) solution.Reaction refluxed 3 hours, and cool to room temperature is crossed filter solid and also discarded then.Vacuum concentrated filtrate is dissolved in CHCl 3(50mL).(1.08g, 7.7mmol), reaction refluxed 3 hours, at room temperature stirred then 72 hours to add vulkacit H.The vacuum concentration reaction mixture, residue is dissolved in acetate: water (1: 1,40mL) and dense HCl (10mL) in.Reaction mixture refluxed 3 hours, cool to room temperature (distributes between 3 * 100mL) at water (100mL) and EtOAc then.Merge organic fraction, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use EtOAc: 1: 9 wash-out of hexane obtains target compound.δ H(CDCl 3)：7.56(1H，t)，7.68(1H，m)，7.84(1H，d)，7.98(1H，d)，8.03(1H，dd)，8.77(1H，s)，10.23(1H，s)。
Preparation example 61:8-chloronaphthalene-2-nitrile
Figure A20068001139500641
With 8-chloronaphthalene-2-formaldehyde (preparation example 60,117mg, 0.61mmol) and hydroxy amine hydrochloric acid salt (51mg, formic acid 0.74mmol) (5mL) vlil 24 hours.The reaction cool to room temperature (distributes between 3 * 30mL) at water (30mL) and EtOAc.Merge organic fraction, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use EtOAc: 1: 9 wash-out of hexane obtains target compound.δ H(CDCl 3)：7.57(1H，m)，7.70(2H，m)，7.83(1H，d)，7.98(1H，d)，8.69(1H，s)。
Preparation example 62:3-dimethylamino-1-naphthalene-1-base third-1-keto hydrochloride
(10g, 59mmol), (2.3g, 78mmol) (6.36g adds dense HCl (0.5mL) to Paraformaldehyde 96 in ethanol 78mmol) (20mL) solution with the dimethyl amine hydrochloride to the 1-acetonaphthone.Reaction reflux 10 hours, cool to room temperature then, vacuum concentration.Residue Et 2O (20mL) grinds, and obtains target compound, m/z (ES +)=228[M+H] +RT=2.22 minute.
Preparation example 63:1-naphthalene-1-base acrylketone
Figure A20068001139500643
(preparation example 62,15.47g 59mmol) are dissolved in the water (400mL), use saturated Na with 3-dimethylamino-1-naphthalene-1-base third-1-keto hydrochloride 2CO 3Solution alkalizes to pH 9.Free alkali extracts into, and EtOAc (in 3 * 150mL), merges organic fraction, dry (MgSO 4), vacuum concentration.Residue is dissolved among the MeOH (25mL) and is cooled to 0 ℃, and the adding methyl iodide (8.4mL, 135mmol).Reaction mixture rises to room temperature and stirred 1 hour.The solid that filtration obtains is used Et 2O (2 * 20mL) washings.Solid is at Et 2O (100mL) and saturated NaHCO 3Vigorous stirring is 16 hours between the solution (100mL).Separate each layer, water layer extracts into EtOAc (2 * 100mL).Merge organic fraction, with 1M HCl (100mL), salt solution (150mL) washing, dry (MgSO 4), vacuum concentration obtains target compound, δ H(CDCl 3): 6.06 (1H, d), 6.28 (1H, d), 6.97 (1H, dd), 7.55 (3H, m), 7.74 (1H, m), 7.91 (1H, m), 8.00 (1H, d), 8.35 (1H, m).
Preparation example 64:3-benzyloxy-1-naphthalene-1-base third-1-ketone
Figure A20068001139500651
With 1-naphthalene-1-base acrylketone (preparation example 63,3.78g, 20.7mmol) and benzylalcohol (3.35g 31mmol) is dissolved among the DCM (40mL), to wherein adding dense H 2SO 4(4).Reaction was at room temperature stirred 16 hours, used DCM (40mL) dilution then, used saturated NaHCO 3Solution (50mL) and water (50mL) washing.Dry organic layer (MgSO 4), vacuum concentration, chromatogram purification on silica gel is used EtOAc: 1: 9 wash-out of hexane.Product is chromatogram purification on silica gel further, uses the DCM wash-out, obtains target compound.δ H(CDCl 3)：3.37(2H，t)，3.99(2H，t)，4.57(2H，s)，7.32(4H，m)，7.56(4H，m)，7.90(2H，m)，8.00(1H，d)，8.63(1H，d)。
Preparation example 65:3-benzyloxy-2-bromo-1-naphthalene-1-base third-1-ketone
Figure A20068001139500661
With 3-benzyloxy-1-naphthalene-1-base third-1-ketone (preparation example 64,2.89g, 9.9mmol) and PTAT (4.12g 10.9mmol) is dissolved among the THF (40mL), at room temperature stirs 72 hours.Filtering-depositing washs and discards with THF (10mL).Vacuum concentrated filtrate, chromatogram purification on silica gel, use EtOAc: 1: 19 wash-out of hexane obtains target compound, δ H(DMSO): 3.95 (1H, dd), 4.20 (1H, dd), 4.60 (2H, d), 5.96 (1H, t), 7.31 (4H, m), 7.65 (4H, m), 8.07 (1H, d), 8.22 (2H, m), 8.38 (1H, d).
Preparation example 66-70
The compound that uses preparation example 15 described processes to prepare preparation example 66-70 from the nitrile that is fit to and Grignard reagent.
Figure A20068001139500662
Figure A20068001139500671
Preparation example 71-79
Use preparation example 1 described process to prepare the compound of preparation example 71-79 from the ketone that is fit to.
Figure A20068001139500672
Figure A20068001139500681
Preparation example 79:6-methylnaphthalene-1-base amine
With 6-methylnaphthalene-1-carboxylic acid (2.50g, 13.4mmol) with Tripyrophosphoric acid (～50mL) and hydroxy amine hydrochloric acid salt (990mg, 14.2mmol) mixing.Mixture heating up to 80 ℃ also stirred 30 minutes.Temperature slowly rises to 160 ℃ (foams), continue to stir 1 hour, then hot solution is added to water/ice mixture (～1.5L) in.The solution that obtains is used solid NaOH furnishing alkalescence then with EtOAc (200mL) washing.With EtOAc (3 * 300mL) extractions, the extract that water (200mL) and salt solution (200mL) washing merge, dry (MgSO 4), vacuum concentration obtains target compound, δ H(DMSO): 2.44 (3H, s), 5.63 (2H, br s), 6.60 (1H, d), 7.01 (1H, d), 7.16 (1H, dd), 7.20 (1H, d), 7.50 (1H, s), 7.97 (1H, d); M/z (ES +)=158.12[M+H] +RT=2.31 minute.
Preparation example 80:1,1-two fluoro-1H-naphthalene-2-ketone
Figure A20068001139500691
With beta naphthal (4.5g 31.21mmol) is dissolved among the DMF (50mL), slowly add then Selectfluor (22.11g, 62.42mmol).Mixture at room temperature stirred 1 hour, and (2 * 50mL) dilution organism are with salt solution (100mL) washing to use EtOAc then.Dry extract (the MgSO that merges 4), vacuum concentration obtains target compound.δ H(DMSO)：6.38(1H，m)，7.60-7.72(3H，m)，7.89(2H，m)。
Preparation example 81:1,1,2,2-tetrafluoro-1,2-dihydronaphthalene
Figure A20068001139500692
With 1, (preparation example 80,6.9g 31.21mmol) are dissolved in the toluene (5mL) 1-two fluoro-1H-naphthalene-2-ketone.In inert atmosphere, add BF 3-Et 2O (0.44mL), (10mL, 54.61mmol), mixture stirred 2 hours down at 60 ℃, cool to room temperature then, restir 16 hours to add Deoxyfluor then.Mixture is cooled to 0 ℃, adds methyl alcohol (0.5mL), drips NaHCO then 3(100mL).Use toluene (2 * 50mL) dilution organic layers then.Dry extract (the MgSO that merges 4), vacuum concentration obtains target compound.δ H(DMSO)：6.37-6.40(1H，m)，7.15(1H，d)，7.54-7.58(2H，m)，7.68(1H，t)，7.82(1H，d)。
Preparation example 82:1,2-two fluoronaphthalenes
Figure A20068001139500693
With 1,1,2,2-tetrafluoro-1, the 2-dihydronaphthalene (preparation example 81,3.9g 19.29mmol) are dissolved among the THF (15mL), add then ammonium hydroxide (30mL) and zinc (6.29g, 96.30mmol).Mixture at room temperature stirred 4 hours in inert atmosphere, filtered then, used hexane wash.Use hexane to filter washing lotion by short silicagel column, vacuum concentration obtains target compound.δ H(DMSO)：7.58-7.62(3H，m)，7.81(1H，m)，8.01(2H，t)。
Preparation example 83:1-(7,8-two fluoronaphthalenes-1-yl) third-1-ketone
With 1, (preparation example 82,1.2g 7.3mmol) are dissolved among the DCM (15mL) 2-two fluoronaphthalenes, are cooled to-15 ℃.Add aluminum chloride (2.9g, 21.9mmol), mixture stirred 15 minutes down at-15 ℃ in batches.Solution is cooled to-78 ℃, drip then propionyl chloride (1.27mL, 14.6mmol).Mixture stirred 16 hours, slowly added HCl (20mL).With EtOAc (100mL) dilution organism, with 1M HCl solution (2 * 50mL) washings, dry (MgSO 4), vacuum concentration obtains target compound.δ H(CDCl 3)：1.25(3H，t)，2.86(2H，m)，7.40-7.45(3H，m)，7.64(1H，m)，7.90(1H，d)。
Preparation example 84:2-bromo-1-(7,8-two fluoronaphthalenes-1-yl) third-1-ketone
To preparation example 1 described similar condition under from 1-(7,8-two fluoronaphthalenes-1-yl) third-1-ketone (preparation example 83) preparation target compound.δ H(CDCl 3)：2.00(3H，m)，5.01(1H，m)，7.25(1H，q)，7.38(1H，t)，7.64(1H，d)，7.73(1H，m)，7.98(1H，d)。
Preparation example 85:4-bromo-2-fluoro-N-methoxyl group-N-methyl-benzamide
Figure A20068001139500711
To preparation example 27 described similar conditions under from 4-bromo-2-fluorobenzoic acid (9.4g, 42.9mmol) preparation target compound.δ H(CDCl 3)：3.40(3H，s)，3.60(3H，s)，7.35(3H，m)。
Preparation example 86:1-(4-bromo-2-fluorophenyl) third-1-ketone
Figure A20068001139500712
To preparation example 28 described similar conditions under from 4-bromo-2-fluoro-N-methoxyl group-N-methyl-benzamide (preparation example 85,5.62g, 21.45mmol) preparation target compound.δ H(CDCl 3)：1.20(3H，t)，3.00(3H，q)，7.40(2H，m)，7.80(1H，t)。
Preparation example 87:2-bromo-1-(4-bromo-2-fluorophenyl) third-1-ketone
To preparation example 29 described similar conditions under from 1-(4-bromo-2-fluorophenyl) third-1-ketone (preparation example 86,1.64g, 7.1mmol) preparation target compound.δ H(CDCl 3)：1.90(3H，d)，5.30(1H，q)，7.35(1H，d)，7.45(1H，d)，7.80(1H，t)。
Preparation example 88:1-(4-bromo-3-aminomethyl phenyl) third-1-ketone
Figure A20068001139500714
To preparation example 42 described similar conditions under from 4-bromo-3-methyl benzonitrile (7.7g, 39.3mmol) preparation target compound.δ H(CDCl 3)：1.20(3H，t)，3.00(2H，q)，7.60(2H，s)，7.80(1H，s)。
Preparation example 89:2-bromo-1-(4-bromo-3-aminomethyl phenyl) third-1-ketone
Figure A20068001139500721
To preparation example 16 described similar conditions under from 1-(4-bromo-3-aminomethyl phenyl) third-1-ketone (preparation example 88,2.31g, 10.13mmol) preparation target compound.δ H(CDCl 3)：1.97(3H，d)，2.50(3H，s)，5.25(1H，q)，7.70(2H，m)，7.80(1H，s)。
Preparation example 90:1-(3, the 4-dichlorophenyl)-3-methyl fourth-1-ketone
Figure A20068001139500722
To preparation example 42 described similar conditions under from 3, the 4-dichlorobenzonitrile (5g, 29.1mmol) preparation target compound.δ H(CDCl 3)：1.05(6H，d)，2.30(1H，m)，2.80(2H，d)，7.60(1H，d)，7.80(1H，d)，8.05(1H，s)。
Preparation example 91:2-bromo-1-(3, the 4-dichlorophenyl)-3-methyl fourth-1-ketone
To preparation example 16 described similar conditions under from 1-(3, the 4-dichlorophenyl)-3-methyl fourth-1-ketone (preparation example 90,1.6g, 6.9mmol) preparation target compound.δ H(CDCl 3)：1.05(3H，d)，1.10(3H，d)，2.50(1H，m)，4.80(1H，d)，7.60(1H，d)，7.80(1H，d)，8.15(1H，s)。
Preparation example 92:1-(4,5-two fluoronaphthalenes-1-yl) third-1-ketone
Figure A20068001139500731
With 1,8-two fluoronaphthalene (1g, 6.1mmol) (according to Mallory F.B, J.Amer.Chem.Soc.1974,96, the preparation of 3536 process) and propionyl chloride (0.54mL, DCM 6.16mmol) (20mL) solution are added to-40 ℃ aluminum chloride, and (2.44g is in DCM 18.3mmol) (5mL) suspension.After 1 hour, reaction rises to room temperature, with hydrochloric acid 2N HCl (10mL) quencher.With EtOAc (3 * 10mL) extraction mixtures.Merge organic layer, with sodium hydroxide (2N, 10mL) washing, dry (MgSO 4), vacuum concentration.By purification by flash chromatography on silica gel (eluent: hexane/EtOAc, 98: 2), obtain target compound.δ H(CDCl 3)：1.30(3H，t)，3.10(2H，q)，7.20(2H，m)，7.60(1H，m)，7.90(1H，m)，8.50(1H，d)。
Preparation example 93:2-bromo-1-(4,5-two fluoronaphthalenes-1-yl) third-1-ketone
Figure A20068001139500732
To preparation example 16 described similar conditions under from 1-(4,5-two fluoronaphthalenes-1-yl) third-1-ketone (preparation example 92,0.86g, 3.91mmol) preparation target compound.δ H(DMSO)：1.80(3H，d)，5.90(1H，q)，7.45(2H，m)，7.80(1H，d)，8.20(1H，d)，8.30(1H，m)。
Preparation example 94:1-(4,5-two fluoronaphthalenes-1-yl) fourth-1-ketone
Figure A20068001139500741
With 1,8-two fluoronaphthalenes (1.0g, 6.1mmol) and butyryl chloride (0.72g, DCM 6.16mmol) (20mL) solution are added to-40 ℃ aluminum chloride, and (2.44g is in DCM 18.3mmol) (5mL) suspension.After 1 hour, reaction rises to room temperature, with hydrochloric acid 2N HCl (10mL) quencher.With EtOAc (3 * 10mL) extraction mixtures.Merge organic layer, with sodium hydroxide (2N, 10mL) washing, dry (MgSO 4), vacuum concentration.By purification by flash chromatography on silica gel (eluent: hexane/EtOAc 98: 2), obtain target compound.δ H(CDCl 3)：1.05(3H，t)，1.80(2H，m)，3.00(2H，t)，7.20(2H，m)，7.60(1H，m)，7.90(1H，m)，8.50(1H，d)。
Preparation example 95:2-bromo-1-(4,5-two fluoronaphthalenes-1-yl) fourth-1-ketone
Figure A20068001139500742
To preparation example 16 described similar conditions under from 1-(4,5-two fluoronaphthalenes-1-yl) fourth-1-ketone (preparation example 94,0.8g, 3.41mmol) preparation target compound.δ H(CDCl 3)：1.20(3H，t)，2.2(1H，m)，2.4(1H，m)，5.1(1H，t)，7.2(2H，m)，7.6(1H，m)，7.9(1H，m)，8.3(1H，d)。
Preparation example 96:1-(4,5-dichloronaphtalene-1-yl) third-1-ketone
Figure A20068001139500751
To preparation example 92 described similar conditions under from 1,8-dichloronaphtalene (0.8g, 4.1mmol) (by Hodgson J.Chem.Soc.1947, the preparation of 80 process) preparation target compound.δ H(CDCl 3)：1.30(3H，t)，3.00(2H，q)，7.50(1H，t)，7.60-7.80(3H，m)，8.40(1H，d)。
Preparation example 97:2-bromo-1-(4,5-dichloronaphtalene-1-yl) third-1-ketone
Figure A20068001139500752
To preparation example 16 described similar conditions under from 1-(4,5-dichloronaphtalene-1-yl) third-1-ketone (preparation example 96,0.84g, 2.53mmol) preparation target compound.δ H(CDCl 3)：2.00(3H，d)，5.25(1H，q)，7.45(1H，t)，7.60-7.80(3H，m)，8.20(1H，d)。
Preparation example 98:1-(5,7-dichloronaphtalene-1-yl) third-1-ketone
Figure A20068001139500753
With 5,7-dichloronaphtalene-1-carboxylic acid (1.5g, 6.25mmol) (Sestanj, Kazimir european patent application (1982), EP 59596 A1 19820908), oxalyl chloride (0.6mL, 6.87mmol), DMF (1) is blended among the DCM (50mL), and stirs 12 hours.Vacuum concentrated mixture, dissolving is cooled to-78 ℃ in THF (40mL).Add acetopyruvic acid iron (III) (66mg, 0.19mmol), drip then ethylmagnesium bromide (2.7mL, 3M solution, 8.12mmol).After 1 hour, reaction rises to room temperature, adds saturated ammonium chloride solution (30mL).(3 * 50mL) extraction mixtures merge organism, dry (MgSO with DCM 4), vacuum concentration.By (the eluent: hexane/ethyl acetate 99: 1), obtain target compound, δ of purification by flash chromatography on silica gel H(CDCl 3): 1.10 (3H, t), 3.00 (2H, q), 7.60 (2H, m), 7.09 (1H, d), 8.40 (1H, d), 8.50 (1H, s).
Preparation example 99:2-bromo-1-(5,7-dichloronaphtalene-1-yl) third-1-ketone
Figure A20068001139500761
To preparation example 16 described similar conditions under from 1-(5,7-dichloronaphtalene-1-yl) third-1-ketone (preparation example 98,0.719g, 2.84mmol) preparation target compound.δ H(CDCl 3)：2.00(3H，d)，5.40(1H，q)，7.70(2H，m)，8.00(1H，d)，8.42(1H，s)，8.50(1H，d)。
Preparation example 100-106:
Use preparation example 18 described processes to prepare the compound of preparation example 100-104, use preparation example 23 described processes to prepare the compound of preparation example 105 and 106.
Figure A20068001139500771
Figure A20068001139500781
Preparation example 107-114:
Use preparation example 16 described processes to prepare the compound of preparation example 107-114 from the ketone that is fit to.
Figure A20068001139500782
Figure A20068001139500791
Preparation example 115:5-methylnaphthalene-1-carboxylic acid tert-butyl ester
Figure A20068001139500801
5-bromo-1-naphthalene-1-carboxylic acid tert-butyl ester (J.Org.Chem. in 2 minutes under-78 ℃; 2002; 67 (4); 1171-1177) (1.00g, add in THF 3.26mmol) (10mL) solution butyllithium (2.5M, 1.56mL).Stir after 40 minutes, add methyl iodide (0.55g), rise to room temperature at 1.5 hours internal reactions.The quencher of reaction water (10mL) (distributes between 3 * 50mL) at water and ether.Dry extract (the MgSO that merges 4), concentrate.By purification by flash chromatography residue (eluent: isohexane/EtOAc:98: 2), obtain target compound, δ H(CDCl 3): 1.70 (9H, s), 2.78 (3H, s), 7.37 (d, 1H), 7.46-7.54 (m, 2H), 8.04 (d, 1H), 8.18 (d, 1H), 8.66 (d, 1H); M/z (ES +)=242.23[M+H] +RT=2.86 minute.
Preparation example 116:5-methylnaphthalene-1-carboxylic acid
Figure A20068001139500802
(preparation example 115,1.37g 4.45mmol) are dissolved among the DCM (10mL), add TFA (3mL) with 5-methylnaphthalene-1-carboxylic acid tert-butyl ester.Stir after 16 hours, the vacuum concentration reaction obtains target compound.δ H(DMSO)：2.71(3H，s)，7.45(1H，d)，7.53(1H，m)，7.64(1H，m)，8.13(1H，d)，8.28(1H，d)，8.68(1H，d)。
Preparation example 117:1-(5-methylnaphthalene-1-yl) third-1-ketone
Figure A20068001139500803
To preparation example 98 described similar conditions under by acyl chlorides from 5-methylnaphthalene-1-carboxylic acid (preparation example 116) preparation target compound.δ H(CDCl 3): 1.20 (3H, t), 2.63 (3H, s), 2.97 (2H, q), 7.29 (1H, d), 7.35-7.46 (2H, m), 7.69 (1H, d), 8.07 (1H, d), 8.22 (1H, d); M/z (ES +)=199.07[M+H] +RT=3.86 minute.
Preparation example 118:5-methoxynaphthalene-1-carboxylate methyl ester
Figure A20068001139500811
According to Can.J.Chem. (2004), the method for 240-253 prepares target compound.
Preparation example 119:5-methoxynaphthalene-1-carboxylic acid
Figure A20068001139500812
(preparation example 118 1.43g) is dissolved in the methyl alcohol (30mL), adds the 2M sodium hydroxide solution, stirs 16 hours, then vacuum concentration with 5-methoxynaphthalene-1-carboxylate methyl ester.Add 1MNaOH (50mL), with EtOAc (50mL) washing, use dense HCl acidifying, DCM (3 * 50mL) is advanced in extraction then.Merge organic fraction, dry (MgSO 4), vacuum concentration obtains target compound, δ H(DMSO): 4.00 (3H, s), 7.06 (1H, d), 7.60 (2H, m), 8.16 (1H, d), 8.42 (2H, m), 13.10 (1H, s).
Preparation example 120:1-(5-methoxynaphthalene-1-yl) third-1-ketone
Figure A20068001139500813
By preparation example 98 described by acyl chlorides from 5-methoxynaphthalene-1-carboxylic acid (preparation example 119) preparation target compound.δ H(DMSO)：1.18(3H，t)，3.10(2H，q)，3.98(3H，s)，7.08(1H，d)，7.55(2H，m)，7.96(1H，d)，8.04(1H，d)，8.40(1H，d)。
Preparation example 121:2-bromo-1-(5-methoxynaphthalene-1-yl) third-1-ketone
Figure A20068001139500821
Under preparation example 16 described conditions, prepare target compound from 1-(5-methoxynaphthalene-1-yl) third-1-ketone (preparation example 120).δ H(CDCl 3)：2.01(3H，d)，4.04(3H，s)，5.45(1H，q)，7.14(1H，d)，7.48(2H，m)，7.98(1H，d)，8.10(1H，d)，8.40(1H，d)。
Preparation example 122:1-(5-chloronaphthalene-1-yl) ethanol
Figure A20068001139500822
To preparation example 187 described similar conditions under with methylmagnesium-chloride from 5-chloronaphthalene-1-formaldehyde (preparation example 55) preparation target compound.δ H(CDCl 3)：1.75(3H，d)，5.70(1H，q)，7.45(1H，m)，7.42(1H，t)，7.60(2H，m)，7.78(2H，d)，8.06(1H，d)，8.27(1H，d)。
Preparation example 123:1-(5-chloronaphthalene-1-yl) ethyl ketone
Figure A20068001139500831
To preparation example 129 described similar conditions under from 1-(5-chloronaphthalene-1-yl) ethanol (preparation example 122) preparation target compound.δ H(CDCl 3)：2.75(3H，s)，7.55(1H，t)，7.72(2H，m)，8.04(1H，m)，8.56(1H，d)，8.70(1H，d)。
Preparation example 124:2-bromo-1-(5-chloronaphthalene-1-yl) ethyl ketone
To preparation example 19 described similar conditions under from 1-(5-chloronaphthalene-1-yl) ethyl ketone (preparation example 123) preparation target compound.δ H(CDCl 3)：4.60(2H，d)，7.63(1H，m)，7.74(3H，m)，8.04(2H，m)。
Preparation example 125:2-bromo-1-(5,6,7,8-naphthane-2-yl) ethyl ketone
To preparation example 44 described similar conditions under prepare target compound from 1-(5,6,7,8-naphthane-2-yl) ethyl ketone.δ H(DMSO)：1.77(4H，m)，2.80(4H，m)，4.87(2H，s)，7.24(1H，d)，7.72(2H，m)。
Preparation example 126:3-(5,6,7,8-naphthane-2-yl)-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139500834
To embodiment 66 described similar conditions under from 2-bromo-1-(5,6,7,8-naphthane-2-yl) ethyl ketone (preparation example 125) and 2-imidazolidine thioketones (imidazolidinethione) preparation target compound.δ H(DMSO): 1.77 (4H, m), 2.80 (4H, m), 4.30 (2H, t), 4.53 (2H, t), 6.95 (1H, s), 7.24 (1H, d), 7.34 (2H, d), 9.61 (1H, br); M/z (ES +)=257.07[M+H] +RT=2.51 minute.
Preparation example 127:2-bromo-3-(5,6,7,8-naphthane-2-yl)-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139500841
To embodiment 11 described similar conditions under from 3-(5,6,7,8-naphthane-2-yl)-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt (preparation example 126) preparation target compound also.δ H(DMSO)：1.79(4H，m)，2.80(4H，m)，4.23(2H，m)，4.32(2H，m)，7.29(3H，m)，9.60(1H，br)。
Preparation example 128:1-(5-trifluoromethyl naphthalene-1-yl) third-1-alcohol
Figure A20068001139500842
(4.0g 14.54mmol) is dissolved among the THF (80mL), cools off down at-78 ℃ in inert atmosphere with 1-bromo-5-trifluoromethyl naphthalene.In 10 minutes, drip n-BuLi (6.4mL, 2.5M solution) then, solution restir 2 hours.In 5 minutes, slowly add then propionic aldehyde (3.2mL, 43.62mmol), mixture restir 1 hour.Remove cooling bath, mixture at room temperature stirred 16 hours, added 2M HCl solution (50mL) then.Mixture stirred 5 minutes, and (3 * 60mL) extract water layer with EtOAc then.Merge organic layer, washing (salt solution), dry (MgSO 4), vacuum concentration.By purification by flash chromatography on silica gel (eluent: hexane/EtOAc:5/1, then 4/1), obtain target compound, δ H(CDCl 3): 1.05 (3H, t), 1.90-2.05 (2H, m), 5.45 (1H, m), 7.55 (1H, t), 7.65 (1H, t), 7.78 (1H, d), 7.90 (1H, d), 8.18 (1H, d), 8.40 (1H, d).
Preparation example 129:1-(5-trifluoromethyl naphthalene-1-yl) third-1-ketone
Figure A20068001139500851
(preparation example 128,2.5g 9.832mmol) are dissolved among the DCM (80mL), at room temperature add Dess-Martin reagent in inert atmosphere in batches with 1-(5-trifluoromethyl naphthalene-1-yl) third-1-alcohol.Mixture at room temperature stirred 16 hours, added saturated NaHCO then 3Solution (80mL), with the DCM extraction, dry (MgSO 4), vacuum concentration.By (the eluent: DCM), obtain target compound, δ of purification by flash chromatography on silica gel H(DMSO): 1.20 (3H, t), 3.17 (2H, q), 7.75 (1H, t), 7.85 (1H, t), 8.10 (1H, d), 8.20 (1H, d), 8.30 (1H, br d), 8.60 (1H, d).
Preparation example 130:2-bromo-1-(5-trifluoromethyl naphthalene-1-yl) third-1-ketone
Figure A20068001139500852
To preparation example 16 described similar conditions under from 1,1-(5-trifluoromethyl naphthalene-1-yl) third-1-ketone (preparation example 129) preparation target compound.δ H(DMSO)：1.95(3H，d)，5.95(1H，q)，7.80-7.90(2H，m)，8.15(1H，d)，8.25-8.35(2H，m)，8.50(1H，d)。
Preparation example 131:2-fluoronaphthalene
With 6-fluoronaphthalene-1-carboxylic acid (15.0g, 78.87mmol) be suspended in Quinidine (Quinidine) (35mL) in, in inert atmosphere, add Cu (0) powder (8.8g, 138.03mmol), reaction reflux 48 hours.Mixture is cooled to room temperature and filtration, with EtOH (20mL) washing leaching cake, uses hexane (20mL) washing then.Merge washing lotion, vacuum concentration.With EtOAc (200mL) dilution organism, (salt solution (100mL) washing is used in 2 * 50mL) washings then, dry (MgSO with 2M HCl solution 4), vacuum concentration.By (the eluent: hexane), obtain target compound, δ of purification by flash chromatography on silica gel H(DMSO): 7.40-7.60 (3H, m), 7.72 (1H, d), 7.90-8.10 (3H, m).
Preparation example 132:1-(7-fluoronaphthalene-1-yl) third-1-ketone
Figure A20068001139500862
(preparation example 131,8.0g 55.10mmol) are dissolved among the DCM (120mL), are reflected at 0 ℃ of cooling with the 2-fluoronaphthalene in inert atmosphere.Disposable then adding AlCl 3(22.8g, 170.82mmol), mixture stirred 15 minutes.Mixture cools off down at-78 ℃ then, and slow adding propionyl chloride in 15 minutes (9.6mL, 110.2mmol).Mixture stirred 16 hours then, the interior during this period room temperature that arrives.With EtOAc (200mL) dilution organism, with 1M HCl solution (2 * 50mL) washings, dry (MgSO 4), vacuum concentration obtains target compound, δ H(DMSO): 1.15 (3H, t), 3.15 (2H, q), 7.52 (1H, m), 7.61 (1H, m), 8.15 (1H, m), 8.25 (2H, m), 8.35 (1H, m).
Preparation example 133:2-bromo-1-(7-fluoronaphthalene-1-yl) third-1-ketone
Figure A20068001139500871
To preparation example 16 described similar conditions under from 1-(7-fluoronaphthalene-1-yl) third-1-ketone (preparation example 132,11.7g, 55.10mmol) preparation target compound.δ H(DMSO)：1.90(3H，m)，5.95(1H，q)，7.55-7.70(2H，m)，8.10-8.20(2H，m)，8.25-8.35(2H，m)。
Preparation example 134:1-(7-fluoronaphthalene-1-yl) fourth-1-ketone
To preparation example 18 described similar conditions under from the 2-fluoronaphthalene (preparation example 131,1.0g, 6.88mmol) and butyryl chloride prepare target compound.δ H(DMSO)：0.95(3H，t)，1.70(2H，m)，3.10(2H，t)，7.55(1H，m)，7.65(1H，m)，8.15(1H，m)，8.22(2H，m)，8.30(1H，m)。
Preparation example 135:2-bromo-1-(7-fluoronaphthalene-1-yl) fourth-1-ketone
Figure A20068001139500873
To preparation example 16 described similar conditions under from 1-(7-fluoronaphthalene-1-yl) fourth-1-ketone (preparation example 134,1.47g, 6.88mmol) preparation target compound.δ H(DMSO)：1.10(3H，t)，2.05(1H，m)，2.15(1H，m)，5.80(1H，t)，7.55-7.70(2H，m)，8.10-8.20(2H，m)，8.25-8.35(2H，m)。
Preparation example 136:3-(3, the 4-dichlorophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139500881
To embodiment 1 described similar condition under prepare target compound from 2-bromo-1-(3, the 4-dichlorophenyl) ethyl ketone and 2-imidazolidine thioketones.δ H(DMSO): 4.30 (2H, m), 4.50 (2H, m), 7.20 (1H, s), 7.60 (1H, d), 7.80 (1H, d), 7.95 (1H, s), 9.60 (1H, br s); M/z (ES +)=271.03[M+H] +RT=2.70 minute.
Preparation example 137:2-bromo-3-(3, the 4-dichlorophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139500882
With 3-(3, the 4-dichlorophenyl)-5, the 6-glyoxalidine also [2,1-b] thiazole hydrobromide salt (preparation example 136,5.0g 13.85mmol) are suspended among the DCM (100.0mL), add saturated NaHCO 3Solution (100mL).Mixture vigorous stirring 15 minutes is separated two-phase; The use dry organic layer of post that is separated uses ice bath 0 ℃ of cooling down.(0.71mL, 13.85mmol), mixture stirred 1 hour in inert atmosphere under 0 ℃ to add bromine then in 5 minutes.Behind the several minutes, form yellow mercury oxide, remove ice bath, mixture stirred 16 hours.Filtering suspension liquid, solid obtains target compound with ether (30.0mL) washing.δ H(DMSO)：4.35-4.15(4H，m)，7.60(1H，d)，7.90(2H，m)，9.55(1H，brs)。
Preparation example 138:3-(3, the 4-dichlorophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde also
In inert atmosphere with the 2.0M ether of ethylmagnesium bromide (10.2mL, 20.36mmol) solution is added in THF (50.0mL) solution, use ice bath with mixture 0 ℃ of cooling down.In 5 minutes with 2-bromo-3-(3, the 4-dichlorophenyl)-5, the 6-glyoxalidine also [2,1-b] thiazole hydrobromide salt (preparation example 137,3.0g 6.79mmol) are added in the above-mentioned solution in batches.Stir after 2 hours, (2.10mL 27.15mmol) is added in the solution, and mixture stirred 16 hours with DMF.Saturated ammonium chloride (50mL) slowly is added in the mixture, between EtOAc (150mL) and saturated sodium-chloride (100mL), distributes then.Dry organic layer (MgSO 4), vacuum concentration obtains target compound.δ H(DMSO)：3.90(2H，m)，4.20(2H，m)，7.75(1H，d)，7.85(1H，d)，8.10(1H，s)，9.20(1H，s)。
Preparation example 139:2-bromo-3-(3, the 4-dichlorophenyl)-3-oxo methyl propionate
Figure A20068001139500891
To preparation example 16 described similar conditions under from 3-(3, the 4-dichlorophenyl)-3-oxo methyl propionate (1.0g, 4.05mmol) preparation target compound.δ H(DMSO)：3.80(3H，s)，6.75(1H，s)，7.90(1H，d)，8.00(1H，d)，8.30(1H，s)。
Preparation example 140:3-(3, the 4-dichlorophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-carboxylate methyl ester also
Figure A20068001139500892
To embodiment 1 described similar condition under from 2-bromo-3-(3, the 4-dichlorophenyl)-3-oxo-methyl propionate (preparation example 139,1.40g, 4.05mmol) and 2-imidazolidine thioketones prepare target compound.δ H(DMSO)：3.70(3H，s)，4.30(4H，m)，7.65(1H，d)，7.90(1H，m)，8.00(1H，s)。
Preparation example 141:2-bromo-1-(4-chloro-3-trifluoromethyl) ethyl ketone
Figure A20068001139500893
To preparation example 16 described similar conditions under from 1-(4-chloro-3-trifluoromethyl) ethyl ketone (5.0g, 22.46mmol) preparation target compound.δ H(DMSO)：4.40(2H，s)，7.70(1H，d)，8.10(1H，d)，8.35(1H，s)。
Preparation example 142:3-(4-chloro-3-trifluoromethyl)-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139500901
To embodiment 1 described similar condition under from 2-bromo-1-(4-chloro-3-trifluoromethyl-phenyl) ethyl ketone (preparation example 141,6.44g, 21.32mmol) and 2-imidazolidine thioketones prepare target compound.δ H(DMSO): 4.30 (2H, m), 4.55 (2H, m), 7.30 (1H, s), 7.95 (2H, m), 8.10 (1H, s), 9.65 (1H, br s); M/z (ES +)=304.93[M+H] +RT=2.44 minute.
Preparation example 143:2-bromo-3-(4-chloro-3-trifluoromethyl)-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139500902
To embodiment 11 described similar conditions under from 3-(4-chloro-3-trifluoromethyl)-5, the 6-glyoxalidine also [2,1-b] thiazole hydrobromide salt (preparation example 142,5.0g, 12.99mmol) and bromine prepare target compound.δ H(DMSO)：4.35-4.20(4H，m)，7.95(1H，d)，8.05(1H，d)，8.10(1H，s)，9.60(1H，br?s)。
Preparation example 144:3-(4-chloro-3-trifluoromethyl)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde also
To preparation example 138 described similar conditions under from 2-bromo-3-(4-chloro-3-trifluoromethyl)-5, the 6-glyoxalidine also [2,1-b] thiazole hydrobromide salt (preparation example 143,1.5g, 3.39mmol) preparation target compound.δ H(DMSO)：3.90(2H，m)，4.20(2H，m)，7.95(1H，m)，8.10(1H，d)，8.25(1H，s)，9.20(1H，s)。
Preparation example 145:1-(4-chloro-3-trifluoromethyl)-3-methyl fourth-1-ketone
(24.0mL, 48.16mmol) solution slowly is added to 0 ℃ of 4-chloro-3-trifluoromethyl cyanobenzene in the following inert atmosphere (3.3g is in THF 16.05mmol) (50.0mL) solution with the 2.0M ether of isobutyl-bromination magnesium in 5 minutes.Mixture stirred 1 hour, removed ice bath then, restir 16 hours.Saturated ammonium chloride (30mL) slowly is added in the mixture, between EtOAc (150mL) and saturated sodium-chloride (100mL), distributes then.Dry organic layer (MgSO 4), vacuum concentration obtains target compound.δ H(DMSO)：0.95(6H，m)，2.15(1H，m)，3.00(2H，m)，7.90(1H，d)，8.30(2H，m)。
Preparation example 146:2-bromo-1-(4-chloro-3-trifluoromethyl)-3-methyl fourth-1-ketone
To preparation example 16 described similar conditions under from 1-(4-chloro-3-trifluoromethyl)-3-methyl fourth-1-ketone (preparation example 145,4.0g, 15.15mmol) preparation target compound.δ H(DMSO)：1.00(3H，d)，1.15(3H，d)，2.35(1H，m)，5.80(1H，d)，7.95(1H，d)，8.40(2H，m)。
Preparation example 147:4-chloro-N-methoxyl group-3, the N-dimethyl benzamide
Figure A20068001139500921
To preparation example 27 described similar conditions under from 4-chloro-3-tolyl acid (10.0g, 58.62mmol) preparation target compound.δ H(CDCl 3)：2.42(3H，s)，3.40(3H，s)，3.60(3H，s)，7.40(1H，d)，7.50(1H，d)，7.60(1H，s)。
Preparation example 148:1-(4-chloro-3-aminomethyl phenyl) third-1-ketone
Figure A20068001139500922
To preparation example 28 described similar conditions under from 4-chloro-N-methoxyl group-3, the N-dimethyl benzamide (preparation example 147,5.0g, 23.40mmol) preparation target compound.δ H(DMSO)：1.10(3H，t)，2.40(3H，s)，3.05(2H，q)，7.60(1H，d)，7.80(1H，d)，8.00(1H，s)。
Preparation example 149:2-bromo-1-(4-chloro-3-aminomethyl phenyl) third-1-ketone
Figure A20068001139500923
To preparation example 16 described similar conditions under from 1-(4-chloro-3-aminomethyl phenyl) third-1-ketone (4.0g, 21.90mmol) preparation target compound.δ H(DMSO)：1.80(3H，d)，2.42(3H，s)，5.85(1H，q)，7.62(1H，d)，7.90(1H，d)，8.10(1H，s)。
Preparation example 150:2-bromo-1-(5-fluoronaphthalene-1-yl) third-1-ketone
Figure A20068001139500931
((1.49g, 3.96mmol), reaction was at room temperature stirred 72 hours to add PTAT in THF 3.96mmol) (30mL) stirred solution for preparation example 183,0.8g to 1-(5-fluoronaphthalene-1-yl) third-1-ketone.Filter reaction mixture, vacuum concentrated filtrate obtains target compound, δ H(CDCl 3): 2.00 (3H, d), 5.40 (1H, q), 7.23 (1H, d), 7.60 (2H, m), 7.98 (1H, d), 8.20 (1H, d), 8.40 (1H, d).
Preparation example 151:2-bromo-3-(7-chloronaphthalene-1-yl)-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139500932
To embodiment 11 described similar conditions under from 3-(7-chloronaphthalene-1-yl)-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt (embodiment 44) preparation target compound also.δ H(DMSO)：3.90(1H，m)，4.20(3H，m)，7.71(1H，d)，7.80(3H，m)，8.05(1H，s)，8.17(1H，d)，8.26(1H，d)，9.60(1H，s)。
Preparation example 152-157:
By shown in the following compound of method preparation.
Figure A20068001139500941
Preparation example 158-166:
By shown in the following compound of method preparation.
Figure A20068001139500951
Preparation example 167-175:
By shown in the following compound of method preparation.
Figure A20068001139500961
Figure A20068001139500971
Preparation example 176:2-bromo-3-(7-chloronaphthalene-1-yl)-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139500972
With 3-(7-chloronaphthalene-1-yl)-5, the 6-glyoxalidine also [2,1-b] thiazole hydrobromide salt (embodiment 51, and 5.30g is 14.4mmol) at saturated NaHCO 3Distribute between solution (200mL) and the EtOAc (200mL).Separates two, water layer is further used EtOAc (2 * 100mL) extractions then.With the extract that salt solution (100mL) washing merges, dry (MgSO 4), concentrate.The crystal residue is dissolved among the DCM, is cooled to 0 ℃, and (0.75mL 14.6mmol) handles with bromine.Remove ice bath, thickness suspension at room temperature stirred 10 hours.Collecting precipitation (target compound) is with isohexane/DCM:1/1 washing, vacuum-drying then, δ H(DMSO): 3.93 (1H, m), 4.21-4.26 (3H, m), 7.70 (1H, dd), 7.76 (1H, dd), 7.82 (1H, d), 8.03 (1H, d), 8.17 (1H, d), 8.26 (1H, d), 9.64 (1H, br s); M/z (ES +)=365.00,366.98[M+H] +RT=2.64 minute.
Preparation example 177:3-(7-chloronaphthalene-1-yl)-5, the 6-glyoxalidine is [2,1-b] thiazole-2-formaldehyde also
Figure A20068001139500981
With 2-bromo-3-(7-chloronaphthalene-1-yl)-5, the 6-glyoxalidine also [2,1-b] thiazole hydrobromide salt (preparation example 176,4.57g 12.4mmol) are dissolved among 0 ℃ the THF (100mL).After 2 hours, (5.6mL, 64.6mmol), mixture at room temperature stirred 12 hours, then at EtOAc (300mL) and saturated NH to add DMF 4Distribute between the Cl solution (100mL).Separate organic layer, washing (saturated NaHCO 3Solution, salt solution then), dry (MgSO 4), vacuum concentration obtains target compound then, δ H(DMSO): 3.57 (2H, m), 4.37 (2H, m), 7.59-7.66 (3H, m), 7.77 (1H, d), 7.96 (1H, d), 8.08 (1H, dd), 9.14 (1H, s); M/z (ES +)=315.00[M+H] +RT=2.49 minute.
Preparation example 178:6-fluoronaphthalene-1-carboxylic acid
Figure A20068001139500982
(65g, (25g is in fluorobenzene 260mmol) (250mL) suspension 487mmol) to be added to furans-2-carboxylic acid of 0 ℃ with Aluminum chloride anhydrous carefully.After 1 hour, remove ice bath, mixture slowly is heated to 75 ℃, is keeping 12 hours in this temperature again.Mixture is added in the 2N HCl solution (1.5L), and extraction is advanced ether (in 3 * 300mL) then.The combined ether layer, saturated NaHCO is used in water (250mL) washing then 3Solution (3 * 250mL) extractions.Use dense HCl solution with basic solution furnishing acidity, with EtOAc (3 * 250mL) extractions once more.Vacuum concentration, dry then (MgSO 4), obtain solid residue, in the presence of toluene (50mL), stirred 12 hours.Filter, obtain target compound, δ H(DMSO): 7.56 (1H, ddd), 7.66 (1H, dd), 7.84 (1H, dd), 8.16 (2H, m), 8.97 (1H, dd), 13.27 (1H, br s); M/z (ES -)=189.19[M-H] +RT=3.14 minute.
Preparation example 179:6,7-two fluoronaphthalenes-1-carboxylic acid
Figure A20068001139500991
Use to preparation example 178 described similar conditions from 1,2-two fluorobenzene prepare target compound.δ H(DMSO)：2.31(3H，s)，7.66(1H，dd)，8.13(1H，dd)，8.21(1H，d)，8.27(1H，d)，8.91(1H，dd)，13.70(1H，br?s)。
Preparation example 180:6-fluoronaphthalene-1-base amine
Figure A20068001139500992
(10.2g, (preparation example 178,20.0g is 105mmol) at CHCl 157mmol) to be added to 6-fluoronaphthalene-1-carboxylic acid of 40 ℃ with sodiumazide in batches in 5 hours 3(400mL) with dense H 2SO 4In the mixture (100mL).Separation of C HCl 3Behind the layer, water layer is added on the ice (1kg).The suspension that obtains is used dense NH under cooling 4OH solution furnishing alkalescence is used Et then 2O (3 * 250mL) extractions.The extract (salt solution) that washing merges, dry (MgSO 4), vacuum concentration obtains target compound, δ H(DMSO): 5.82 (2H, br s), 6.66 (1H, d), 7.06 (1H, d), 7.23-7.27 (2H, m), 7.49 (1H, dd), 8.16 (1H, dd); M/z (ES +)=162.06[M+H] +RT=2.57 minute.
Preparation example 181:1-chloro-6-fluoronaphthalene
Figure A20068001139500993
(2.16g, water 31.3mmol) (50mL) solution are added to 0 ℃ 6-fluoronaphthalene-1-base amine, and ((100mL is 6M) in the suspension for rare HCl 34.2mmol) for preparation example 180,5.50g with Sodium Nitrite in 15 minutes.The mixture that obtains stirred 1 hour under cooling, and (100mL is 6M) in the suspension to be added to rare HCl of cuprous chloride (I) then.After the vigorous stirring 2 hours, (1L) is added in the suspension with water, with ether (3 * 200mL) extractions.Dry extract (the MgSO that merges 4), vacuum concentration obtains residue then, by (the eluent: hexane/EtOAc:6/1), obtain target compound, δ of purification by flash chromatography on silica gel H(DMSO): 7.33 (1H, dd), 7.38 (1H, ddd), 7.46 (1H, d), 7.63 (1H, dd), 7.72 (1H, d), 8.01 (1H, dd).
Preparation example 182:1-(5-fluoronaphthalene-1-yl) third-1-alcohol
Figure A20068001139501001
With n-Butyl Lithium (5.5mL, 2.5M hexane solution) slowly be added to-78 ℃ 1-bromo-5-fluoronaphthalene (people such as M.S.Newman, J.Org.Chem., 1959,24,509-512) (2.40g is in THF 10.7mmol) (50mL) solution.Stir after 1 hour, (2.5mL 34.7mmol) is added in the green solution, removes CO with propionic aldehyde 2/ IPA bathes.Behind the restir 90 minutes, mixture is added to saturated NH 4In the Cl solution (250mL).With EtOAc (3 * 100mL) extractions, the dry extract (MgSO that merges 4), vacuum concentration obtains residue then, by (the eluent: hexane/EtOAc:4/1), obtain target compound, δ of purification by flash chromatography on silica gel H(DMSO): 0.93 (3H, t), 1.72 (2H, m), 5.24 (1H, m), 5.37 (1H, d), 7.33 (1H, dd), 7.53 (1H, m), 7.64 (1H, dd), 7.74 (1H, d), 7.98 (1H, d), 8.01 (1H, d).
Preparation example 183:1-(5-fluoronaphthalene-1-yl) third-1-ketone
Figure A20068001139501002
To 1-(5-fluoronaphthalene-1-yl) third-1-alcohol (preparation example 182,1.62g, add in dried DCM (75mL) solution 7.93mmol) DMP reagent (3.40g, 8.02mmol).Stir after 2 hours under the room temperature, add alkaline hypo solution (8.0g Na 2SO 3Be dissolved in the saturated NaHCO of 30mL 3In the solution), emulsion is vigorous stirring 10 minutes again, water (～100mL) dilution then.(3 * 50mL) extractions are with the extract of saturated sodium bicarbonate (50mL) and salt solution (50mL) washing merging with EtOAc.Dry (MgSO 4) and vacuum concentration after, residue by on silica gel purification by flash chromatography (eluent: hexane/EtOAc:4/1), obtain target compound, δ H(DMSO): 1.17 (3H, t), 3.14 (2H, q), 7.43 (1H, dd), 7.61 (1H, m), 7.73 (1H, dd), 8.16 (1H, d), 8.26 (2H, m).
Preparation example 184:1-(5-fluoronaphthalene-1-yl) fourth-1-alcohol
Figure A20068001139501011
To preparation example 182 described similar conditions under prepare target compound from 1-bromo-5-fluoronaphthalene and butyraldehyde.δ H(DMSO)：0.91(3H，t)，1.44，1.55(4H，2m)，5.30(1H，m)，5.37(1H，d)，7.33(1H，dd)，7.54(1H，m)，7.62(1H，dd)，7.75(1H，d)，7.98(1H，d)，8.01(1H，d)。
Preparation example 185:1-fluoro-6-methylnaphthalene
Figure A20068001139501012
(1.84g, water 26.7mmol) (20mL) solution are added to 0 ℃ 6-methylnaphthalene-1-base amine in batches, and ((40mL is 6M) in the suspension for rare HCl 26.1mmol) for preparation example 79,4.10g with Sodium Nitrite under the vigorous stirring.After 2 hours, add Tetrafluoroboric acid (9.5mL, 48%), mixture restir 30 minutes under cooling.Collecting precipitation is with tetrafluoroborate solution (50mL, 20%) and water (50mL) washing, vacuum-drying at room temperature 3 days.Pulverous diazonium salt is heated to 160 ℃ to be kept 15 minutes.Behind the cool to room temperature, residue is absorbed in the ether (300mL), uses NaHCO 3Solution and salt water washing.Dry (MgSO 4), vacuum concentration obtains residue, by (the eluent: hexane/EtOAc:9/1), obtain target compound of purification by flash chromatography on silica gel.Diazonium salt: δ H(DMSO): 2.62 (3H, s), 7.98-8.05 (2H, m), 8.22 (1H, s), 8.43 (1H, d), 8.83 (1H, d), 9.13 (1H, d); Target compound: δ H(DMSO): 2.51 (3H, s), 7.25 (1H, dd), 7.45-7.50 (1H, m), 7.69 (1H, d), 7.79 (1H, s), 7.97 (1H, d).
Preparation example 186:5-fluoronaphthalene-2-formaldehyde
Figure A20068001139501021
(2.07g, 18.7mmol) (4.58mmol) the mixture heating up in the Zai diox (20mL) refluxed 7 days for preparation example 185,734mg with 1-fluoro-6-methylnaphthalene with tin anhydride.Mixture filters with EtOAc (200mL) dilution, water (50mL) and salt solution (50mL) washing.Dry (MgSO 4), vacuum concentration obtains residue, by (the eluent: hexane/EtOAc:4/1), obtain target compound of purification by flash chromatography on silica gel.δ H(CDCl 3)：7.27(1H，dd)，7.46(1H，ddd)，7.74(1H，d)，7.93(1H，dd)，8.13(1H，d)，8.29(1H，s)，10.11(1H，s)。
Preparation example 187:1-(5-fluoronaphthalene-2-yl) third-1-alcohol
Figure A20068001139501022
Ethylmagnesium chloride (0.8mL, 2M ethereal solution) is added to 5-fluoronaphthalene-2-formaldehyde of-78 ℃, and (preparation example 186,117mg is in THF solution 0.672mmol).Remove CO 2/ IPA bathes, and mixture at room temperature stirred 12 hours, added saturated NH then 4Cl solution (50mL).Separate each layer, (3 * 30mL) extract water layer with EtOAc.Merge organic layer, washing (salt solution), dry (MgSO 4), vacuum concentration.By (the eluent: hexane/EtOAc:4/1), obtain target compound, δ of purification by flash chromatography on silica gel H(CDCl 3): 0.99 (3H, t), 1.91 (2H, dq), 4.82 (1H, t), 7.16 (1H, dd), 7.43 (1H, ddd), 7.56 (1H, dd), 7.65 (1H, d), 7.84 (1H, s), 8.13 (1H, d).
Embodiment 1:3-naphthalene-1-base-5,6-glyoxalidine be [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501031
(2.58mmol) (0.264g 2.58mmol) is dissolved among EtOH (15mL) and the AcOH (7mL), reaction reflux 16 hours with 2-imidazolidine thioketones for preparation example 1,0.643g with 2-bromo-1-naphthalene-1-base-ethyl ketone.The reaction mixture cool to room temperature, filtering-depositing is used Et 2(2 * 20mL) washings, drying obtains target compound to O, δ H(DMSO): 4.06 (2H, m), 4.26 (2H, m), 7.03 (1H, s), 7.62-7.70 (4H, m), 7.98 (1H, m), 8.07 (1H, m), 8.14 (1H, m), 9.66 (1H, br s); M/z (ES +)=253[M+H] +RT=2.44 minute.
Embodiment 2:3-naphthalene-2-base-5,6-glyoxalidine be [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501032
(0.25g, 1mmol) (0.1g 1mmol) is dissolved among EtOH (8mL) and the AcOH (4mL), reaction reflux 4 hours with 2-imidazolidine thioketones with 2-bromo-1-naphthalene-2-base ethyl ketone.Reaction mixture cool to room temperature then, filtering-depositing is used Et 2(2 * 20mL) washings, vacuum-drying obtains target compound to O.δ H(DMSO): 4.06 (2H, m), 4.26 (2H, m), 7.03 (1H, s), 7.62-7.70 (4H, m), 7.98 (1H, m), 8.07 (1H, m), 8.14 (1H, m), 9.66 (1H, br s); M/z (ES +)=253[M+H] +RT=2.44 minute.
Embodiment 3:2-methyl-3-naphthalene-2-base-5,6-glyoxalidine be [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501041
With 2-bromo-1-naphthalene-2-base third-1-ketone (preparation example 3,3.74g, 14.2mmol) and 2-imidazolidine thioketones (1.45g 14.2mmol) is dissolved among AcOH (20mL) and the EtOH (40mL), and reflux 16 hours.The reaction mixture cool to room temperature filters the solid of separating out, and uses Et 2(2 * 40mL) washings, drying obtains target compound to O, δ H(DMSO): 2.31 (3H, s), 4.25 (2H, m), 4.37 (2H, m), 7.64 (3H, m), 8.04 (2H, m), 8.11-8.15 (2H, m), 9.60 (1H, br s); M/z (ES +)=267.1[M+H] +RT=2.42 minute.
Embodiment 4:2-bromo-3-naphthalene-2-base-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501042
With 3-naphthalene-2-base-5, the 6-glyoxalidine also [2,1-b] thiazole hydrobromide salt (embodiment 2, and 1g is 3.0mmol) at saturated Na 2CO 3Solution (30mL) and DCM (distribute between 3 * 30mL).Merge organic fraction, dry (MgSO 4), vacuum concentration.Residue is dissolved among the DCM (10mL) and is cooled to 0 ℃.(154 μ L 3.0mmol), are reflected at 0 ℃ and stirred 30 minutes down, rise to room temperature then and stir 1 hour to add bromine.Reaction mixture Et 2O (30mL) dilute filtration solid is used Et 2(2 * 30mL) washings obtain target compound, δ to O H(DMSO): 4.25 (2H, m), 4.38 (2H, m), 7.66 (3H, m), 8.04 (1H, d), 8.08 (1H, d), 8.14 (1H, d), 8.21 (1H, s), 9.62 (1H, br s); M/z (ES +)=331[M+H] +RT=2.86 minute.
Embodiment 5:2-chloro-3-naphthalene-1-base-5, the 6-glyoxalidine is [2,1-b] thiazole hydrochloride also
Figure A20068001139501043
With 3-naphthalene-1-base-5, the 6-glyoxalidine also [2,1-b] thiazole hydrobromide salt (embodiment 1, and 1g is 3.0mmol) at saturated NaHCO 3Solution (40mL) and DCM (distribute between 2 * 50mL).Merge organic fraction, dry (MgSO 4), vacuum concentration.Residue is dissolved in the acetone (70mL) and is cooled to 0 ℃.Add benzyl trimethyl tetrachloro ammonium iodate in 5 minutes (1.28g 3.1mmol), is reflected at 0 ℃ and stirred 1 hour down, at room temperature stirs then 2 hours in batches.Filter reaction mixture is used MeCN: Et 2(1: 2, Et was used in 2 * 25mL) washings to O then 2O (2 * 25mL) washings.Solid is with warm iPrOH grinds, and obtains target compound.δ H(DMSO): 3.91 (1H, m), 4.19 (3H, m), 7.71 (4H, m), 7.91 (1H, m), 8.10 (1H, m), 8.20 (1H, m), 10.42 (1H, br s); M/z (ES +)=286[M+H] +RT=2.56 minute.
Embodiment 6:3-thieno-[2,3-b] thiophene-2-base-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501051
With 2-bromo-1-thieno-[2,3-b] thiophene-2-base ethyl ketone (preparation example 6,420mg, 1.61mmol) and 2-imidazolidine thioketones (164mg, 1.61mmol) reflux 48 hours in AcOH (5mL) and EtOH (10mL).The reaction mixture cool to room temperature filters the solid of separating out, and uses Et 2The O washing obtains target compound.δ H(DMSO): 4.34 (2H, m), 4.64 (2H, m), 7.05 (1H, s), 7.38 (1H, d), 7.72 (1H, d), 7.75 (1H, s), 9.75 (1H, br s); M/z (ES +)=265[M+H] +RT=2.54 minute.
Embodiment 7:3-(4-methylnaphthalene-1-yl)-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501052
With 2-bromo-1-(4-methylnaphthalene-1-yl) ethyl ketone (preparation example 7,0.54g, 1.9mmol) and imidazolidine-2-thioketones (0.2g, EtOH 1.9mmol) (10mL) stirred solution reflux, and add AcOH (5mL).Reaction stirring and refluxing 24 hours is cooled to 0 ℃ then.Solid collected by filtration obtains target compound.δ H(DMSO): 2.73 (3H, s), 4.01 (2H, m), 4.24 (2H, m), 6.94 (1H, s), 7.51 (1H, d), 7.57 (1H, d), 7.67 (2H, m), 7.97 (1H, d), 8.16 (1H, d), 9.59 (1H, br s); M/z (ES +)=267[M+H] +RT=2.90 minute.
Embodiment 8:2-(5, the 6-glyoxalidine is [2,1-b] thiazole-3-yl also) quinoline hydrobromate
Figure A20068001139501061
To 2-bromo-1-quinoline-2-base ethyl ketone (preparation example 11,98mg, 0.392mmol) EtOH and AcOH (2: 1, add in the solution of mixture 15mL) imidazolidine-2-thioketones (42mg, 0.411mmol), the suspension reflux that obtains 12 hours.Through in ice bath, cooling off, spontaneously form precipitation, collect, with the EtOAc washing, obtain target compound, δ H(DMSO): 4.39 (2H, dd), 5.07 (2H, dd), 7.72 (1H, m), 7.83 (1H, s), 7.88 (1H, m), 8.08 (2H, m), 8.16 (1H, d), 8.55 (1H, d), 9.69 (1H, br s); M/z (ES +)=254.09[M+H] +RT=2.64 minute.
Embodiment 9:3-(4-fluoronaphthalene-1-yl)-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501062
With 2-bromo-1-(4-fluoronaphthalene-1-yl) ethyl ketone (preparation example 12,0.60g, 2.25mmol) and 2-imidazolidine thioketones (0.23g, 2.25mmol) reflux 16 hours in AcOH (7mL) and EtOH (14mL).The reaction mixture cool to room temperature filters the solid of separating out, and uses Et 2The O washing obtains target compound.δ H(DMSO): 4.06 (2H, m), 4.27 (2H, m), 7.04 (1H, s), 7.52 (1H, m), 7.75 (3H, m), 8.05 (1H, m), 8.19 (1H, m), 9.68 (1H, br s); M/z (ES +)=271[M+H] +RT=1.77 minute.
Embodiment 10:3-naphthalene-2-base-5,6-glyoxalidine be [2,1-b] thiazole-2-carboxylic acid, ethyl ester hydrobromate also
Figure A20068001139501071
With 2-bromo-3-naphthalene-2-base-3-oxo ethyl propionate (preparation example 14,5.58g, 17.4mmol) and 2-imidazolidine thioketones (1.78g, 17.4mmol) reflux 16 hours in AcOH (25mL) and EtOH (50mL).Solvent removed in vacuo, residue are dissolved in MeCN (80mL) and Et 2Among the O (5mL).The solid that filtration is separated out is used Et 2(2 * 40mL) washings obtain target compound, δ to O H(DMSO): 1.03 (3H, t), 4.12 (2H, q), 4.29 (4H, m), 7.66 (3H, m), 8.04 (2H, d), 8.08 (1H, d), 8.24 (1H, s), 10.10 (1H, br s); M/z (ES +)=325[M+H] +RT=2.69 minute.
Embodiment 11:2-bromo-3-naphthalene-1-base-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501072
With 3-naphthalene-1-base-5, the 6-glyoxalidine also [2,1-b] thiazole hydrobromide salt (embodiment 1, and 5g is 15.0mmol) at saturated NaHCO 3Solution (70mL) and DCM (distribute between 2 * 75mL).Merge organic fraction, dry (MgSO 4), vacuum concentration.Residue is dissolved among the DCM (50mL) and is cooled to 0 ℃.(reaction rises to room temperature and stirred 3 hours dripping bromine for 0.77mL, DCM 15.0mmol) (7mL) solution.Reaction mixture Et 2O (50mL) dilution, filtering-depositing is used MeCN: Et 2(2: 1, Et was used in 3 * 50mL) washings to O then 2(2 * 30mL) washings obtain target compound, δ to O H(DMSO): 3.90 (1H, m), 4.17 (3H, m), 7.66 (2H, m), 7.72 (2H, m), 7.89 (1H, m), 8.10 (1H, m), 8.20 (1H, d), 9.66 (1H, br s); M/z (ES +)=331[M+H] +RT=2.44 minute.
Embodiment 12:2-methyl-3-naphthalene-1-base-5,6-glyoxalidine be [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501081
With 2-bromo-1-naphthalene-1-benzylacetone (preparation example 16,4.28g, 16.3mmol) and imidazolidine-2-thioketones (1.64g 16.3mmol) is dissolved among EtOH (15mL) and the AcOH (7.5mL), reaction reflux 4 hours.The reaction mixture cool overnight is filtered collecting precipitation, with acetonitrile (20mL) and Et 2O (2 * 20mL) washings, dry then, obtain target compound, δ H(DMSO): 2.05 (3H, s), 3.82 (1H, m), 4.07 (1H, m), 4.28 (2H, m), 7.65-7.70 (4H, m), 7.81 (1H, m), 8.05 (1H, m), 8.18 (1H, m), 9.58 (1H, br s); M/z (ES +)=266.99[M+H] +RT=2.62 minute.
Embodiment 13:3-naphthalene-1-base-5,6-glyoxalidine be [2,1-b] thiazol-2-yl methyl alcohol also
Figure A20068001139501082
In argon gas atmosphere with 3-naphthalene-1-base-5, the 6-glyoxalidine also [2,1-b] thiazole-2-formaldehyde (preparation example 17,281mg 1.0mmol) are suspended among the MeOH (10mL) and are cooled to 0 ℃.(57mg 1.5mmol), is reflected at 0 ℃ and stirred 2 hours down, at room temperature stirs then 16 hours to add sodium borohydride.Add entry (40mL), filtering-depositing, (2 * 20mL) washings 40 ℃ of following vacuum-dryings, obtain target compound, δ to water H(DMSO): 3.32 (2H, s), 3.98 (4H, m), 5.19 (1H, br s), 7.59 (4H, m), 7.85 (1H, m), 8.04 (2H, m); M/z (ES +)=283[M+H] +RT=2.26 minute.
Embodiment 14:2-ethynyl-3-naphthalene-1-base-5,6-glyoxalidine be [2,1-b] thiazole also
Figure A20068001139501091
(0.256mL, (89.4 μ L are in THF solution 0.64mmol) 0.64mmol) to be added to 0 ℃ Diisopropylamine with n-Butyl Lithium.After 10 minutes, solution is cooled to-78 ℃, adds trimethyl silyl diazomethane (2M is among the THF for 0.51mL, 1.02mmol).After 1 hour, drip 3-naphthalene-1-base-5, the 6-glyoxalidine also [2,1-b] thiazole-2-formaldehyde (preparation example 17,150mg, THF 0.535mmol) (10mL) solution, reaction rises to room temperature.After the reflux 3 hours, solution cooling, DCM (3 * 25mL) and water (20mL) between distribution.Separate organic layer, dry (MgSO 4), filter vacuum concentration.Residue is purifying on silica gel, uses acetone: hexane (1: 1) wash-out obtains target compound, δ H(CDCl 3): 7.85 (3H, m), 7.42 (4H, m), 4.10 (2H, m), 3.40 (2H, m), 2.90 (1H, s); M/z (ES +)=277.01[M-H] +RT=2.45 minute.
Embodiment 15:3-(7-chloronaphthalene-1-yl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501092
To 2-bromo-1-(7-chloronaphthalene-1-yl) third-1-ketone (preparation example 19,1.45g, 4.87mmol) EtOH and AcOH (1: 1, add imidazolidine-2-thioketones (580mg in the solution in mixture 100mL), 5.68mmol), the suspension reflux that obtains 12 hours.Solvent removed in vacuo, residue are distributed between dilute NaOH solution (300mL) and EtOAc (100mL).Separate that this is two-layer, water layer is with EtOAc (2 * 100mL) extractions once more then.With the extract that salt solution (100mL) washing merges, dry (MgSO 4), concentrate.By purification by flash chromatography on silica gel (eluent DCM: MeOH, 10: 1), obtain the free alkali of target compound.Free alkali is absorbed among the MeOH (150mL), and the usefulness Hydrogen bromide (30%, in the acetate, 1.0mL) handle.Remove desolvate after, residue EtOAc and acetonitrile (10: 1, stir in mixture 50mL), separate out up to the target compound crystallization, filter and collect, δ H(DMSO): 2.06 (3H, s), 3.89 (1H, ddd), 4.06-4.27 (3H, m), 7.69 (1H, dd), 7.72-7.78 (2H, m), 7.94 (1H, s), 8.16 (1H, d), 8.23 (1H, dd), 9.55 (1H, br s); M/z (ES +)=300.96[M+H] +RT=2.56 minute.
Embodiment 16:1-(3-naphthalene-1-base-5,6-glyoxalidine be [2,1-b] thiazol-2-yl also) ethanol
Figure A20068001139501101
In argon gas atmosphere with 3-naphthalene-1-base-5, the 6-glyoxalidine also [2,1-b] thiazole-2-formaldehyde (preparation example 17,200mg 0.71mmol) are dissolved among the THF (25mL), and are cooled to 0 ℃.Add methyl-magnesium-bromide (3.0M, Et 2Among the O, 0.71mL 2.14mmol), is reflected at 0 ℃ and stirred 1 hour down, at room temperature stirs then 16 hours.The quencher of reaction water (40mL), EtOAc (3 * 40mL) is advanced in extraction.Merge organic fraction, dry (MgSO 4), vacuum concentration obtains target compound, δ H(CDCl 3): 1.24,1.35 (3H, 2d), 2.52 (1H, br s), 3.30 (2H, m), 4.03 (2H, m), 4.49 (1H, m), 7.27-7.53 (4H, m), 7.73-7.90 (3H, m); M/z (ES +)=297[M+H] +RT=2.26 minute.
Embodiment 17:3-naphthalene-1-base-5,6-glyoxalidine be [2,1-b] thiazole-2-nitrile also
Figure A20068001139501102
With 3-naphthalene-1-base-5, the 6-glyoxalidine also [2,1-b] thiazole-2-formaldehyde (preparation example 17,300mg, 1.07mmol) and hydroxy amine hydrochloric acid salt (97mg 1.39mmol) is dissolved in the formic acid (10mL), is heated to 100 ℃ and keeps 16 hours.Reaction mixture Et 2Filter solid is crossed in O (50mL) dilution, uses Et 2O (2 * 30mL) washings.Solid is chromatogram purification on silica gel, uses MeOH: DCM (3: 97) wash-out obtains target compound.δ H(CDCl 3): 3.50 (1H, m), 3.61 (1H, m), 4.28 (2H, m), 7.62 (4H, m), 7.79 (1H, d), 7.97 (1H, d), 8.04 (1H, d); M/z (ES +)=278[M+H] +RT=2.31 minute.
Embodiment 18:2-methyl sulfane base-3-naphthalene-1-base-5, the 6-glyoxalidine is [2,1-b] thiazole also
Figure A20068001139501111
In argon gas atmosphere with 2-bromo-3-naphthalene-1-base-5, the 6-glyoxalidine also [2,1-b] thiazole hydrobromide salt (embodiment 11, and 0.5g 1.21mmol) is suspended among the THF (20mL) and is cooled to 0 ℃.Drip ethylmagnesium chloride (2.0M, Et in 5 minutes 2Among the O, 1.8mL 3.64mmol), is reflected at 0 ℃ and stirred 2 hours down.(0.22mL, 2.43mmol), reaction mixture at room temperature stirred 16 hours to add dimethyl disulfide.The saturated NH of reaction 4Cl solution (40mL) quencher, EtOAc (3 * 30mL) is advanced in extraction then.Merge organic fraction, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use MeOH: DCM (1: 19) wash-out obtains target compound.δ H(CDCl 3): 2.18 (3H, s), 3.41 (2H, m), 4.10 (2H, m), 7.45 (1H, d), 7.55 (3H, m), 7.83 (1H, m), 7.95 (2H, m); M/z (ES +)=299[M+H] +RT=2.45 minute.
Embodiment 19:(3-naphthalene-2-base-5,6-glyoxalidine be [2,1-b] thiazol-2-yl also) methyl alcohol
In argon gas atmosphere with 3-naphthalene-2-base-5, the 6-glyoxalidine also [2,1-b] thiazole-2-formaldehyde (preparation example 20,0.5g 1.78mmol) are suspended among the MeOH (20mL) and are cooled to 0 ℃.(0.10g 2.68mmol), is reflected at 0 ℃ and stirred 0.5 hour down, rises to room temperature then and keeps 2 hours to add sodium borohydride.Add entry (40mL), filtering-depositing, water (2 * 20mL) and Et 2(2 * 20mL) washings, drying obtains target compound to O, δ H(DMSO): 3.70 (2H, m), 4.01 (2H, m), 4.28 (2H, d), 5.34 (1H, m), 7.58 (3H, m), 7.98 (3H, m), 8.03 (1H, m); M/z (ES +)=283[M+H] +RT=2.27 minute.
Embodiment 20:1-(3-naphthalene-2-base-5,6-glyoxalidine be [2,1-b] thiazol-2-yl also) ethanol
In argon gas atmosphere with 3-naphthalene-2-base-5, the 6-glyoxalidine also [2,1-b] thiazole-2-formaldehyde (preparation example 20,200mg 0.71mmol) are dissolved among the THF (25mL) and are cooled to 0 ℃.Drip methyl-magnesium-bromide (3.0M, Et 2Among the O, 0.71mL, 2.14mmol), the reaction remain on 0 ℃ following 1 hour, at room temperature stirred then 16 hours.Add entry (40mL), reaction mixture extracts into EtOAc (3 * 30mL).Merge organic fraction, dry (MgSO 4), vacuum concentration obtains target compound, δ H(CDCl 3): 1.46 (3H, d), 3.40 (1H, br s), 3.66 (2H, m), 4.14 (2H, m), 4.86 (1H, m), 7.47 (1H, d), 7.56 (2H, m), 7.90 (4H, m); M/z (ES +)=297[M+H] +RT=2.40 minute.
Embodiment 21:2-(3-naphthalene-2-base-5,6-glyoxalidine be [2,1-b] thiazol-2-yl also) propan-2-ol
Figure A20068001139501122
With 3-naphthalene-2-base-5, the 6-glyoxalidine also [2,1-b] thiazole-2-carboxylic acid, ethyl ester hydrobromate (embodiment 10, and 1g is 2.5mmol) at saturated NaHCO 3Solution (40mL) and DCM (distribute between 3 * 30mL).Merge organic fraction, dry (MgSO 4), vacuum concentration.Residue is dissolved among the THF (20mL) and is cooled to 0 ℃ in argon gas atmosphere.Drip methyl-magnesium-bromide (3.0M, Et 2Among the O, 2.5mL 7.4mmol), is reflected at 0 ℃ and stirred 1 hour down, at room temperature stirs then 16 hours.Add entry (40mL), reaction mixture extracts into EtOAc (3 * 30mL).Merge organic fraction, dry (MgSO 4), vacuum concentration obtains target compound, δ H(CDCl 3): 1.37 (6H, s), 3.43 (2H, m), 4.06 (2H, m), 7.44 (1H, dd), 7.56 (2H, m), 7.89 (4H, m); M/z (ES +)=311[M+H] +RT=2.45 minute.
Embodiment 22:3-(4-fluoronaphthalene-1-yl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501131
With 2-bromo-1-(4-fluoronaphthalene-1-yl) third-1-ketone (preparation example 22,4.59g, 16.3mmol) and 2-imidazolidine thioketones (1.67g, 16.3mmol) reflux 24 hours in AcOH (20mL) and EtOH (40mL).Solvent removed in vacuo, residue are dissolved among the MeCN (10mL), add Et then 2O (80mL).The solid that filtration is separated out is used Et 2(2 * 30mL) washings obtain target compound, δ to O H(DMSO): 2.05 (3H, s), 3.85 (1H, m), 4.09 (1H, m), 4.20 (2H, m), 7.54 (1H, m), 7.71 (1H, m), 7.75 (2H, m), 7.88 (1H, m), 8.20 (1H, m), 9.56 (1H, br s); M/z (ES +)=285[M+H] +RT=2.56 minute.
Embodiment 23:2-ethyl-3-naphthalene-1-base-5,6-glyoxalidine be [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501132
With 2-bromo-1-naphthalene-1-Ji Ding-1-ketone (preparation example 24,0.82g, 3.0mmol) and 2-imidazolidine thioketones (0.30g 3.0mmol) is dissolved among AcOH (10mL) and the EtOH (20mL), and reflux 8 hours, at room temperature stirs then 72 hours.Solvent removed in vacuo, residue is at saturated NaHCO 3Solution (40mL) and EtOAc (distribute between 2 * 40mL).Merge organic fraction, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel is used MeOH: DCM (2: 23) wash-out.Residue is dissolved among the EtOAc (20mL), adds the 30%HBr among the AcOH (1ML).Solvent removed in vacuo obtains target compound, δ H(DMSO): 1.04 (3H, t), 2.33-2.47 (2H, m), 3.83 (1H, m), 4.06 (1H, m), 4.21 (2H, m), 7.67 (4H, m), 7.83 (1H, m), 8.09 (1H, m), 8.17 (1H, m), 9.68 (1H, br s); M/z (ES +)=281[M+H] +RT=2.52 minute.
Embodiment 24:2-sec.-propyl-3-naphthalene-1-base-5,6-glyoxalidine be [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501141
With 2-bromo-3-methyl isophthalic acid-naphthalene-1-Ji Ding-1-ketone (preparation example 26,0.39g, 1.3mmol) and 2-imidazolidine thioketones (0.14g 1.3mmol) is dissolved among AcOH (5mL) and the EtOH (10mL), and reflux 16 hours.Solvent removed in vacuo, residue is at saturated NaHCO 3Solution (40mL) and EtOAc (distribute between 3 * 30mL).Merge organic fraction, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel is used MeOH: DCM (2: 23) wash-out.Residue is dissolved among the MeCN (20mL), adds the 30%HBr among the AcOH (0.5mL) then.Solvent removed in vacuo, residue are dissolved among the MeCN (5mL), and are added to Et 2Among the O (25mL).Cross filter solid, drying obtains target compound.δ H(DMSO): 1.10 (3H, d), 1.15 (3H, d), 2.69 (1H, m), 3.80 (1H, m), 4.01 (1H, m), 4.20 (2H, m), 7.68 (4H, m), 7.84 (1H, m), 8.09 (1H, m), 8.17 (1H, m), 9.74 (1H, br s); M/z (ES +)=295[M+H] +RT=2.62 minute.
Embodiment 25:[3-(7-chloronaphthalene-1-yl)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-methyl alcohol
To 3-(7-chloronaphthalene-1-yl)-5, the 6-glyoxalidine also [2,1-b] thiazole-2-formaldehyde (preparation example 177,1.14g, ethanol/water 3.62mmol): add in 5/1 (60mL) solution sodium borohydride (300mg, 7.92mmol).Stir after 12 hours, with rare HCl solution souring soln, water (100mL) dilution again.Behind the vacuum concentration, (～50mL) condistillation twice is then at EtOAc (200mL) and saturated NaHCO for residue and methyl alcohol 3Distribute between the solution (200mL).Separate organic layer, water layer is used EtOAc (2 * 100mL) extractions again.The extract (salt solution) that washing merges, dry (MgSO 4), concentrate.By purification by flash chromatography residue (eluent: DCM/ methyl alcohol: 8/2), obtain target compound, δ H(DMSO): 3.35 (1H, m), 3.47 (1H, m), 3.95-4.05 (3H, m), 5.40 (1H, br s), 7.64-7.69 (3H, m), 7.86 (1H, d), 8.11-8.15 (2H, m); M/z (ES +)=317.05[M+H] +RT=2.50 minute.
Embodiment 26:3-(6-fluoronaphthalene-2-yl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501152
With 2-bromo-1-(6-fluoronaphthalene-2-yl) third-1-ketone (preparation example 32,0.86g, 4.1mmol) and imidazolidine-2-thioketones (0.42g, 4.1mmol) the stirred solution reflux in EtOH (20mL), and add AcOH (10mL).Reaction stirring and refluxing 24 hours, cool to room temperature then.Add acetonitrile (20mL), separate out solid.Filter collecting precipitation, obtain target compound, δ H(DMSO): 2.31 (3H, s), 4.24 (2H, m), 4.35 (2H, m), 7.56 (1H, td), 7.69 (1H, d), 7.85 (1H, dd), 8.10 (1H, d) 8.15 (1H, m), 8.19 (1H, s), 9.50 (1H, br s); M/z (ES +)=285[M+H] +RT=2.56 minute.
Embodiment 27:3-(6-chloronaphthalene-2-yl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501161
With 2-bromo-1-(6-chloronaphthalene-2-yl) third-1-ketone (preparation example 36,1.27g, 4.3mmol) and imidazolidine-2-thioketones (0.43g, 4.3mmol) the stirred solution reflux in EtOH (20mL) add AcOH (10mL).Reaction stirring and refluxing 24 hours.The reaction cool to room temperature filters and collects the precipitation that obtains, and obtains target compound.δ H(DMSO): 2.31 (3H, s), 4.25 (2H, m), 4.35 (2H, m), 7.65 (1H, dd), 7.77 (1H, dd), 8.11 (2H, m), 8.18 (2H, s), 9.52 (1H, br s); M/z (ES +)=301[M+H] +RT=2.74 minute.
Embodiment 28:2-ethyl-3-naphthalene-2-base-5,6-glyoxalidine be [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501162
With 2-bromo-1-naphthalene-2-Ji Ding-1-ketone (preparation example 38,0.87g, 3.5mmol) and imidazolidine-2-thioketones (0.36g, 3.5mmol) the stirred solution reflux in EtOH (10mL) add AcOH (5mL).Reaction stirring and refluxing 48 hours, cool to room temperature then.Solvent removed in vacuo adds EtOAc and acetonitrile, separates out solid.Solvent removed in vacuo obtains solid, uses Et 2O grinds, and filters then and collects, and obtains target compound, δ H(DMSO): 1.17 (3H, t), 2.69 (2H, q), 4.24 (2H, m), 4.31 (2H, m), 7.64 (3H, m), 8.04 (2H, m), 8.11 (2H, m), 9.70 (1H, br s); M/z (ES +)=281[M+H] +RT=2.64 minute.
Embodiment 29:3-(2-methyl-5,6-glyoxalidine be [2,1-b] thiazole-3-yl also) benzo [d] isothiazole hydrobromate
Figure A20068001139501171
With 1-benzo [d] isothiazole-3-base-2-bromine third-1-ketone (preparation example 43,0.4g, 1.8mmol) and imidazolidine-2-thioketones (0.18g, 1.8mmol) the stirred solution reflux in EtOH (10mL) add AcOH (5mL).Reaction reflux 48 hours, cool to room temperature, solvent removed in vacuo.EtOAc is added in the residue, observes precipitation.Solid collected by filtration obtains target compound, δ H(DMSO): 2.28 (3H, s), 4.24 (4H, m), 7.64 (1H, t), 7.74 (1H, t), 8.12 (1H, d), 8.39 (1H, d), 9.57 (1H, br s); M/z (ES +)=274[M+H] +RT=2.12 minute.
Embodiment 30:3-(5-chloronaphthalene-1-yl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501172
With 2-bromo-1-(5-chloronaphthalene-1-yl) third-1-ketone (preparation example 71,118mg, 0.4mmol) and 2-imidazolidine thioketones (41mg, 0.4mmol) reflux 24 hours in EtOH (10mL) and AcOH (5mL).The reaction mixture cool to room temperature, vacuum concentration.EtOAc (20mL) is added in the residue, filters the precipitation that obtains, obtain target compound.δ H(DMSO): 2.05 (3H, s), 3.84 (1H, m), 4.07 (1H, m), 4.19 (2H, t), 7.62 (1H, t), 7.85 (4H, m), 8.43 (1H, d), 9.52 (1H, br s); RT=2.56 minute; M/z (ES +)=301[M+H] +
Embodiment 31:3-naphthalene-1-base-2-propyl group-5,6-glyoxalidine be [2,1-b] thiazole hydrobromide salt also
With 2-bromo-1-naphthalene-1-base penta-1-ketone (preparation example 71,1.57g, 5.4mmol) and 2-imidazolidine thioketones (0.55g, 5.4mmol) reflux 16 hours in EtOH (20mL) and AcOH (10mL).The reaction mixture cool to room temperature, vacuum concentration.Add EtOAc (20mL), use Et 2O grinds the precipitation that obtains, and filters, and uses Et 2(2 * 20mL) washings, vacuum-drying obtains target compound to O, δ H(DMSO): 0.73 (3H, t), 1.44 (2H, m), 2.31 (1H, m), 2.43 (1H, m), 3.82 (1H, m), 4.05 (1H, m), 4.21 (2H, t), 7.67 (4H, m), 7.84 (1H, m), 8.08 (1H, m), 8.16 (1H, m), 9.71 (1H, br s); M/z (ES +)=295[M+H] +RT=2.69 minute.
Embodiment 32:2-methoxymethyl-3-naphthalene-1-base-5,6-glyoxalidine be [2,1-b] thiazole also
Figure A20068001139501182
With 3-benzyloxy-2-bromo-1-naphthalene-1-base third-1-ketone (preparation example 65,1.44g, 3.9mmol) and 2-imidazolidine thioketones (0.40g, 3.9mmol) reflux 48 hours in AcOH (10mL) and MeOH (20mL).Solvent removed in vacuo, residue is at saturated NaHCO 3Solution (100mL) and EtOAc (distribute between 3 * 100mL).Merge organic fraction, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use MeOH: 1: 49～3: 97 wash-outs of DCM obtain target compound, δ H(CDCl 3): 3.45 (2H, m), 4.09 (2H, s), 4.18 (2H, m), 5.34 (3H, s), 7.47 (1H, m), 7.57 (3H, m), 7.95 (3H, m); M/z (ES +)=297[M+H] +RT=2.47 minute.
Embodiment 33:3-(4-chloronaphthalene-1-yl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501191
With 2-bromo-1-(4-chloronaphthalene-1-yl) third-1-ketone (preparation example 72,6.05g, 20.3mmol) and 2-imidazolidine thioketones (2.08g, 20.3mmol) reflux 24 hours in EtOH (100mL) and AcOH (50mL).The reaction mixture cool to room temperature, vacuum concentration.With Et 2O (100mL) is added in the residue, at room temperature stirs 30 minutes.Cross filter solid, use Et 2(2 * 40mL) washings, vacuum-drying obtains target compound to O, δ H(DMSO): 2.06 (3H, s), 3.86 (1H, m), 4.09 (1H, m), 4.20 (2H, t), 7.69 (1H, d), 7.76 (1H, m), 7.83 (1H, m), 7.91 (2H, d), 8.34 (1H, d), 9.53 (1H, br s); M/z (ES +)=301[M+H] +RT=2.61 minute.
Embodiment 34:2-cyclopropyl-3-naphthalene-1-base-5,6-glyoxalidine be [2,1-b] thiazole hydrobromide salt also
With 2-bromo-2-cyclopropyl-1-naphthalene-1-base ethyl ketone (preparation example 73,282mg, 0.98mmol) and 2-imidazolidine thioketones (100mg, 0.98mmol) reflux 16 hours in EtOH (10mL) and AcOH (5mL).The reaction mixture cool to room temperature, vacuum concentration.Residue is at saturated NaHCO 3Solution (30mL) and EtOAc (distribute between 3 * 30mL).Merge organic fraction, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel is used MeOH: 7: 93 wash-outs of DCM.Product obtains target compound with HBr (30%, among the AcOH) acidifying, residue with MeCN and acetone crystallization.δ H(DMSO): 0.51 (2H, m), 0.75 (2H, m), 1.69 (1H, m), 3.83 (1H, m), 4.09 (1H, m), 4.19 (2H, t), 7.65 (2H, m), 7.71 (2H, m), 7.89 (1H, m), 8.09 (1H, m), 8.17 (1H, d), 9.69 (1H, br s); M/z (ES +)=293[M+H] +RT=2.45 minute.
Embodiment 35:3-(5-chloronaphthalene-1-yl)-2-ethyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501201
2-bromo-1-(5-chloronaphthalene-1-yl) fourth-1-ketone (preparation example 74,0.43g, 1.38mmol) and 2-imidazolidine thioketones (0.14g, 1.38mmol) reflux 16 hours in EtOH (10mL) and AcOH (5mL).The reaction cool to room temperature, vacuum concentration.Residue grinds with acetone (20mL) and EtOAc (30mL), crosses filter solid, with EtOAc (20mL), and Et 2(2 * 20mL) washings, vacuum-drying obtains target compound to O, δ H(DMSO): 1.03 (3H, t), 2.39 (2H, m), 3.82 (1H, m), 4.05 (1H, m), 4.20 (2H, t), 7.63 (1H, m), 7.84 (4H, m), 8.43 (1H, d), 9.66 (1H, br s); M/z (ES +)=315[M+H] +RT=2.79 minute.
Embodiment 36:2-sec.-propyl-3-naphthalene-2-base-5,6-glyoxalidine be [2,1-b] thiazole also
With 2-bromo-3-methyl isophthalic acid-naphthalene-2-Ji Ding-1-ketone (preparation example 75,0.70g, 2.4mmol) and 2-imidazolidine thioketones (0.24g, 2.4mmol) reflux 16 hours in EtOH (10mL) and AcOH (5mL).The reaction mixture cool to room temperature, vacuum concentration.Residue is at saturated NaHCO 3Solution (50mL) and EtOAc (distribute between 3 * 20mL).Merge organic fraction, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use MeOH: 7: 93 wash-outs of DCM obtain target compound.δ H(CDCl 3): 1.20 (6H, d), 3.04 (1H, m), 3.65 (2H, t), 4.15 (2H, t), 7.42 (1H, m), 7.56 (2H, m), 7.79 (1H, s), 7.90 (3H, m); M/z (ES +)=295[M+H] +RT=2.62 minute.
Embodiment 37:3-(4-fluoronaphthalene-1-yl)-2-sec.-propyl-5, the 6-glyoxalidine is [2,1-b] thiazole also
Figure A20068001139501211
With 2-bromo-1-(4-fluoronaphthalene-1-yl)-3-methyl fourth-1-ketone (preparation example 76,0.59g, 1.9mmol) and 2-imidazolidine thioketones (0.22g, 2.1mmol) reflux 24 hours in EtOH (10mL) and AcOH (5mL).The reaction mixture cool to room temperature, vacuum concentration.Residue is at saturated NaHCO 3Solution (50mL) and EtOAc (distribute between 3 * 20mL).Merge organic fraction, dry (MgSO 4), vacuum concentration, chromatogram purification on silica gel, use MeOH: 1: 9 wash-out of DCM obtains target compound, δ H(CDCl 3): 1.07 (3H, d), 1.18 (3H, d), 2.69 (1H, m), 3.47 (2H, m), 4.16 (2H, m), 7.22 (1H, m), 7.38 (1H, m), 7.65 (2H, m), 7.81 (1H, m), 8.21 (1H, m); M/z (ES +)=313[M+H] +RT=2.87 minute.
Embodiment 38:3-(5-chloronaphthalene-1-yl)-2-cyclopropyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501212
With 2-bromo-1-(5-chloronaphthalene-1-yl)-2-cyclopropyl ethyl ketone (preparation example 77,140mg, 0.43mmol) and 2-imidazolidine thioketones (44mg, 0.43mmol) reflux 24 hours in EtOH (6mL) and AcOH (3mL).The reaction mixture cool to room temperature, vacuum concentration.Residue Et 2O (20mL) grinds, and filters, and uses Et 2(2 * 10mL) washings obtain target compound, δ to O H(DMSO): 0.51 (2H, m), 0.75 (2H, m), 1.68 (1H, m), 3.83 (1H, m), 4.08 (1H, m), 4.17 (2H, m), 7.64 (1H, t), 7.88 (4H, m), 8.43 (1H, d), 9.65 (1H, br s); M/z (ES +)=327[M+H] +RT=2.74 minute.
Embodiment 39:3-(8-chloronaphthalene-2-yl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501221
With 2-bromo-1-(8-chloronaphthalene-2-yl) third-1-ketone (preparation example 78,222mg, 0.75mmol) and 2-imidazolidine thioketones (76mg, 0.75mmol) reflux 16 hours in EtOH (10mL) and AcOH (5mL).The reaction mixture cool to room temperature, vacuum concentration.EtOAc (20mL) is added in the residue, filters, with cold EtOAc (2 * 10mL), Et 2(2 * 10mL) washings, vacuum-drying obtains target compound to O, δ H(DMSO): 2.32 (3H, s), 4.25 (2H, m), 4.33 (2H, m), 7.65 (1H, t), 7.77 (1H, m), 7.83 (1H, d), 8.07 (1H, d), 8.24 (1H, d), 8.29 (1H, s), 9.55 (1H, br s); M/z (ES +)=301[M+H] +RT=2.77 minute.
Embodiment 40:3-(4,5-two fluoronaphthalenes-1-yl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501222
(3.91mmol) (0.399g 3.91mmol) is dissolved in ethanol (10mL)/acetate (5mL) mixture, reaction reflux 16 hours with 2-imidazolidine thioketones for preparation example 93,1.17g with 2-bromo-1-(4,5-two fluoronaphthalenes-1-yl) third-1-ketone.The reaction mixture cool to room temperature, vacuum evaporating solvent.Grind with acetonitrile, obtain target compound.δ H(DMSO): 2.02 (3H, s), 3.80 (1H, q), 4.10 (1H, q), 4.2 (2H, m), 7.60-7.80 (5H, m); M/z (ES +)=303.07[M+H] +RT=2.45 minute.
Embodiment 41:3-(4,5-two fluoronaphthalenes-1-yl)-2-ethyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501231
To embodiment 12 described similar conditions under from 2-bromo-1-(4,5-two fluoronaphthalenes-1-yl) fourth-1-ketone (preparation example 95,1.1g, 3.41mmol) preparation target compound.δ H(DMSO): 1.00 (3H, t), 2.40 (2H, m), 3.80 (1H, q), 4.10 (1H, q), 4.20 (2H, m), 7.50-7.80 (5H, m), 9.60 (1H, br); M/z (ES +)=317.17[M+H] +RT=2.7 minute.
Embodiment 42:3-(5,7-dichloronaphtalene-1-yl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501232
To embodiment 12 described similar conditions under from 2-bromo-1-(5,7-dichloronaphtalene-1-yl)-third-1-ketone (preparation example 99,0.945g, 2.84mmol) and 2-imidazolidine thioketones prepare target compound.δ H(DMSO): 2.05 (3H, s), 3.85 (1H, q), 4.10 (1H, q), 4.20 (2H, t), 7.90 (3H, m), 8.00 (1H, d), 8.40 (1H, d), 9.50 (1H, br); M/z (ES +)=336.97[M+H] +RT=2.92 minute.
Embodiment 43-50:
Use embodiment 1 described process to prepare the compound of embodiment 43-50.
Figure A20068001139501241
Figure A20068001139501251
Embodiment 51:3-(5-methoxynaphthalene-1-yl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501261
To embodiment 1 described similar condition under from 2-bromo-1-(5-methoxynaphthalene-1-yl) third-1-ketone (preparation example 121) preparation target compound.δ H(DMSO): 2.1 (3H, s), 3.80 (1H, m), 4.05 (1H, m), 4.20 (2H, m), 7.08 (1H, d), 7.36 (1H, d), 7.57 (1H, m), 7.64 (2H, m), 8.40 (1H, m), 9.50 (1H, s); M/z (ES +)=297.08[M+H] +RT=2.70 minute.
Embodiment 52:2-methyl-3-(5-trifluoromethyl naphthalene-1-yl)-5, the 6-dihydro-imidazol-is [2,1-b] thiazole hydrochloride also
Figure A20068001139501262
(7.93mmol) (0.810g 7.93mmol) is dissolved in ethanol (40mL)/acetate (20mL) mixture, reaction reflux 16 hours with 2-imidazolidine thioketones for preparation example 130,2.625g with 2-bromo-1-(5-trifluoromethyl naphthalene-1-yl) third-1-ketone.The reaction mixture cool to room temperature, vacuum evaporating solvent.Use saturated NaHCO 3The alkalization organism is with DCM (3 * 50mL) extractions, dry (MgSO 4), vacuum concentration.By purification by flash chromatography on silica gel (eluent: DCM/MeOH, 4/1), obtain free alkali, with the acidifying of cold 2M HCl (excessive) ethereal solution, obtain target compound through vacuum-evaporation, δ H(DMSO): 2.10 (3H, s), 3.90 (1H, q), 4.10 (1H, q), 4.22 (2H, m), 7.80 (1H, t), 7.90 (1H, d), 7.95 (1H, t), 8.15 (1H, d), 8.20 (1H, d), 8.30 (1H, d), 11.00 (1H, br); M/z (ES +)=335.97[M+H] +RT=2.82 minute.
Embodiment 53:3-(7-fluoronaphthalene-1-yl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501271
To embodiment 1 described similar condition under prepare target compound from 2-bromo-1-(7-fluoronaphthalene-1-yl)-third-1-ketone (preparation example 133) and 2-imidazolidine thioketones.δ H(DMSO): 2.05 (3H, s), 3.90 (1H, q), 4.10 (1H, q), 4.20 (2H, t), 7.55-7.75 (4H, m), 8.05 (2H, m), 9.50 (1H, br); M/z (ES +)=285.05[M+H] +RT=2.55 minute.
Embodiment 54:3-(5-fluoronaphthalene-1-yl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
With 2-bromo-1-(5-fluoronaphthalene-1-yl) third-1-ketone (preparation example 150,1.1g, 3.96mmol) and imidazolidine-2-thioketones (404mg 3.96mmol) is dissolved among EtOH (15mL) and the AcOH (7.5mL), reaction reflux 16 hours.The reaction mixture cool overnight is filtered collecting precipitation, with acetonitrile (20mL) washing, obtains target compound.δ H(DMSO): 2.10 (3H, s), 3.85 (1H, m), 4.10 (1H, m), 4.20 (2H, m), 7.50 (1H, m), 7.70 (2H, m), 7.80 (2H, m), 8.25 (1H, m), 9.58 (1H, br s); M/z (ES +)=284.95[M+H] +RT=2.59 minute.
Embodiment 55-63:
Use embodiment 1 described process to prepare the compound of embodiment 55-63.
Figure A20068001139501281
Figure A20068001139501291
Embodiment 64:3-(3, the 4-dichlorophenyl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501301
To 2-bromo-1-(3, the 4-dichlorophenyl) third-1-ketone (preparation example 44,1.50g, add in EtOH 5.10mmol) (10.0mL) and acetate (5.0mL) solution imidazolidine-2-thioketones (530mg, 5.10mmol).Mixture stirred 16 hours in inert atmosphere under 110 ℃.Removal of solvent under reduced pressure, the solid Et that obtains 2(2 * 10mL) grind O, and (1 * 5mL) grinds, and obtains target compound, δ to use acetonitrile then H(DMSO): 9.50 (1H, br s), 7.90 (2H, m), 7.55 (1H, d), 4.30-4.20 (4H, m), 2.25 (3H, s); M/z (ES +)=284.92[M-H] +RT=2.36 minute.
Embodiment 65:3-(3-chloro-4-aminomethyl phenyl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501302
Method according to embodiment 64 prepares from 2-bromo-1-(4-chloro-3-aminomethyl phenyl) third-1-ketone and imidazolidine-2-thioketones.δ H(DMSO): 9.50 (1H, br s), 7.60 (1H, d), 7.55 (1H, s), 7.40 (1H, t), 4.30-4.20 (4H, m), 2.40 (3H, s), 2.20 (3H, s); M/z (ES +)=265.01[M-H] +RT=2.65 minute.
Embodiment 66:3-(4-bromo-3-aminomethyl phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501303
(0.2788g, (preparation example 47,790mg is in EtOH 2.73mmol) (10mL)/acetate (3mL) solution 2.73mmol) to be added to 2-bromo-1-(4-bromo-3-aminomethyl phenyl) ethyl ketone with imidazolidine-2-thioketones.Mixture stirred 16 hours in inert atmosphere under 110 ℃.Solvent removed in vacuo is with EtOH and Et 2The solid that the O washing obtains obtains target compound.δ H(MeOH): 7.68 (1H, d), 7.60 (1H, s), 7.40 (1H, d), 6.98 (1H, s), 4.60-4.40 (4H, m), 2.42 (3H, s); M/z (ES +)=296.01[M-H] +RT=2.31 minute.
Embodiment 67～70:
Use and the following compound of above-mentioned similar process preparation:
Embodiment 67: cyclopropyl [3-(3, the 4-dichlorophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] methyl alcohol
Embodiment 68:[3-(4-bromophenyl)-5,6-glyoxalidine be [2,1-b] thiazol-2-yl also] methyl alcohol
Embodiment 69:3-(4-bromophenyl)-2-methyl-5,6-glyoxalidine be [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501313
Embodiment 70:3-(4-bromo-3-fluorophenyl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501321
Embodiment 71:3-(4-chloro-3-trifluoromethyl)-2-sec.-propyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
To embodiment 1 described similar condition under from 2-bromo-1-(4-chloro-3-trifluoromethyl)-3-methyl fourth-1-ketone (preparation example 146,3.6g, 10.48mmol) and 2-imidazolidine thioketones prepare target compound.δ H(DMSO): 1.20 (6H, m), 3.00 (1H, m), 4.20 (4H, brs), 7.90 (1H, d), 8.00 (1H, d), 8.05 (1H, s), 9.70 (1H, br s); M/z (ES +)=346.98[M+H] +RT=2.74 minute.
Embodiment 72:1-[3-(4-chloro-3-trifluoromethyl)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] ethanol
To embodiment 64 described similar conditions under from 3-(4-chloro-3-trifluoromethyl)-5, the 6-glyoxalidine also [2,1-b] thiazole-2-formaldehyde (preparation example 144,0.50g, 1.503mmol) preparation target compound.δ H(DMSO): 1.25 (3H, m), 3.50 (1H, m), 3.65 (1H, m), 4.00 (2H, m), 4.55 (1H, m), 5.40 (1H, m), 7.80 (1H, d), 7.85 (1H, d), 7.95 (1H, s); M/z (ES +)=348.93[M+H] +RT=2.40 minute.
Embodiment 73:2-[3-(3, the 4-dichlorophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-propan-2-ol
Figure A20068001139501331
With 3-(3, the 4-dichlorophenyl)-5,6-glyoxalidine also [2,1-b] thiazole-2-carboxylate methyl ester (preparation example 140,1.50g, 3.67mmol) THF (30.0mL) solution under 0 ℃, in inert atmosphere, cool off, add ether (7.30mL, 14.67mmol) solution of methyl-magnesium-bromide 2.0M in 5 minutes.Mixture stirred 1 hour, removed ice bath then, restir 16 hours.Slowly add saturated ammonium chloride (50mL), vigorous stirring 15 minutes is filtered the suspension that obtains then.(2 * 5.0mL) washings, vacuum-drying obtains target compound to the solid water that obtains.δ H(DMSO): 1.25 (6H, s), 4.00 (2H, m), 4.15 (2H, m), 6.25 (1H, s), 7.55 (1H, d), 7.90 (2H, m); M/z (ES +)=328.94[M+H] +RT=2.34 minute.
Embodiment 74:1-[3-(3, the 4-dichlorophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] ethanol
With 3-(3, the 4-dichlorophenyl)-5,6-glyoxalidine also [2,1-b] (THF 1.67mmol) (20.0mL) solution cools off in inert atmosphere under 0 ℃ thiazole-2-formaldehyde for preparation example 138,0.50g, the ether (1.67mL, 5.01mmol) solution that add methyl-magnesium-bromide 3.0M in 5 minutes.Mixture stirred 1 hour, removed ice bath then, restir 16 hours.Add entry (40mL) then, vigorous stirring 15 minutes, (3 * 50mL) extract dry organic layer (MgSO to water layer with EtOAc then 4), vacuum concentration.Obtain yellow solid, (2 * 2.0mL) grind, and vacuum is removed residual solvent, obtains target compound, δ with DCM H(DMSO): 1.25 (3H, d), 3.70-3.50 (2H, m), 4.00 (2H, m), 4.55 (1H, m), 5.40 (1H, m), 7.50 (1H, d), 7.80 (2H, m); M/z (ES +)=314.91[M+H] +RT=2.39 minute.
Embodiment 75:[3-(3, the 4-dichlorophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also] methyl alcohol
Figure A20068001139501341
To 3-(3, the 4-dichlorophenyl)-5, the 6-glyoxalidine also [2,1-b] thiazole-2-formaldehyde (preparation example 138,0.50g, disposable adding sodium borohydride in 0 ℃ of methyl alcohol (10.0mL) suspension 1.672mmol) (95.0mg, 2.51mmol).Said mixture stirred 2 hours in inert atmosphere under 0 ℃, removed cooling bath then, stirred then 16 hours.Add entry (40mL) then, vigorous stirring 1 hour is filtered the suspension that obtains then.The solid Et that obtains 2(2 * 10mL) washings, vacuum-drying obtains target compound to O.δ H(DMSO): 3.65 (2H, m), 4.00 (2H, m), 4.20 (2H, m), 5.40 (1H, m), 7.50 (1H, d), 7.80 (2H, m); M/z (ES +)=300.94[M+H] +RT=2.29 minute.
Embodiment 76:3-(3, the 4-dichlorophenyl)-2-sec.-propyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501342
To embodiment 12 described similar conditions under from 2-bromo-1-(3, the 4-dichlorophenyl)-3-methyl fourth-1-ketone (preparation example 91,1.6g, 5.16mmol) and 2-imidazolidine thioketones prepare target compound.δ H(d 4MeOH): 1.25 (6H, d), 3.10 (1H, m), 4.30 (4H, m), 7.40 (1H, d), 7.80 (2H, m); M/z (ES +)=314.97[M+H] +RT=2.72 minute.
Embodiment 77:3-(4-bromo-3-aminomethyl phenyl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501351
To embodiment 12 described similar conditions under from 2-bromo-1-(4-bromo-3-aminomethyl phenyl) third-1-ketone (preparation example 89,2g, 0.65mmol) and 2-imidazolidine thioketones prepare target compound.δ H(d 4MeOH): 2.25 (3H, s), 2.50 (3H, s), 4.30 (4H, m), 7.20 (1H, d), 7.40 (1H, s), 7.80 (1H, d); M/z (ES +)=310.9[M+H] +RT=2.42 minute.
Embodiment 78:3-(4-bromo-2-fluorophenyl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501352
To embodiment 12 described similar conditions under from 2-bromo-1-(4-bromo-2-fluorophenyl) third-1-ketone (preparation example 87,3.1g, 100mmol) and 2-imidazolidine thioketones prepare target compound.δ H(CDCl 3): 2.21 (3H, s), 4.30-4.65 (4H, m), 7.50 (3H, m); M/z (ES +)=314.88[M+H] +RT=2.36 minute.
Embodiment 79:2-methyl-3-(7,8-two fluoronaphthalenes-1-yl)-5, the 6-glyoxalidine is [2,1-b] thiazole hydrochloride also
Figure A20068001139501353
To embodiment 64 described similar conditions under from 2-bromo-1-(7,8-two fluoronaphthalenes-1-yl)-third-1-ketone (preparation example 84) preparation target compound.δ H(CDCl 3): 1.81 (3H, s), 3.35 (2H, m), 4.15 (2H, m), 7.39 (2H, m), 7.43 (1H, t), 7.61 (1H, m), 7.85 (1H, d); M/z+ (ES +)=302.94[M+H] +RT=2.54 minute.
Embodiment 80:3-(4,5-dichloronaphtalene-1-yl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501361
To embodiment 12 described similar conditions under from 2-bromo-1-(4,5-dichloronaphtalene-1-yl) third-1-ketone (preparation example 97,0.73g, 2.2mmol) preparation target compound.δ H(DMSO): 2.00 (3H, s), 3.80 (1H, q), 4.10 (1H, q), 4.25 (2H, m), 7.60 (1H, t), 7.70 (1H, d), 7.90 (3H, m), 9.60 (1H, br); (ES +)=336.93[M+H] +RT=2.77 minute.
Embodiment 81:3-(4-hydroxyl naphthalene-1-yl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole also
In 2 minutes to 3-(4-methoxynaphthalene-1-yl)-2-methyl-5 of 0 ℃, the 6-glyoxalidine also [2,1-b] thiazole hydrobromide salt (embodiment 49, and 0.207g adds BBr in DCM 0.549mmol) (10mL) solution 3(1.0M, 1.64mL).After at room temperature stirring 16 hours, be reflected between saturated sodium bicarbonate solution (100mL) and the EtOAc and distribute.Dry extract (the MgSO that merges 4), concentrate, obtain oil, be dissolved in the methyl alcohol, handle with the HBr in the acetate.Evaporating solvent makes the target compound precipitation by adding EtOAc, obtains target compound, filters and collects, δ H(CDCl 3): 2.13 (3H, s), 3.31 (1H, br s), 3.91-3.97 (1H, m), 4.09-4.15 (1H, m), 4.27-4.31 (2H, m), 6.96 (1H, d), 7.44 (1H, d), 7.51-7.63 (3H, m), 8.34 (1H, d); M/z (ES +)=283.09[M+H] +RT=2.49 minute.
Embodiment 82:3-(7-hydroxyl naphthalene-1-yl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole also
Figure A20068001139501371
From 3-(7-methoxynaphthalene-1-yl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt (embodiment 48) preparation target compound also according to the process of embodiment 81.δ H(DMSO): 1.88 (3H, s), 3.38-3.43 (2H, m), 3.90-4.03 (2H, m), 7.13-7.16 (2H, m), 7.34-7.38 (1H, m), 7.43-7.45 (1H, d), 7.87-7.92 (2H, m), 9.94 (1H, br s); M/z (ES +)=283.03[M+H] +RT=2.43 minute.
Embodiment 83:3-(5-chloronaphthalene-1-yl)-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501372
To embodiment 1 described similar condition under from 2-bromo-1-(5-chloro-naphthalene-1-yl) ethyl ketone (preparation example 124) preparation target compound.δ H(DMSO): 4.04 (2H, m), 4.30 (2H, m), 7.64 (1H, m), 7.84 (3H, m), 8.03 (1H, d), 8.40 (1H, d), 9.61 (1H, s); M/z (ES +)=287.14[M+H] +RT=2.67 minute.
Embodiment 84:2-methyl sulfane base-3-(5,6,7,8-naphthane-2-yl)-5, the 6-dihydro-imidazol-is [2,1-b] thiazole hydrochloride also
Figure A20068001139501381
To embodiment 18 described similar conditions under from 2-bromo-3-(5,6,7,8-naphthane-2-yl)-5,6-glyoxalidine also [2,1-b] thiazole hydrobromide salt (preparation example 127) and dimethyl disulfide prepares target compound.δ H(DMSO): 1.79 (4H, m), 2.40 (3H, s), 2.81 (4H, m), 4.18-4.33 (4H, m), 7.27 (3H, m), 10.20 (1H, br); M/z (ES +)=303.04[M+H] +RT=2.79 minute.
Embodiment 85:2-ethyl-3-(7-fluoronaphthalene-1-yl)-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501382
To embodiment 1 described similar condition under from 2-bromo-1-(7-fluoronaphthalene-1-yl) fourth-1-ketone and 2-imidazolidine thioketones (preparation example 135) preparation target compound.δ H(DMSO): 1.05 (3H, t), 2.30-2.50 (2H, m), 3.85 (1H, q), 4.05 (1H, q), 4.22 (2H, t), 7.55-7.75 (4H, m), 8.20-8.25 (2H, m), 9.60 (1H, br); M/z (ES +)=300.1[M+H] +RT=2.62 minute.
Embodiment 86: cyclopropyl [3-(3, the 4-dichlorophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazol-2-yl also]-methyl alcohol
With 3-(3, the 4-dichlorophenyl)-5,6-glyoxalidine also [2,1-b] thiazole-2-formaldehyde (preparation example 138,0.80g, 2.67mmol) THF (30.0mL) solution under 0 ℃, in inert atmosphere, cool off, the 0.5M that adds cyclopropyl bromination magnesium in 10 minutes is at THF (16.0mL, 8.01mmol) solution in.Mixture stirred 1 hour, removed ice bath then, restir 16 hours.Add entry (40mL) then, vigorous stirring 15 minutes, (3 * 50mL) extract dry organic layer (MgSO to water layer with EtOAc then 4), vacuum concentration.Obtain yellow solid, (2 * 2.0mL) grind, and vacuum is removed residual solvent, obtains target compound with DCM.δ H(DMSO): 0.10 (1H, m), 0.45-0.30 (3H, m), 1.00 (1H, m), 3.50 (1H, q), 3.75 (1H, q), 4.00 (3H, m), 5.40 (1H, m), 7.50 (1H, d), 7.75 (1H, d), 7.80 (1H, s); M/z (ES +)=340.90[M+H] +RT=2.56 minute.
Embodiment 87:3-(4-chloro-3-aminomethyl phenyl)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501391
To embodiment 1 described similar condition under from 2-bromo-1-(4-chloro-3-aminomethyl phenyl) third-1-ketone (preparation example 149,5.15g, 19.71mmol) and 2-imidazolidine thioketones prepare target compound.δ H(DMSO): 2.21 (3H, s), 2.41 (1H, s), 4.20-4.35 (4H, m), 7.40 (1H, d), 7.55 (1H, s), 7.65 (1H, d), 9.45 (1H, br s); M/z (ES +)=264.99[M+H] +RT=2.39 minute.
Embodiment 88:2-allyl group-3-(7-chloronaphthalene-1-yl)-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt also
Figure A20068001139501392
2-bromo-3-in 0 ℃ of following inert atmosphere (7-chloronaphthalene-1-yl)-5, the 6-glyoxalidine is [2,1-b] thiazole hydrobromide salt (preparation example 151 also, 3.42g) THF (150mL) solution in add ethylmagnesium bromide solution (40%, in the ether, 7.65mL), and stirred 20 minutes.Drip allyl bromide 98 (6.6mL), stirred 20 minutes down, rise to room temperature, stirred 16 hours at 0 ℃.Add saturated ammonium chloride (40mL), reaction mixture extracts into EtOAc (3 * 300mL).Merge organic fraction, dry (MgSO 4), vacuum concentration.Carry out column chromatography (DCM: MeOH, 96: 4), obtain required product, handle MeOH solution by the 30%HBr in the acetate and change into hydrobromate, filter then, obtain target compound, δ H(DMSO): 3.18 (2H, m), 3.85 (1H, m), 4.10 (1H, m), 4.22 (2H, m), 5.80 (1H, m), 7.70 (3H, m), 8.01 (1H, s), 8.18 (1H, d), 8.25 (1H, d), 9.68 (1H, s); M/z (ES +)=327.05[M+H] +RT=2.97 minute.
The biological activity of The compounds of this invention can detect by following analytical system:
The people recombinate in the membrane product with noradrenaline transporter site (transporter site) bonded [ 3H] nisoxetine
Film:
Use from the MDCK in expressing human noradrenaline transporter site stablize film that recombinant cell lines obtains study compound of the present invention to [ 3H] influence of nisoxetine bonded.
Binding analysis:
In the displacement experiment, single concentration of film usefulness 1.0nM [ 3H] nisoxetine and damping fluid (total binding) or test compounds (10 -6M or concentration range) or Desipramine (1 μ M; Non-specific binding) 4 ℃ of following incubation 90 minutes.
Selectively, film with single concentration of 1.0nM [ 3H] nisoxetine and damping fluid (total binding) or test compounds (11 concentration) or nisoxetine (2 μ M, non-specific binding) be 4 ℃ of following incubations 4 hours.
Obtain the film binding radioactivity by filtering.With the quick washing filter of ice-cold buffer, measure radioactivity by liquid scintillation counting(LSC).
2.[ 3H] norepinephrine mixes in the rat hypothalamus synaptosome
The preparation of synaptosome
[ 3H]-norepinephrine mixes analysis:
Prepare the rat hypothalamus synaptosome according to standard procedure, with test compounds (concentration range) or protriptyline 37 ℃ of following incubations 20 minutes.
Mix by filtering the acquisition synaptosome.With the quick washing filter of ice-cold buffer, measure radioactivity by liquid scintillation counting(LSC).
The people recombinate in the membrane product with 5-HT transport sites bonded [ 3H] imipramine
Film:
Use from the HEK-293 of expressing human serotonin transport sites stablize film that recombinant cell lines obtains study compound of the present invention to [ 3H] influence of imipramine bonded.
Binding analysis:
In the displacement experiment, single concentration of film usefulness 2.0nM [ 3H] imipramine and damping fluid (total binding) or test compounds (10 -6M or concentration range) or imipramine (10 μ M; Non-specific binding) 22 ℃ of following incubation 30 minutes.
Selectively, bonded characterize and to be to use [ 3H] paroxetine.In these displacement experiments, single concentration of film usefulness 0.5nM [ 3H] paroxetine and damping fluid (total binding) or test compounds (11 concentration) or paroxetine (2 μ M, non-specific binding) be 4 ℃ of following incubations 4 hours.
Obtain the film binding radioactivity by filtering.With the quick washing filter of ice-cold buffer, measure radioactivity by liquid scintillation counting(LSC).
4.[ 3H] serotonin mixes in the rat brain synaptosomes
The preparation of synaptosome
[ 3H]-serotonin mixes analysis:
Prepare the rat hypothalamus synaptosome according to standard procedure, with test compounds (concentration range) or imipramine 37 ℃ of following incubations 15 minutes.
Mix by filtering the acquisition synaptosome.With the quick washing filter of ice-cold buffer, measure radioactivity by liquid scintillation counting(LSC).
5. the people 5HT in the membrane product that recombinates 1ABinding analysis and [ 35S] GTP γ S binding analysis
Film:
Use from the HEK-293 of expressing human serotonin 1A acceptor stablize recombinant cell lines or CHO-K1 stablize film that recombinant cell lines obtains study compound of the present invention to [ 3H] 8-OH-DPAT in conjunction with and [ 35S] influence of GTP γ S bonded.
Binding analysis:
In the displacement experiment, single concentration of film usefulness 0.5nM [ 3H] 8-OH-DPAT and damping fluid (total binding) or test compounds (10 -6M or concentration range) or 8-OH-DPAT (10 μ M; Non-specific binding) 22 ℃ of following incubation 60 minutes.
Selectively, film with single concentration of 1nM [ 3H] 8-OH-DPAT and damping fluid (total binding) or test compounds (11 concentration) or 5-HT (2 μ M, non-specific binding) be 30 ℃ of following incubations 60 minutes.
Obtain the film binding radioactivity by filtering.With the quick washing filter of ice-cold buffer, measure radioactivity by liquid scintillation counting(LSC).
Function [ 35S] GTP γ S binding analysis:
[ 35S] in the GTP γ S binding analysis, film is with test compounds (concentration range) incubation 16 minutes at room temperature.Then, with the 150pM of incubation in advance [ 35S] GTP γ S is added on the film, and under 30 ℃ incubation 45 minutes again.At other 5-HT and the buspirone mass action curve drawn of test compounds.
Obtain the film binding radioactivity by filtering.With the quick washing filter of ice-cold buffer, measure radioactivity by liquid scintillation counting(LSC).
When under concentration 1 μ M, measuring, the representational compound of the present invention shows＞50% displacement.
In these analytical systems, embodiment 1-88 shows 5-HT 1AAgonism and norepinephrine reuptake restraining effect or 5-HT 1AAgonism, norepinephrine reuptake restraining effect and 5-HT reuptake inhibition.
The biological activity of The compounds of this invention also can be tested in body inner model well known by persons skilled in the art.Therefore, for example behind thin male Sprague Dawley rat or the administration of female Wistar rats acute oral, compare with control group, the representational compound of the present invention has significantly reduced ingestion of food with the degree higher than sibutramine in maximum 24 hours.Inferior chronic orally give representative compounds has significantly weakened the weight increase in the obesity mice model of diet induced in 21 days, and has reduced weight increase to the inferior chronic oral administration once a day of the male Sprague Dawley rat of feed high fat diet 21 days with the degree higher than sibutramine.
Also verified, to compare with the control group of vehicle treated behind the chronic orally give in the rat Central Asia, the effect of representative compounds comprises the blood plasma level that reduces the fat pad quality and/or reduce leptin, glucose, Regular Insulin or tri-glyceride.In addition, compare with sibutramine, at dosage during apparently higher than the dosage of performance effect, the representational compound of the present invention does not show heart rate in the normotensive rat of sentient, remote sensing or mean arterial blood pressure increases.

Claims (22)

1. the compound of a formula (I) or the acceptable salt of its pharmacology:
Figure A2006800113950002C1
Wherein
R 1The C that is hydrogen, halogen, is randomly replaced by one or more halogen atoms or hydroxyl 1-6Alkyl, the C that is randomly replaced by one or more halogen atoms or hydroxyl 3-6Cycloalkyl, the C that is randomly replaced by one or more halogen atoms or hydroxyl 1-2Alkyl C 3-6Cycloalkyl, C 1-6Alkoxy carbonyl, cyano group ,-C=N-OR 7, randomly replaced and wherein hydroxyl is not and the direct-connected C of the either carbon of two keys by one or more halogen atoms or hydroxyl 2-6Thiazolinyl, randomly replaced and wherein hydroxyl is not and the direct-connected C of the either carbon of three key by one or more halogen atoms or hydroxyl 2-6Alkynyl, (CH 2) mNR 5R 6, C 1-3Alkoxyl group, C 1-3Alkylthio, C 1-3Alkoxy C 1-3Alkyl or C 1-3Alkylthio C 1-3Alkyl;
R 2Be randomly to contain maximum 3 first bicyclic aryls of heteroatomic 8-to 10-that are selected from N and S, or phenyl, condition is R 2It or not benzo [b] thiophene;
R 2Can randomly be selected from halogen, cyano group, hydroxyl, NR 5R 6, CONR 5R 6, or COOR 7, or C 1-3Alkyl, C 2-3Thiazolinyl, C 1-3Alkynyl, C 3-6Cycloalkyl, C 1-3Alkoxyl group, C 1-3Hydroxyalkyl, C 2-3Alkoxyalkyl or C 1-3Alkyl S (O) nOne or more groups replace, arbitrary above-mentioned substituting group can randomly be replaced by one or more halogen atoms; Or work as R 2When being phenyl, two substituting groups on the phenyl can be connected to form and condense C 5-6Carbocyclic ring;
R 3And R 4Be hydrogen or C independently 1-3Alkyl;
R 5And R 6Be hydrogen or C independently 1-3Alkyl, or form 5-or 6-unit heterocyclic radical with the nitrogen that they connected;
R 7Be hydrogen or C 1-3Alkyl;
M is 1,2 or 3; And
N is 0,1 or 2;
Condition is that described compound is not:
A) 3-naphthalene-1-base-5,6-glyoxalidine be [2,1-b] thiazole hydrobromide salt also,
B) 3-naphthalene-2-base-5,6-glyoxalidine be [2,1-b] thiazole hydrobromide salt also,
C) 3-(3-chloro-4-propoxy-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
D) 3-(4-chloro-phenyl-)-2-ethyl-5, the 6-glyoxalidine is [2,1-b] thiazole also,
E) 3-(4-chloro-phenyl-)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole also,
F) 3-(3, the 4-dichlorophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
G) 3-(2-hydroxy-5-methyl base phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
H) 3-(4-aminophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
I) 3-(2-chloro-phenyl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
J) 3-(3-chloro-phenyl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
K) 3-(4-chloro-phenyl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
L) 3-(2,4 dichloro benzene base)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
M) 3-(2, the 5-dichlorophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
N) 3-(4-bromophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
O) 3-(2,4 difluorobenzene base)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
P) 3-(2-aminomethyl phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Q) 3-(3-aminomethyl phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
R) 3-(4-aminomethyl phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
S) 3-(2, the 4-3,5-dimethylphenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
T) 3-(3, the 4-3,5-dimethylphenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
U) 3-(4-cyano-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
V) 3-(4-carboxyl phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
W) 3-(2-p-methoxy-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
X) 3-(3-p-methoxy-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Y) 3-(4-p-methoxy-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Z) 3-(2-hydroxy phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Aa) 3-(3-hydroxy phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Ab) 3-(4-hydroxy phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Ac) 3-(3, the 4-dihydroxy phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Ad) 3-(2-hydroxyl-4-p-methoxy-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Ae) 3-(3-hydroxyl-4-p-methoxy-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Af) 3-(4-hydroxy 3-methoxybenzene base)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Ag) 3-(4-hydroxyl-3-chloro-phenyl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Ah) 3-(4-hydroxy-3-methyl phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also, or
Ai) 3-(3, the 4-dichlorophenyl)-2-phenyl-5, the 6-glyoxalidine is [2,1-b] thiazole also.
2. the compound of a formula (Ia) or the acceptable salt of its pharmacology:
Figure A2006800113950004C1
Wherein
R 1The C that is hydrogen, halogen, is randomly replaced by one or more halogen atoms or hydroxyl 1-6Alkyl, the C that is randomly replaced by one or more halogen atoms or hydroxyl 3-6Cycloalkyl, the C that is randomly replaced by one or more halogen atoms or hydroxyl 1-2Alkyl C 3-6Cycloalkyl, C 1-6Alkoxy carbonyl, cyano group ,-C=N-OR 7, randomly replaced and wherein hydroxyl is not and the direct-connected C of the either carbon of two keys by one or more halogen atoms or hydroxyl 2-6Thiazolinyl, randomly replaced and wherein hydroxyl is not and the direct-connected C of the either carbon of three key by one or more halogen atoms or hydroxyl 2-6Alkynyl, (CH 2) mNR 5R 6, C 1-3Alkoxyl group, C 1-3Alkylthio, C 1-3Alkoxy C 1-3Alkyl or C 1-3Alkylthio C 1-3Alkyl;
R 2Be randomly to contain maximum 3 first bicyclic aryls of heteroatomic 8-to 10-that are selected from N and S, condition is R 2It or not benzo [b] thiophene;
R 2Can randomly be selected from halogen, cyano group, hydroxyl, NR 5R 6, CONR 5R 6, or COOR 7, or C 1-3Alkyl, C 1-3Alkoxyl group, C 1-3Hydroxyalkyl, C 2-3Alkoxyalkyl or C 1-3Alkyl S (O) nOne or more groups replace, arbitrary above-mentioned substituting group can randomly be replaced by one or more halogen atoms;
R 3And R 4Be hydrogen or C independently 1-3Alkyl;
R 5And R 6Be hydrogen or C independently 1-3Alkyl, or form 5-or 6-unit heterocyclic radical with the nitrogen that they connected;
R 7Be hydrogen or C 1-3Alkyl;
M is 1,2 or 3; And
N is 0,1 or 2;
Condition is that described compound is not:
A) 3-naphthalene-1-base-5,6-glyoxalidine be [2,1-b] thiazole hydrobromide salt also, or
B) 3-naphthalene-2-base-5,6-glyoxalidine be [2,1-b] thiazole hydrobromide salt also.
3. the compound of a formula (Ib) or the acceptable salt of its pharmacology:
Figure A2006800113950005C1
Wherein
R 1The C that is hydrogen, halogen, is randomly replaced by one or more halogen atoms or hydroxyl 1-6Alkyl, the C that is randomly replaced by one or more halogen atoms or hydroxyl 3-6Cycloalkyl, the C that is randomly replaced by one or more halogen atoms or hydroxyl 1-2Alkyl C 3-6Cycloalkyl, C 1-6Alkoxy carbonyl, cyano group ,-C=N-OR 7, randomly replaced and wherein hydroxyl is not and the direct-connected C of the either carbon of two keys by one or more halogen atoms or hydroxyl 2-6Thiazolinyl, randomly replaced and wherein hydroxyl is not and the direct-connected C of the either carbon of three key by one or more halogen atoms or hydroxyl 2-6Alkynyl, (CH 2) mNR 5R 6, C 1-3Alkoxyl group, C 1-3Alkylthio, C 1-3Alkoxy C 1-3Alkyl or C 1-3Alkylthio C 1-3Alkyl;
R 2Be selected from halogen, cyano group, hydroxyl, NR 5R 6, CONR 5R 6, or COOR 7, or C 1-3Alkyl, C 2-3Thiazolinyl, C 2-3Alkynyl, C 3-6Cycloalkyl, C 1-3Alkoxyl group, C 1-3Hydroxyalkyl, C 2-3Alkoxyalkyl or C 1-3Alkyl S (O) nThe phenyl that replaces of one or more groups, arbitrary above-mentioned substituting group can randomly be replaced by one or more halogen atoms;
R 3And R 4Be hydrogen or C independently 1-3Alkyl:
R 5And R 6Be hydrogen or C independently 1-3Alkyl, or form 5-or 6-unit heterocyclic radical with the nitrogen that they connected;
R 7Be hydrogen or C 1-3Alkyl;
M is 1,2 or 3; And
N is 0,1 or 2;
Condition is that described compound is not:
C) 3-(3-chloro-4-propoxy-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
D) 3-(4-chloro-phenyl-)-2-ethyl-5, the 6-glyoxalidine is [2,1-b] thiazole also,
E) 3-(4-chloro-phenyl-)-2-methyl-5, the 6-glyoxalidine is [2,1-b] thiazole also,
F) 3-(3, the 4-dichlorophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
G) 3-(2-hydroxy-5-methyl base phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
H) 3-(4-aminophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
I) 3-(2-chloro-phenyl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
J) 3-(3-chloro-phenyl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
K) 3-(4-chloro-phenyl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
L) 3-(2,4 dichloro benzene base)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
M) 3-(2, the 5-dichlorophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
N) 3-(4-bromophenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
O) 3-(2,4 difluorobenzene base)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
P) 3-(2-aminomethyl phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Q) 3-(3-aminomethyl phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
R) 3-(4-aminomethyl phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
S) 3-(2, the 4-3,5-dimethylphenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
T) 3-(3, the 4-3,5-dimethylphenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
U) 3-(4-cyano-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
V) 3-(4-carboxyl phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
W) 3-(2-p-methoxy-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
X) 3-(3-p-methoxy-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Y) 3-(4-p-methoxy-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Z) 3-(2-hydroxy phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Aa) 3-(3-hydroxy phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Ab) 3-(4-hydroxy phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Ac) 3-(3, the 4-dihydroxy phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Ad) 3-(2-hydroxyl-4-p-methoxy-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Ae) 3-(3-hydroxyl-4-p-methoxy-phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Af) 3-(4-hydroxy 3-methoxybenzene base)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Ag) 3-(4-hydroxyl-3-chloro-phenyl-)-5, the 6-glyoxalidine is [2,1-b] thiazole also,
Ah) 3-(4-hydroxy-3-methyl phenyl)-5, the 6-glyoxalidine is [2,1-b] thiazole also, or
Ai) 3-(3, the 4-dichlorophenyl)-2-phenyl-5, the 6-glyoxalidine is [2,1-b] thiazole also.
4. as claim 1-3 each described compound, wherein R 1The C that is hydrogen, is randomly replaced by one or more halogen atoms or hydroxyl 1-6Alkyl, the C that is randomly replaced by one or more halogen atoms or hydroxyl 3-6Cycloalkyl or the C that is randomly replaced by one or more halogen atoms or hydroxyl 1-2Alkyl C 3-6Cycloalkyl.
5. compound as claimed in claim 4, wherein R 1Be C 1-6Alkyl.
6. as claim 1,2,4 or 5 described compound, wherein R 2Be naphthyl, thienothiophene base, indyl, quinolyl, isoquinolyl or benzisothiazole base, or the acceptable salt of its pharmacology.
7. compound as claimed in claim 6, wherein R 2Be naphthalene-1-base, naphthalene-2-base, thieno-[2,3-b] thiophene-2-base, quinoline-2-base, isoquinolyl or benzisothiazole-3-base.
8. compound as claimed in claim 7, wherein R 2It is naphthalene-1-base.
9. as claim 1,2 or 4～8 each described compound, wherein R 2Be selected from halogen and C 1-3One or two substituting group of alkyl replaces.
10. as claim 1 or 3～5 each described compound, wherein R 2Be by the C that is selected from halogen and is randomly replaced in 3-, 4-and/or 5-position by one or more halogen atoms 1-3The phenyl that one or two substituting group of alkyl replaces.
11. each described compound, wherein R of claim as described above 3And R 4All be hydrogen.
12. as the compound of the formula (I) of any definition among the embodiment 3-88, it is free alkali or the acceptable salt of its pharmacology.
13. a pharmaceutical composition comprises as each described compound of claim 1-12 or acceptable salt of its pharmacology and pharmacology acceptable carrier.
14. one kind is used for the treatment of norepinephrine wherein and the randomly disease that works of serotonin reuptake transporter or the method for illness, it comprise to the individuality that these needs are arranged give significant quantity comprise restrictive clause a), b) and f)～ai) described in the step as each described compound of claim 1-12 or the acceptable salt of its pharmacology of compound.
15. one kind be used for the treatment of wherein norepinephrine and randomly serotonin reuptake transporter work and wherein need 5-HT 1AThe disease of agonism or the method for illness, it comprise to the individuality that these needs are arranged give significant quantity comprise restrictive clause a), b) and f)～ai) described in the step as each described compound of claim 1-12 or the acceptable salt of its pharmacology of compound.
16. the method that adjusting is ingested and/or satiated, it comprise to the individuality that these needs are arranged give significant quantity comprise restrictive clause a), b) and f)～ai) described in the step as each described compound of claim 1～12 or the acceptable salt of its pharmacology of compound.
17. treat fat method for one kind, it comprise to the individuality that these needs are arranged give significant quantity comprise restrictive clause a), b) and f)～ai) described in the step as each described compound of claim 1-12 or the acceptable salt of its pharmacology of compound.
18. a treatment is selected from the method for type ii diabetes, metabolism syndrome (syndrome X), glucose tolerance reduction, dyslipidaemia, hyperlipidaemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels and hypertensive metabolic trouble, it comprise to the individuality that these needs are arranged give significant quantity comprise restrictive clause a), b) and f)～ai) step as each described compound of claim 1～12 or the acceptable salt of its pharmacology of compound.
19. a method that is reduced in as the cardiovascular side effects possibility in each described disease of claim 13-18 or the treatment for diseases, it comprise to the individuality that these needs are arranged give significant quantity comprise restrictive clause a), b) and f)～ai) described in the step as each described compound of claim 1-3 or the acceptable salt of its pharmacology of compound.
20. the method for a preparation formula (I) compound, it comprises the step of the compound reaction of the compound that makes formula (III) and formula (IV):
Figure A2006800113950010C1
R wherein 1～R 4Such as claim 1 definition, and G is hydrogen or leavings group.
21. the compound of a formula (II):
Figure A2006800113950010C2
R wherein 1, R 2, R 3And R 4Such as claim 1 definition.
22. the compound of a formula (X):
Figure A2006800113950010C3
R wherein 2, R 3And R 4Such as claim 1 definition.
CNA2006800113959A 2005-02-08 2006-02-08 Dihydroimidazothiazole derivatives Pending CN101155817A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108610246A (en) * 2018-06-01 2018-10-02 山东潍坊润丰化工股份有限公司 A kind of Cyproconazole intermediate 1-（4- chlorphenyls）The preparation method of -2- cyclopropyl -1- acetone
CN115745817A (en) * 2022-10-17 2023-03-07 台州国赐医药技术有限公司 Method for preparing 3- (dimethylamino) -1- (naphthalene-1-yl) -1-acetone hydrochloride

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108610246A (en) * 2018-06-01 2018-10-02 山东潍坊润丰化工股份有限公司 A kind of Cyproconazole intermediate 1-（4- chlorphenyls）The preparation method of -2- cyclopropyl -1- acetone
CN115745817A (en) * 2022-10-17 2023-03-07 台州国赐医药技术有限公司 Method for preparing 3- (dimethylamino) -1- (naphthalene-1-yl) -1-acetone hydrochloride

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