CN101959881A - The 5-O-that is used for medical use replaces 3-N-phenyl-1,3,4-oxadiazole ketone - Google Patents
The 5-O-that is used for medical use replaces 3-N-phenyl-1,3,4-oxadiazole ketone Download PDFInfo
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- CN101959881A CN101959881A CN2008801276810A CN200880127681A CN101959881A CN 101959881 A CN101959881 A CN 101959881A CN 2008801276810 A CN2008801276810 A CN 2008801276810A CN 200880127681 A CN200880127681 A CN 200880127681A CN 101959881 A CN101959881 A CN 101959881A
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Abstract
The present invention relates to have 5-O-and replace 3-N-phenyl-1,3 shown in (I), the compound of 4-oxadiazole ketone structural unit, described compound have FAAH (fatty amide hydrolase) restraining effect of unexpected high level.
Description
Technical field
The present invention relates to have 5-O-and replace 3-N-phenyl-1,3, the compound of 4-oxadiazole ketone structural unit, described compound have FAAH (fatty acid amide hydrolase) restraining effect of unexpected high level.
Background technology
FAAH is for example integral protein of Endocannabinoids arachidonic thanomin (IMP) of hydrolysis biological activity acid amides, it is Cannabined receptor and the TRPV1 novel vanilloid receptor agonist to free fatty acids and thanomin, referring to, for example, McKinney M.K., Cravatt B.F., Ann.Rev.Biochem.74:411 (2005).
Because it regulates the ability of arachidonic thanomin level, FAAH is regarded as attractive drug targets (attractive drug target) instantly.When URB 597 ([3-(3-carbamyl phenyl) phenyl] N-cyclohexyl carbamate) was widely regarded as instantly the FAAH inhibitor of " gold grade ", the example of FAAH inhibitor comprised PMSF (phenylmethylsulfonyl fluoride), MAFP (methoxyl group arachidonic base hexafluorophosphoric acid ester) and ATMK (arachidonic base trifluorumethylketone).Find before clinical that URB597 can increase the production of the Endocannabinoids that causes the antidepressant that can measure and analgesic effect in the laboratory test, for example, referring to, Russo R. etc., J Pharmacol Exp Ther.322 (1): 236-42 (2007).
The FAAH inhibitor is considered to play an important role in multiple medical conditions, referring to example: Pharmacol.Rev.58:389-462 such as Pacher (2006), incorporates it into specification sheets fully for your guidance.
The FAAH inhibitor relates to following illness:
(i) pain, especially acute or chronic neural source pain is migraine and neuropathic pain (for example diabetes nerve pain, postherpetic neuralgia, trigeminal neuralgia) for example; Acute or the chronic pain relevant: for example sacroiliitis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn disease and irritable bowel syndrome with following inflammatory disease; Acute or chronic peripheral pain;
(ii) dizzy, the vomiting and gastric disorder causing nausea, especially cause by chemotherapy;
The (iii) emaciation of the disturbance of food intake, particularly apocleisis and various character;
(iv) neural and spiritual pathology is for example trembled, dyskinesia, myodystonia, spasticity, obsession behavior, Tourette syndrome, any character of all formation and dysthymia disorders and anxiety, affective disorder and the psychosis (psychoses) of origin;
(v) acute and chronic neurodegenerative disease, for example parkinsonism, Alzheimer's disease, senile dementia, huntington Huntington's chorea, damage relevant pathology with cerebral ischemia and cranium brain and oblongata;
(vi) epilepsy;
(vii) somnopathy comprises sleep apnea;
(viii) for example heart failure of cardiovascular disorder, hypertension, heart disorder, arteriosclerosis, heart stalk, myocardial ischemia and renal ischaemia;
(ix) cancer, for example benign skin tumour, benign encephaloma and optimum papilloma, tumor of prostate and cerebral tumor (glioblastoma multiforme, medulloepithelioma, medulloblastoma, neuroblastoma, tire source property tumour, astrocytoma, astroblastoma, ependymoma, oligodendroglioma, clump tumour, neuroepithelioma, epiphysis knurl, ependymoblastoma, malignant meningioma, sarcosis, malignant melanoma and schwannoma);
(x) immune system disorder autoimmune disorder especially, for example psoriasis, lupus erythematosus, connective tissue disease (CTD) or collagenosis, sjogren syndrome (
Syndrome), ankylosing spondylitis, do not break up spondylitis, Behcet, autoimmune hemolytic anemia, multiple sclerosis, amyotrophic lateral sclerosis, amyloidosis, transplant rejection, the disease that influences plasmacytic series, anaphylactic disease, type or delayed hypersensitivity, allergic rhinitis or irritated conjunctivitis, allergic contact dermatitis;
(xi) parasite, virus or bacterial infectious disease, for example AIDS and meningitis;
(xii) inflammation, especially joint disease be sacroiliitis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn disease, irritable bowel syndrome for example;
(xiii) osteoporosis;
(xiv) for example ocular hypertension and glaucoma of eye conditions;
(xv) lung's illness comprises respiratory tract disease, bronchospasm, cough, asthma, chronic bronchitis, chronic obstructive airway and pulmonary emphysema;
(xvi) for example irritable bowel syndrome, the imbalance of inflammatory enteron aisle, ulcer, diarrhoea, urinary incontinence and urocystitis of gastrointestinal illness.
Have been found that, have 5-O-and replace 3-N-phenyl-1,3, the compound of 4-oxadiazole ketone structural unit has beat all high-caliber FAAH to be suppressed, and makes these compounds become to be used for the treatment of or the candidate substances likely (candidates) of the medicament of the medical conditions that prevention is relevant with FAAH.In addition, can confirm that this activity also is present in the in vivo test.
In addition, in these in vivo test, unexpected discovery has 5-O-and replaces 3-N-phenyl-1,3, and the compound of 4-oxadiazole ketone structural unit has presented FAAH and suppressed active, that is the activity in CNS has peripheral selectivity.Therefore, expect that the administration of these compounds can reduce the nervus centralis side effect of being seen when the periphery do not had FAAH inhibitor optionally using.
Therefore, compound of the present invention can be used for treating above-mentioned illness, thereby also can be used for treating these illnesss in the medicament preparation.The present invention also comprises: treat the method for these diseases, this method comprises need be administered to patient with The compounds of this invention by it; And the pharmaceutical composition that comprises The compounds of this invention.
Most preferably application envisioned for The compounds of this invention is a treatment of pain, particularly:
-acute or chronic neural source treatment of pain, for example migraine and neuropathic pain comprise diabetes nerve pain, postherpetic neuralgia, trigeminal neuralgia;
-with the treatment of the acute or chronic pain of following inflammation-related: for example sacroiliitis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn disease, irritable bowel syndrome; And
The treatment of-acute or chronic peripheral pain.
The term treatment and the various variation thereof that are used for herein are meant as " treat " or " treating " and can promote the well-being of mankind or non-human animal's any way.Treatment may be about existing illness or may be prevention (prophylactic treatment).Treatment can comprise curative effect, alleviate effect or prophylactic effects.Treatment can prevent or delayed onset, delay of progression or improve disease or the symptom of illness.
At several publication US 5 for example, 093,343, US 5,236,939, US 4,076,824, among WO 03/043997A1, EP 1 263 745 B1, WO 03/072098 A1, WO 01/17981 A1, WO 03/072555 A1 and the JP-A48 58 140, describe 5-O-and replaced 3-N-phenyl-1,3,4-oxadiazole ketone.Yet none relates to the inhibition of FAAH or relates to the treatment of the medical conditions relevant with FAAH in these publication.
In an embodiment, the present invention relates to the compound of a kind of general formula (I), perhaps acceptable salt or ester or prodrug on its steric isomer, the pharmacology,
Wherein
R
1To R
5Independent separately expression:
Hydrogen;
C
1-C
6Alkyl, C
3-C
8Cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxy carbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8Cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base (sulfoxy), C
6-C
10Aryl sulphur oxygen base, wherein each group is selectively replaced once or several by following group:
C
1-C
6-alkyl; C
1-C
6-alkoxyl group; C
6-C
10-aryloxy; CO
2H; SO
3H; CONH
2SO
2NH
2CONH
2Or SO
2NH
2, wherein amido functional group is selected from down more than the residue replacement once of group: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4Alkyl, and wherein at two-C
1-C
6Under the situation of-alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
CO
2H；
SO
3H；
Amino;
The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl;
Dibasic amino of general formula (II):
Wherein o represent 0 or 1 and W represent O, CH
2, or R
6Be selected from hydrogen atom and C
1-C
6The NR of-alkyl
6And wherein the methylene group in general formula (II) is selectively by C
1-C
6-alkyl, fluorine atom or chlorine atom replace once or twice;
CONH
2；
SO
2NH
2；
Wherein amido functional group is selected from down the residue replacement CONH once or twice of group
2Or SO
2NH
2: C
1-C
6-alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
6Alkyl, and wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring;
Thiol group;
Hydroxyl;
Nitro;
Cyano group;
Fluorosulfonyl;
Be selected from the halogen atom of fluorine atom, chlorine atom, bromine atoms or iodine atom;
CF
3；
OCF
3Perhaps
Saturated, the unsaturated or aromatic heterocycle system of maximum 10 atoms, this heterocyclic system are replaced once or several by following group alternatively:
C
1-C
6-alkyl; C
1-C
6-alkoxyl group; COOH; SO
3H; CONH
2SO
2NH
2CONH
2Or SO
2NH
2, wherein amido functional group is selected from down more than the residue replacement once of group: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10-aryl-C
1-C
4Alkyl, and wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
And, R wherein
1To R
5Thereby can become key to form more than two to condense (anellated) saturated, unsaturated or aromatics homogeneity member ring systems or heterocyclic system arbitrarily;
N represents 0 or 1; M represents 0,1,2,3,4,5 or 6;
X represents O or S;
Y represents:
A) hydrogen atom;
B) C
1-C
18-alkyl, single unsaturated or polyunsaturated C
2-C
18Alkylene, C
3-C
8Cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxy carbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8Cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Saturated, the unsaturated or aromatic heterocycle system of aryl sulphur oxygen base or maximum 10 atoms, wherein each group is selectively replaced once or several by following group:
B1) C
1-C
6Alkyl, C
3-C
8Cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxy carbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8Cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base; Wherein each group is selectively replaced once or several: C by following group
1-C
6Alkyl; C
1-C
6Alkoxyl group; CONH
2SO
2NH
2CONH
2Or SO
2NH
2, wherein amido functional group is by C
1-C
6Alkyl replaces once or twice; SO
3H; CO
2H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
Wherein, several substituting groups in b1) can become key to form to condense saturated, unsaturated or aromatics homogeneity (homo-) member ring systems or heterocyclic system;
Perhaps
B2) hydroxyl; Thiol group; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3CO
2H; SO
3H; OCF
3CONH
2SO
2NH
2CONH
2Or SO
2NH
2, wherein amido functional group is selected from C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
6The residue of alkyl replaces once or twice, and wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Dibasic amino of perhaps following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or R
6Be selected from hydrogen atom and C
1-C
6The NR of alkyl
6, and wherein the methylene radical in general formula (II) alternatively can be by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice;
Perhaps
B3) saturated, the unsaturated or aromatic heterocycle system of maximum 10 atoms, this heterocyclic system are replaced once or several: C by following group alternatively
1-C
6Alkyl; C
1-C
6Alkoxyl group; COOH; SO
3H; CONH
2SO
2NH
2CONH
2Or SO
2NH
2, wherein amido functional group is selected from C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4More than the residue of alkyl replaces once, and wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
C) SO
3H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; CONH
2SO
2NH
2CONH
2Or SO
2NH
2, wherein amido functional group is selected from C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4The residue of alkyl replaces once or twice, and wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorosulfonyl; Be selected from the halogen atom of fluorine atom, chlorine atom, bromine atoms or iodine atom; CF
3Or OCF
3
Further embodiment relates to the application of above-claimed cpd, and it is used for the inhibition of fatty acid amide hydrolase (FAAH) and the treatment that medical conditions is produced positive influence by the inhibition of FAAH.As in the article of people such as Pacher (Pharmacol.Rev.58:389-462 (2006)), particularly pointing out the highlighted treatment that is used for above-mentioned disease and medical conditions of above-claimed cpd.
The invention still further relates to the pharmaceutical composition that comprises following component: acceptable salt or prodrug on the compound of above-mentioned general formula (I) or its enantiomer, the pharmacology; And be used for by administration pharmaceutically on the compound, its enantiomer, pharmacology of the above-mentioned general formula (I) of effective dose acceptable salt or prodrug treat the method for above-mentioned disease and illness.
In the application's meaning, term C
1-C
4Alkyl is preferably represented methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl and the tertiary butyl.
In the application's meaning, term C
1-C
6Alkyl is preferably represented methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, amyl group or hexyl.
In the application's meaning, term C
1-C
18Alkyl is preferably represented methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, amyl group, hexyl, octyl group, decyl, dodecyl, tetradecyl and octadecyl.
In the application's meaning, the unsaturated or how unsaturated C of term list
2-C
18Alkylene is preferably represented vinyl, positive propenyl, pseudoallyl, n-butene base, secondary butenyl, uncle's butenyl, pentenyl, hexenyl, octenyl, decene base, laurylene base, tetradecene base, octadecylene base, 12 dialkylenes, 14 dialkylenes and 18 dialkylenes.
In the application's meaning, term C
3-C
8The preferred representative ring propyl group of cycloalkyl, cyclobutyl, cyclopentyl or cyclohexyl.
In the application's meaning, term C
6-C
10Aryl is preferably represented phenyl, pentalene base, indenyl, indanyl, isoindolinyl, chromanyl, naphthyl, fluorenyl, anthryl, phenanthryl or pyrenyl.
In the application's meaning, term C
6-C
10Aryl-C
1-C
8Alkyl, C
6-C
10Aryl-C
1-C
6Alkyl and C
6-C
10Aryl-C
1-C
4Alkyl is preferably represented by the phenyl or naphthyl of methyl, ethyl, propyl group or butyl replacement.Preferred especially residue is phenmethyl and styroyl.
In the application's meaning, term C
1-C
4Alkoxyl group is preferably represented methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, sec-butoxy and tert.-butoxy.
In the application's meaning, term C
1-C
6Alkoxyl group is preferably represented methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, sec-butoxy, tert.-butoxy, pentyloxy or hexyloxy.
In the application's meaning, term C
6-C
10Aryloxy is preferably represented phenoxy group, naphthyloxy, indenes oxygen base (indenoxy), fluorenes oxygen base (fluorenoxy) or luxuriant and rich with fragrance oxygen base (phenanthroxy).
In the application's meaning, term C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
6-C
10Aryl-C
1-C
6Alkoxyl group and C
6-C
10Aryl-C
1-C
4Alkoxyl group is preferably represented benzoyloxy, benzene oxyethyl group, benzene propoxy-or benzene butoxy.Preferred especially residue is benzoyloxy and benzene oxyethyl group.
In the application's meaning, term C
1-C
6Carbalkoxy is preferably represented methoxycarbonyl, ethoxycarbonyl, the positive third oxygen carbonyl, different third oxygen carbonyl or the butoxy carbonyl.
In the application's meaning, term C
6-C
10Aryloxy carbonyl is preferably represented phenyloxycarbonyl or naphthyloxy carbonyl.
In the application's meaning, term C
6-C
10Aryl-C
1-C
8Carbalkoxy is preferably represented benzoyloxy carbonyl or benzene ethoxy carbonyl.
In the application's meaning, term C
1-C
6Alkyl carbonyl is preferably represented first carbonyl, B carbonyl, positive third carbonyl, isopropyl carbonyl or fourth carbonyl.
In the application's meaning, term C
6-C
10Aromatic carbonyl is preferably represented phenylcarbamoyl or naphthalene carbonyl.
In the application's meaning, term C
6-C
10Aryl-C
1-C
8Alkyl carbonyl is preferably represented benzene first carbonyl or benzene B carbonyl.
In the application's meaning, term C
1-C
6The alkane carboxyl is preferably represented carboxyphenyl, second carboxyl, positive third carboxyl, different third carboxyl or fourth carboxyl.
In the application's meaning, term C
6-C
10The virtue carboxyl is preferably represented benzene carboxyl or naphthalene carboxyl.
In the application's meaning, term C
1-C
6The alkane sulfydryl is preferably represented first sulfydryl, second sulfydryl, positive third sulfydryl, different third sulfydryl or fourth sulfydryl.
In the application's meaning, term C
6-C
10Aromatic thiohydroxy is preferably represented benzene sulfydryl or naphthalene sulfydryl.
In the application's meaning, term C
1-C
6Alkane sulfydryl carbonyl is preferably represented first sulfydryl carbonyl, second sulfydryl carbonyl, the positive third sulfydryl carbonyl, the different third sulfydryl carbonyl or fourth sulfydryl carbonyl.
In the application's meaning, term C
3-C
8The preferred representative ring third sulfydryl carbonyl of cycloalkanes sulfydryl carbonyl, ring fourth sulfydryl carbonyl, ring penta sulfydryl carbonyl or hexamethylene sulfydryl carbonyl.
In the application's meaning, term C
6-C
10The aromatic thiohydroxy carbonyl is preferably represented benzene sulfydryl carbonyl or naphthalene sulfydryl carbonyl.
In the application's meaning, term C
1-C
6Alkane sulfydryl carboxyl is preferably represented first sulfydryl carboxyl, second sulfydryl carboxyl, the positive third sulfydryl carboxyl, the different third sulfydryl carboxyl or fourth sulfydryl carboxyl.
In the application's meaning, term C
6-C
10The aromatic thiohydroxy carboxyl is preferably represented benzene sulfydryl carboxyl or naphthalene sulfydryl carboxyl.
In the application's meaning, term C
1-C
6Alkyl sulphonyl is preferably represented methylsulfonyl, ethylsulfonyl, positive third alkylsulfonyl, positive fourth alkylsulfonyl, Zhong Ding alkylsulfonyl, uncle's fourth alkylsulfonyl, penta alkylsulfonyl or own alkylsulfonyl.
In the application's meaning, term C
6-C
10Aryl sulfonyl is preferably represented benzenesulfonyl or naphthalene sulfonyl base.
In the application's meaning, term C
1-C
6Alkyl sulfide oxygen base is preferably represented methyl sulphur oxygen base, ethyl sulphur oxygen base, n-propyl sulphur oxygen base, normal-butyl sulphur oxygen base, sec-butyl sulphur oxygen base or tertiary butyl sulphur oxygen base.
In the application's meaning, term C
6-C
10Aryl sulphur oxygen base is preferably represented phenyl sulphur oxygen base or naphthyl sulphur oxygen base.
In addition, in the optional embodiment of the present invention, preferred above-mentioned substituting group is for being replaced once or several: C by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, CO
2H, CONH
2, SO
2NH
2, SO
3H, amino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Or OCF
3In this optional substituent qualification, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy is preferably represented residue same as described above.
In the meaning of this application, term " be substituted alternatively once or for several times " be meant comprise with above-mentioned optional substituent nothing more than replace, single replacement or polysubstituted.Under polysubstituted situation, substituting group can be selected independently of one another.
In meaning of the present invention, be selected from C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
6-C
10Aryl-C
1-C
6Alkyl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10The residue of aryl sulfonyl replaces once above amino and preferably is expressed as by following substituting group and replaces once or twice amino independently of each other: at C
1-C
6Replaced by methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, amyl group or hexyl under the situation of alkyl; At C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
6-C
10Aryl-C
1-C
6Alkyl or C
6-C
10Aryl-C
1-C
8Replaced by phenyl, phenmethyl or styroyl under the situation of alkyl; At C
1-C
6Alkyl carbonyl and C
6-C
10Replaced by first carbonyl, B carbonyl or phenylcarbamoyl under the situation of aromatic carbonyl; And at C
1-C
6Alkyl sulphonyl and C
6-C
10Replaced by methylsulfonyl, ethylsulfonyl or benzenesulfonyl under the situation of aryl sulfonyl.
In the application's meaning, term " dibasic amino of following general formula (II) "
Preferred expression piperidyl, piperazinyl, pyrrolidyl, morpholinyl, N methyl piperazine or 2,2,6, the 6-tetramethyl piperidine, wherein o represents 0 or 1, and W represents O, CH
2, or R
6Be selected from hydrogen and C
1-C
6The NR of alkyl
6, and wherein the methylene radical in general formula (II) alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice.
In meaning of the present invention, CONH
2Or SO
2NH
2Preferably be expressed as and be derived from N, N-dimethylformamide, N-methane amide, N-ethanamide, N-benzamide, N, each residue of N-dimethyl methyl acid amides, N-sulfonyloxy methyl amine, N-ethyl sulfonamide and N-benzsulfamide, wherein CONH
2Or SO
2NH
2In the amido functional group residue that is selected from down group replace once more than: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl or C
6-C
10Aryl-C
1-C
6Alkyl, and wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring.Under the disubstituted situation of the alkyl of amido functional group, thereby also preferred two residues become key to form five-ring or six-ring.The example of these amido functional groups includes but not limited to tetramethyleneimine and piperidines.
In the meaning of this application, term " replaced once by following group alternatively or saturated, the unsaturated or aromatic heterocycle system of maximum 10 atoms for several times:
C
1-C
6Alkyl; C
1-C
6Alkoxyl group; COOH; SO
3H; CONH
2SO
2NH
2Wherein amido functional group is selected from down the once above CONH of residue replacement of group
2Or SO
2NH
2: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10-aryl-C
1-C
4Alkyl, and wherein at two-C
1-C
6Under the situation of-alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3"
Preferably be expressed as and comprise one to four saturated, unsaturated or aromatic heterocycle system that is selected from heteroatomic maximum 10 atoms of N, O or S.These preferred maximum 10 atoms saturated, unsaturated or aromatic heterocycle includes but not limited to benzoglyoxaline, cumarone, thionaphthene, benzoxazoles, benzothiazole, carbazole, cinnolines, Dioxins, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furans, imidazoles, tetrahydroglyoxaline, imidazoles alkene, indoles, indoline, indolizine, indazole, isoindole, isoquinoline 99.9 isoxazole, isothiazole, morpholine, naphthyridines oxazole oxadiazole Evil thiazole, oxo thiazoline (oxathiazolidine) oxazine oxadiazine, azophenlyene, thiodiphenylamine phenoxazine, phthalazines, piperazine, piperidines, pteridine, purine, pyrans, pyrazine, pyrazoles, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, the pyrroles, tetramethyleneimine, pyrroline, quinoline quinoxaline, quinazoline, quinolizine, tetrahydrofuran (THF), tetrazine, tetrazolium, thiophene, thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, sulfo-naphthalene (thianaphthalene), thiapyran, triazine, triazole, with trithian and all isomers configurations thereof.These heterocycles can be by C
1-C
6Alkyl, C
1-C
6Alkoxyl group, COOH, SO
3H, CONH
2, SO
2NH
2, CONH
2Or SO
2NH
2Replacement once or for several times, wherein amido functional group is selected from C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4More than the residue of alkyl replaces once, and wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby described alkyl residue can become key to form five-ring or six-ring; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3Preferred especially optional substituting group is methyl, methoxyl group, amino, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Or OCF
3
Saturated, the unsaturated or aromatic heterocycle of most preferred maximum 10 atoms comprises: 2-pyridine, 3-pyridine and 4-pyridine, all these three groups are selected from methyl, amino, fluorine atom, chlorine atom or CF alternatively
3An above residue replace; And be selected from methyl, amino, fluorine atom, chlorine atom or CF alternatively
3The N-that replaces of an above residue connect the pyrroles.
In further embodiment of the present invention, R
1To R
5Thereby become key to form more than two to condense (anellated) saturated, unsaturated or aromatics homogeneity member ring systems or heterocyclic system arbitrarily; The example of these member ring systems includes but not limited to benzoglyoxaline, cumarone, thionaphthene, benzoxazoles and benzothiazole.
In above-mentioned general formula (I) preferably, R
1To R
5Independent separately expression
Hydrogen atom;
Hydroxyl;
C
1-C
6Alkyl, C
6-C
10-aryl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
6Alkoxyl group, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, wherein each group is alternatively by C
1-C
6Alkyl, C
1-C
6Alkoxyl group, amino, C
1-C
6Alkylamino, two-C
1-C
6-alkylamino, hydroxyl, fluorine atom, chlorine atom, bromine atoms, cyano group, CF
3Or OCF
3Replace once or for several times;
Amino;
Be selected from C
1-C
6Alkyl, C
6-C
10The residue of aryl replaces once above amino;
Be selected from C alternatively
1-C
6Alkyl, amino, fluorine atom, chlorine atom or CF
3An above residue 1-pyrryl, 2-pyrryl or the 3-pyrryl that replace; Dibasic amino of general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or R
6Be selected from hydrogen and C
1-C
6The NR of alkyl
6, and wherein the methylene radical in general formula (II) alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice;
CONH
2；
SO
2NH
2；
CONH
2Or SO
2NH
2, wherein amido functional group is selected from C
1-C
6Alkyl or C
6-C
10The residue of aryl replaces once or twice;
Fluorine atom;
The chlorine atom;
Bromine atoms;
CF
3Or
OCF
3。
In above-mentioned general formula (I) further preferably, R
1To R
5In represent hydrogen atom, fluorine atom or chlorine atom more than one.More preferably R
1Or R
5Expression hydrogen atom or fluorine atom.R most preferably
1Or R
5The expression fluorine atom.
In above-mentioned general formula (I) further preferably, R
1To R
5In represent hydroxyl more than one; C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
6Alkoxyl group, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, amino, C
1-C
4Alkylamino, two-C
1-C
4Alkylamino, alternatively by C
1-C
6Alkyl or C
6-C
10Aryl replaces CONH once or twice
2Or SO
2NH
2, hydroxyl, fluorine atom, chlorine atom, bromine atoms, cyano group, CF
3Or OCF
3
More preferably R
2, R
3Or R
4In expression hydroxyl, a C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
6Alkoxyl group, wherein each group is replaced once or several: C by following group alternatively
1-C
4Alkyl, C
1-C
4Alkoxyl group, amino, C
1-C
4Alkylamino, two-C
1-C
4Alkylamino, alternatively by C
1-C
6Alkyl or C
6-C
10Aryl replaces CONH once or twice
2Or SO
2NH
2, hydroxyl, fluorine atom, chlorine atom or bromine atoms.
Further preferred in above-mentioned general formula (I), R
1To R
5In expression more than amino; Be selected from C
1-C
6Alkyl, C
6-C
10The residue of aryl replaces once above amino; Dibasic amino of perhaps following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or R
6Be selected from hydrogen and C
1-C
4The NR of alkyl
6, and wherein the methylene radical in general formula (II) alternatively by C
1-C
4Alkyl, fluorine atom or chlorine atom replace once or twice.
More preferably R
2, R
3Or R
4In an expression amino; Be selected from C
1-C
6Alkyl, C
6-C
10The residue of aryl replaces amino once or twice; Dibasic amino of perhaps following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or R
6Be selected from hydrogen and C
1-C
4The NR of alkyl
6, and wherein the methylene radical in general formula (II) alternatively by C
1-C
4Alkyl, fluorine atom or chlorine atom replace once or twice.
Further preferred in general formula (I), wherein n represents 0; M represents 0,1,2,3,4,5 or 6; And Y represents C
3-C
6Cycloalkyl or C
6-C
10Aryl, wherein each group is replaced once or several by following group alternatively:
A) C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
4Alkoxyl group, wherein each group is replaced once by following group or for several times:
C
1-C
6Alkyl; C
1-C
6Alkoxyl group; COOH; CONH
2SO
2NH
2By C
1-C
6Alkyl or C
6-C
10Aryl replaces CONH once or twice
2Or SO
2NH
2SO
3H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
Perhaps
B) hydroxyl; Thiol group; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3OCF
3CO
2H; SO
3H; CONH
2SO
2NH
2CONH
2Or SO
2NH
2, wherein amido functional group is selected from down more than the residue replacement once of group: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4Alkyl, and at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; By C
1-C
6Alkyl or phenyl replaces once or amino for several times; Dibasic amino of following general formula (II);
Wherein o represents 0 or 1, and W represents O, CH
2, or R
6Be to be selected from hydrogen atom and C
1-C
4The NR of alkyl
6, and wherein the methylene group in general formula (II) alternatively by C
1-C
4Alkyl, fluorine atom or chlorine atom replace once or twice;
Perhaps
C) replaced once by following group alternatively or saturated, the unsaturated or aromatic heterocycle system of maximum 10 atoms for several times:
C
1-C
6Alkyl; C
1-C
6Alkoxyl group; COOH; CONH
2SO
2NH
2By C
1-C
6Alkyl or C
6-C
10Aryl replaces CONH once or twice
2Or SO
2NH
2SO
3H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
More preferably n represents 0; M represents 0 or 1; And Y represents phenyl, 1-naphthyl, 2-naphthyl, 2-pyridyl, 3-pyridyl or 4-pyridyl ring system.
In this regard, more preferably Y is replaced once or several: C by following group
1-C
4Alkyl; Phenyl; C
1-C
4Alkoxyl group; Hydroxyl; Fluorine atom; The chlorine atom; Bromine atoms; CF
3OCF
3Optionally by C
1-C
4Alkyl replaces CONH once or twice
2Or SO
2NH
2, these optional C wherein
1-C
4Thereby alkyl residue can become key to form five-ring or six-ring; Perhaps amino.
In this regard, further preferred m represents 0, and Y represents by hydroxyl, fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice.
In this regard, most preferably m represents 0, and the Y phenyl representing to be replaced in the 4-position by fluorine atom, the phenyl that is replaced in the 4-position by the chlorine atom, the phenyl that is replaced in 2-position and 4-position by fluorine atom, the phenyl that is replaced in 2-position and 4-position by the chlorine atom or the phenyl that is replaced in the 4-position by phenyl.
Preferred especially in above-mentioned general formula (I), m represents 0; N represents 0; Y represents by fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice; And R
2To R
4Any one represent wherein R
7Be selected from hydrogen atom and C
1-C
4The OR of alkyl
7
Also very preferably, m is 0 in above-mentioned general formula (I); N is 0; The phenyl that Y represents to be replaced in the 4-position by fluorine atom, the phenyl that is replaced in the 4-position by the chlorine atom, the phenyl that is replaced in 2-position and 4-position by fluorine atom or the phenyl that is replaced in 2-position and 4-position by the chlorine atom, and R
2To R
4Any one represent wherein R
7Be selected from hydrogen atom and C
1-C
4The OR of alkyl
7
In above-mentioned general formula (I) also very preferably m be 0; N is 0; Y represents by fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice, and R
3Or R
3And R
4The expression hydroxyl.
In above-mentioned general formula (I) also very preferably m be 0; N is 0; The phenyl that Y represents to be replaced in the 4-position by fluorine atom, the phenyl that is replaced in the 4-position by the chlorine atom, the phenyl that is replaced in 2-position and 4-position by fluorine atom or the phenyl that is replaced in 2-position and 4-position by the chlorine atom, and R
3Or R
3And R
4The expression hydroxyl.
Preferred especially in above-mentioned general formula (I), m is 0; N is 0; Y represents by fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice; And R
2To R
4Any one represent wherein R
7Be selected from hydrogen atom and C
1-C
4The OR of alkyl
7And R
1Expression hydrogen atom or fluorine atom.
Preferred especially in above-mentioned general formula (I), m is 0; N is 0; The phenyl that Y represents to be replaced in the 4-position by fluorine atom, the phenyl that is replaced in the 4-position by the chlorine atom, the phenyl that is replaced in 2-position and 4-position by fluorine atom or the phenyl that is replaced in 2-position and 4-position by the chlorine atom, and R
2To R
4Any one represent wherein R
7Be selected from hydrogen atom and C
1-C
4The OR of alkyl
7And R
1Expression hydrogen atom or fluorine atom.
Preferred especially m is 0 in above-mentioned general formula (I); N is 0; Y represents by fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice, R
3Or R
3And R
4The expression hydroxyl; And R
1Expression hydrogen atom or fluorine atom.
Preferred especially m is 0 in above-mentioned general formula (I); N is 0; The phenyl that Y represents to be replaced in the 4-position by fluorine atom, the phenyl that is replaced in the 4-position by the chlorine atom, the phenyl that is replaced in 2-position and 4-position by fluorine atom or the phenyl that is replaced in 2-position and 4-position by the chlorine atom; R
3Or R
3And R
4The expression hydroxyl; And R
1Expression hydrogen atom or fluorine atom.
In addition, in above-mentioned general formula (I), also preferably when n be 0, when m is 0 or 1, Y represents C
6-C
10Aryl, preferred phenyl; Phenmethyl, styroyl, hydrocinnamyl, benzene butyl or benzene hexyl, wherein above-mentioned group are replaced once or several by following group alternatively:
A) C
1-C
6Alkyl, C
3-C
8Cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, hydroxyl, CO
2H, C
1-C
6Carbalkoxy, C
6-C
10Aryloxy carbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6-alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8Cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base;
Wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, COOH, alternatively by C
1-C
6Alkyl replaces CONH once or twice
2, SO
3H, amino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Perhaps OCF
3
Thereby several the become keys wherein in these optional substituting groups form and condense saturated, unsaturated or aromatics homogeneity member ring systems or heterocyclic system; Perhaps
B) replaced once or saturated, unsaturated or aromatic heterocycle: C for several times by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, COOH, alternatively by C
1-C
6Alkyl replaces CONH once or twice
2, SO
3H, amino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Perhaps OCF
3
C) SO
3H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; CONH
2SO
2NH
2CONH
2Or SO
2NH
2, wherein amido functional group is selected from down more than the residue replacement once of group: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorosulfonyl; Be selected from the halogen atom of fluorine atom, chlorine atom, bromine atoms, iodine atom; CF
3, OCF
3
Also preferred n=0 and m=0 or 1 in the above-mentioned general formula (I).
Also preferred R
1To R
5Independent separately expression: hydrogen atom; Hydroxyl; C
1-C
4Alkyl; C
6-C
10Aryl; C
1-C
4Alkoxyl group; C
6-C
10Aryloxy; C
6-C
10Aryl-C
1-C
4Alkoxyl group; COOH; C
1-C
6The alkane carboxyl; C
6-C
10The virtue carboxyl; C
1-C
6The alkane sulfydryl; C
6-C
10Aromatic thiohydroxy; C
1-C
6Alkyl sulphonyl; C
6-C
10Aryl sulfonyl; C
1-C
6Alkyl sulfide oxygen base; C
6-C
10Aryl sulphur oxygen base; SO
3H, amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorosulfonyl; Be selected from the halogen atom of fluorine atom, chlorine atom, bromine atoms, iodine atom; CF
3OCF
3Perhaps replaced once or saturated, unsaturated or aromatic heterocycle: C for several times by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, COOH, SO
3H, amino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Perhaps OCF
3
More preferably R
1To R
5Be selected from: hydroxyl, methyl, the tertiary butyl, phenyl, methoxyl group, oxyethyl group, phenoxy group, amino, thiol group, hydroxyl, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3, OCF
3, pyridine, CONH
2, SO
2NH
2, tetrazolium or triazole.
Also preferred R
1To R
5In any one be further to be replaced once or phenyl for several times by following group: hydroxyl, C
1-C
6Alkoxyl group, COOH, SO
3H, amino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Perhaps OCF
3
Also preferred in general formula (I), Y represent by following group at the ortho position, the phenyl or benzyl of a position and/or para-orientation: C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, hydroxyl, nitro, amino, CONH
2, SO
2NH
2, fluorine atom, chlorine atom or OCF
3More preferably, Y represent to be independently selected from following group substituting group at the ortho position and/or para-orientation once, the phenyl of twice or three times: methoxyl group, oxyethyl group, tert.-butoxy, phenoxy group, hydroxyl, nitro, CONH
2, SO
2NH
2, fluorine atom, chlorine atom or OCF
3
Also preferably in general formula (I), when n=0 and m=0 or 1, R
1To R
5Be selected from: methyl, the tertiary butyl, phenyl, methoxyl group, oxyethyl group, phenoxy group, amino, thiol group, hydroxyl, cyano group, fluorine atom, chlorine atom, bromine atoms, nitro, CF
3, OCF
3, pyridine, CONH
2, SO
2NH
2, tetrazolium, triazole or further replaced once or phenyl for several times: C by following group
1-C
6Alkoxyl group, COOH, SO
3H, amino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Or OCF
3, and Y represents by following group at the ortho position and/or the phenyl of para-orientation: C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, hydroxyl, nitro, CONH
2, SO
2NH
2, fluorine atom, chlorine atom or OCF
3
In optional embodiment, the present invention relates to the compound of a kind of general formula (I),
Wherein
R
1To R
5Independent separately expression:
Hydrogen;
C
1-C
6Alkyl, C
3-C
8-cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxy carbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8-cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base, wherein each group is replaced once or several by following group alternatively:
C
1-C
6Alkyl; C
1-C
6Alkoxyl group; C
6-C
10Aryloxy; CO
2H; SO
3H; CONH
2SO
2NH
2CONH
2Or SO
2NH
2, wherein amido functional group is selected from down more than the residue replacement once of group: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4Alkyl, and at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
CO
2H；
SO
3H；
Amino;
The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl;
Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or R
6Be selected from hydrogen atom and C
1-C
6The NR of alkyl
6, and wherein in general formula (II) methylene group alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice;
CONH
2；
SO
2NH
2；
CONH
2Or SO
2NH
2, wherein the amido functional group residue that is selected from down group replaces once or twice: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
6Alkyl, and at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring;
Thiol group;
Hydroxyl;
Nitro;
Cyano group;
Fluorosulfonyl;
Be selected from the halogen atom of fluorine atom, chlorine atom, bromine atoms or iodine atom;
CF
3；
OCF
3Perhaps
Replaced once by following group alternatively or saturated, the unsaturated or aromatic heterocycle system of maximum 10 atoms for several times:
C
1-C
6Alkyl; C
1-C
6Alkoxyl group; COOH; SO
3H; CONH
2SO
2NH
2CONH
2Or SO
2NH
2, wherein amido functional group is selected from down more than the residue replacement once of group: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4Alkyl, and at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
And R wherein
1To R
5Thereby in can become key to form more than two to condense saturated, unsaturated or aromatics homogeneity member ring systems or heterocyclic system arbitrarily;
N represents 0; M represents 0;
Y represents to be replaced once or phenyl for several times by following group alternatively:
A) C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxy carbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8-cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base;
Wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl; C
1-C
6Alkoxyl group; Alternatively by C
1-C
6Alkyl replaces CONH once or twice
2Or SO
2NH
2SO
3H; CO
2H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
Thereby several the become keys wherein in these optional substituting groups form and condense saturated, unsaturated or aromatics homogeneity member ring systems or heterocyclic system; Perhaps
B) replaced once by following group alternatively or saturated, unsaturated or aromatic heterocycle system: the C of maximum 10 atoms for several times
1-C
6Alkyl; C
1-C
6Alkoxyl group; COOH; Alternatively by C
1-C
6Alkyl replaces CONH once or twice
2Or SO
2NH
2SO
3H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3Perhaps
C) hydroxyl; Thiol group; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3OCF
3CO
2H; SO
3H; CONH
2SO
2NH
2CONH
2Or SO
2NH
2, wherein amido functional group is selected from down more than the residue replacement once of group: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4Alkyl, and at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or R
6Be selected from hydrogen atom and C
1-C
4The NR of alkyl
6, and wherein the methylene group in general formula (II) alternatively by C
1-C
4Alkyl, fluorine atom or chlorine atom replace once or twice;
Supplementary condition are:
A) R
2Or R
4Do not represent substituting group C (=A)-N (B)-SO
2-NR
6R
7, wherein A represents O or S, B represents hydrogen atom, cyano group, C
1-C
6Alkyl, C
1-C
6Alkoxyalkyl, C
3-C
7Cycloalkyl, C
3-C
6Alkylene, C
3-C
6Alkynyl or substituted alternatively phenmethyl derivative, and R
6And R
7Independently represent hydrogen atom or organic residue separately or represent organic ring structure altogether;
B) when Y represents not have the phenyl of replacement, R
1To R
5Do not represent hydrogen atom, fluorine atom, chlorine atom, bromine atoms, iodine atom or alkyl independently of one another;
C) R
2Or R
4Do not represent the pyrazole-3-yl derivative; And
D) by R
1To R
5The phenyl ring and the Y that replace are not expressed as follows combination:
| By R 1To R 5The phenyl ring that replaces | Y |
| The 2-chloro-phenyl- | The 4-chloro-phenyl- |
| 2, the 3-3,5-dimethylphenyl | The 4-chloro-phenyl- |
| The 2,4 dichloro benzene base | The 4-chloro-phenyl- |
| 2-chloro-3-tolyl | The 4-chloro-phenyl- |
| 2, the 5-difluorophenyl | The 4-tolyl |
| 2-methoxyl group-4-chloro-phenyl- | The 4-chloro-phenyl- |
| The 2-chloro-phenyl- | The 4-tolyl |
| 2, the 6-dichlorophenyl | The 4-chloro-phenyl- |
| 2-(trifluoromethyl sulfydryl) phenyl | Phenyl |
| 2,3, the 4-trimethylphenyl | The 4-chloro-phenyl- |
| 2, the 5-difluorophenyl | The 4-bromophenyl |
| 2, the 4-xylyl | The 4-chloro-phenyl- |
| The 4-chloro-phenyl- | The 4-chloro-phenyl- |
| The 3-chloro-phenyl- | The 4-chloro-phenyl- |
| The 4-bromophenyl | The 4-chloro-phenyl- |
| The 2-chloro-phenyl- | The 4-bromophenyl |
| 2, the 5-difluorophenyl | The 4-chloro-phenyl- |
| The 4-chloro-phenyl- | The 4-bromophenyl |
| 3, the 5-3,5-dimethylphenyl | The 4-chloro-phenyl- |
| The 4-Trifluoromethoxyphen-l | The hot phenyl of 4- |
| The 4-Trifluoromethoxyphen-l | The 3-Phenoxyphenyl |
| 2,3-dihydro-2,2-dimethyl-7-benzofuryl | Phenyl |
Preferred R in general formula (I)
1To R
5Independent separately expression:
Hydrogen atom;
Hydroxyl;
C
1-C
6Alkyl, C
6-C
10Aryl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
6Alkoxyl group, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, amino, C
1-C
6Alkylamino, two C
1-C
6Alkylamino, hydroxyl, fluorine atom, chlorine atom, bromine atoms, cyano group, CF
3Perhaps OCF
3
Amino;
Be selected from C
1-C
6Alkyl, C
6-C
10The residue of aryl replaces once above amino;
Be selected from C alternatively
1-C
6Alkyl, amino, fluorine atom, chlorine atom or CF
3An above residue 1-pyrryl, 2-pyrryl or the 3-pyrryl that replace;
Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or R
6Be selected from hydrogen atom and C
1-C
6The NR of alkyl
6, and wherein the methylene group in general formula (II) alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice;
CONH
2；
SO
2NH
2；
CONH
2Or SO
2NH
2, wherein amido functional group is selected from C
1-C
6Alkyl, C
6-C
10The residue of aryl replaces once or twice;
Fluorine atom;
The chlorine atom
Bromine atoms;
CF
3Perhaps
OCF
3。
Further preferred R in general formula (I)
1To R
5In represent hydrogen atom, fluorine atom or chlorine atom more than one.R most preferably
1Or R
5Expression hydrogen atom or fluorine atom.
Further preferred R in general formula (I)
1To R
5In represent hydroxyl more than one; Perhaps
C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
6Alkoxyl group, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, amino, C
1-C
6Alkylamino, two-C
1-C
6Alkylamino, alternatively by C
1-C
6Alkyl or C
6-C
10Aryl replaces CONH once or twice
2Or SO
2NH
2, hydroxyl, fluorine atom, chlorine atom, bromine atoms, cyano group, CF
3Or OCF
3
More preferably R
2, R
3Or R
4In an expression: hydroxyl; Perhaps
C
1-C
6Alkoxyl group, C
6-C
10Aryloxy or C
6-C
10Aryl-C
1-C
6Alkoxyl group, wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, amino, C
1-C
6Alkylamino, two-C
1-C
6Alkylamino, alternatively by C
1-C
6Alkyl or C
6-C
10Aryl replaces CONH once or twice
2Or SO
2NH
2, hydroxyl, fluorine atom, chlorine atom or bromine atoms;
Further preferred R in above-mentioned general formula (I)
1To R
5In more than one expression amino; Be selected from C
1-C
6Alkyl, C
6-C
10The residue of aryl replaces once above amino; Dibasic amino of perhaps following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or R
6Be selected from hydrogen atom and C
1-C
4The NR of alkyl
6, and wherein the methylene group in general formula (II) alternatively by C
1-C
4Alkyl, fluorine atom or chlorine atom replace once or twice.
Further preferred R
2, R
3Or R
4In an expression amino; Be selected from C
1-C
6Alkyl, C
6-C
10The residue of aryl replaces amino once or twice; Dibasic amino of perhaps following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or R
6Be selected from hydrogen atom and C
1-C
4The NR of alkyl
6, and wherein the methylene group in general formula (II) alternatively by C
1-C
4Alkyl, fluorine atom or chlorine atom replace once or twice.
The Y that further preferably represents phenyl in general formula (I) is replaced once or several by following group:
A) C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
6Alkoxyl group, wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl; C
1-C
6Alkoxyl group; SO
3H; CO
2H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl; C
1-C
6Alkyl carbonyl; C
6-C
10Aromatic carbonyl; C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom, chlorine atom, bromine atoms, iodine atom; CF
3CONH
2SO
2NH
2OCF
3Perhaps CONH
2Or SO
2NH
2, wherein amido functional group is by C
1-C
6Alkyl replaces once or twice;
Perhaps
B) hydroxyl; Thiol group; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3OCF
3CO
2H; SO
3H; CONH
2SO
2NH
2Perhaps CONH
2Or SO
2NH
2, wherein the amido functional group group that is selected from down group replaces once or twice: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl is wherein at two-C
1-C
6Under the situation of alkyl-substituted amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; By C
1-C
6Alkyl or phenyl replaces once or amino for several times; Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or R
6Be selected from hydrogen atom and C
1-C
6The NR of alkyl
6, and wherein the methylene group in general formula (II) alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice;
Perhaps
C) replaced once by following group alternatively or saturated, unsaturated or aromatic heterocycle system: the C of maximum 10 atoms for several times
1-C
6Alkyl; C
1-C
6Alkoxyl group; COOH; CONH
2SO
2NH
2CONH
2Or SO
2NH
2, wherein amido functional group can be become key to form the C of five-ring or six-ring
1-C
6Alkyl replaces once or twice; SO
3H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
More preferably Y represents to be replaced once or phenyl for several times: C by following group
1-C
6Alkyl; Phenyl; C
1-C
6Alkoxyl group; Hydroxyl; Fluorine atom; The chlorine atom; Bromine atoms; CF
3OCF
3Amino; Perhaps alternatively by C
1-C
6Alkyl replaces CONH once or twice
2Or SO
2NH
2, these optional C wherein
1-C
6Alkyl residue can become key to form five-ring or six-ring.
More preferably m represent 0 and Y represent to be replaced once or twice phenyl by hydroxyl, fluorine atom, chlorine atom or bromine atoms.
Most preferably m represents 0 and the Y phenyl representing to be replaced in the 4-position by fluorine atom, the phenyl that is replaced in the 4-position by the chlorine atom, the phenyl that is replaced in 2-position and 4-position by fluorine atom, the phenyl that is replaced in 2-position and 4-position by the chlorine atom or the phenyl that is replaced in the 4-position by phenyl.
Preferred especially m is 0 in general formula (I); N is 0; And Y represents by fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice; And R
2To R
4In any one the expression OR
7, R wherein
7Be selected from hydrogen atom and C
1-C
4Alkyl.
In general formula (I) also very preferably m be 0; N is 0; And the phenyl that Y represents to be replaced in the 4-position by fluorine atom, the phenyl that is replaced in the 4-position by the chlorine atom, the phenyl that is replaced in 2-position and 4-position by fluorine atom or the phenyl that is replaced in 2-position and 4-position by the chlorine atom; And R
2To R
4In any one the expression OR
7, R wherein
7Be selected from hydrogen atom and C
1-C
4Alkyl.
In general formula (I) also very preferably m be 0; N is 0; And Y represents by fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice, and R
3, or R
3And R
4The expression hydroxyl.
In general formula (I) also very preferably m be 0; N is 0; And the phenyl that Y represents to be replaced in the 4-position by fluorine atom, the phenyl that is replaced in the 4-position by the chlorine atom, the phenyl that is replaced in 2-position and 4-position by fluorine atom or the phenyl that is replaced in 2-position and 4-position by the chlorine atom, and R
3, or R
3And R
4The expression hydroxyl.
Preferred especially m is 0 in general formula (I); N is 0; Y represents by fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice; R
2To R
4In any one the expression OR
7, R wherein
7Be selected from hydrogen atom and C
1-C
4Alkyl; And R
1The expression fluorine atom.
Preferred especially m is 0 in general formula (I); N is 0; The phenyl that Y represents to be replaced in the 4-position by fluorine atom, the phenyl that is replaced in the 4-position by the chlorine atom, the phenyl that is replaced in 2-position and 4-position by fluorine atom, the phenyl that is replaced in 2-position and 4-position by the chlorine atom; R
2To R
4In any one the expression OR
7, R wherein
7Be selected from hydrogen atom and C
1-C
4Alkyl; And R
1The expression fluorine atom.
Preferred especially m is 0 in general formula (I); N is 0; And Y represents by fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice; And R
3Or R
3And R
4The expression hydroxyl; And R
1The expression fluorine atom.
Preferred especially m is 0 in general formula (I); N is 0; And the phenyl that Y represents to be replaced in the 4-position by fluorine atom, the phenyl that is replaced in the 4-position by the chlorine atom, the phenyl that is replaced in 2-position and 4-position by fluorine atom or the phenyl that is replaced in 2-position and 4-position by the chlorine atom; And R
3Or R
3And R
4The expression hydroxyl; And R
1The expression fluorine atom.
In addition, also preferred R in general formula (I)
1To R
5Be selected from: hydroxyl, methyl, the tertiary butyl, phenyl, methoxyl group, oxyethyl group, phenoxy group, amino, thiol group, hydroxyl, cyano group, fluorine atom, chlorine atom, bromine atoms, nitro, CF
3, OCF
3, pyridine, CONH
2, SO
2NH
2, tetrazolium or triazole.
Also preferred R
1To R
5In at least one is to be replaced once or saturated, unsaturated or aromatic heterocycle: C for several times by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, COOH, SO
3H, amino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Perhaps OCF
3Perhaps further replaced once or phenyl for several times: C by following group
1-C
6Alkoxyl group, COOH, SO
3H, amino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Perhaps OCF
3
In addition, also preferred R
1To R
5In at least one is CONH
2SO
2NH
2CONH
2Or SO
2NH
2, wherein amido functional group is selected from down more than the residue replacement once of group: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl C
1-C
4Alkyl.
Also preferred in general formula (I), Y is illustrated in the phenyl that ortho position and/or contraposition are replaced by following group: C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, hydroxyl, nitro, amino, CONH
2, SO
2NH
2, fluorine atom, chlorine atom or OCF
3
Even more preferably, the substituting group that Y represents to be independently selected from down group at the ortho position and/or para-orientation once, the phenyl of twice or three times: methoxyl group, oxyethyl group, tert.-butoxy, phenoxy group, hydroxyl, nitro, CONH
2, SO
2NH
2, fluorine atom, chlorine atom or OCF
3
Also preferred, Y is illustrated in the phenyl that ortho position and/or contraposition are replaced by following group: C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, hydroxyl, nitro, CONH
2, SO
2NH
2, fluorine atom, chlorine atom or OCF
3
Also preferred R in general formula (I)
1To R
5Be selected from: methyl; The tertiary butyl; Phenyl; Methoxyl group; Oxyethyl group; Phenoxy group; Amino; Thiol group; Hydroxyl; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; Nitro; CF
3OCF
3Pyridine; CONH
2SO
2NH
2Tetrazolium; Triazole; Perhaps further replaced once or phenyl for several times: C by following group
1-C
6Alkoxyl group, COOH, SO
3H, amino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3, OCF
3, and Y represents by following group at the ortho position and/or the phenyl of para-orientation: C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, hydroxyl, nitro, CONH
2, SO
2NH
2, fluorine atom, chlorine atom or OCF
3
In optional embodiment, the present invention relates to the compound of a kind of general formula (I),
Wherein
R
1To R
5Independent separately expression:
Hydrogen atom;
C
1-C
6Alkyl, C
3-C
8Cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxy carbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8Cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base, wherein each group is replaced once by following group or for several times alternatively:
C
1-C
6Alkyl; C
1-C
6Alkoxyl group; C
6-C
10Aryloxy; CO
2H; SO
3H; CONH
2SO
2NH
2Wherein amido functional group is selected from down the once above CONH of residue replacement of group
2Or SO
2NH
2: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10-aryl-C
1-C
4Alkyl, and wherein at two-C
1-C
6Thereby alkyl residue can become key to form five-ring or six-ring under the situation of-alkyl-substituted-amino functional group; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
CO
2H；
SO
3H；
Amino;
The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl;
Dibasic amino of following general formula (II):
Wherein o represent 0 or 1 and W represent O, CH
2, or R
6Be selected from hydrogen atom and C
1-C
6The NR of alkyl
6And wherein the methylene group in general formula (II) is selectively by C
1-C
6-alkyl, fluorine atom or chlorine atom replace once or twice;
CONH
2；
SO
2NH
2；
CONH
2Or SO
2NH
2, wherein the amido functional group residue that is selected from down group replaces once or twice: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
6Alkyl, and wherein at two-C
1-C
6Thereby alkyl residue can become key to form five-ring or six-ring under the situation of-alkyl-substituted-amino functional group;
Thiol group;
Hydroxyl;
Nitro;
Cyano group;
Fluorosulfonyl;
Be selected from the halogen atom of fluorine atom, chlorine atom, bromine atoms or iodine atom;
CF
3；
OCF
3Perhaps
Saturated, the unsaturated or aromatic heterocycle system of maximum 10 atoms that replaced by following group alternatively:
C
1-C
6Alkyl; C
1-C
6Alkoxyl group; COOH; SO
3H; CONH
2SO
2NH
2CONH
2Or SO
2NH
2, wherein amido functional group is selected from down more than the residue replacement once of group: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4Alkyl, and wherein at two-C
1-C
6Thereby alkyl residue can become key to form five-ring or six-ring under the situation of-alkyl-substituted-amino functional group; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
And R wherein
1To R
5Thereby in can become key to form more than two to condense saturated, unsaturated or aromatics homogeneity member ring systems or heterocyclic system arbitrarily;
N represents 0; M represents 1;
Y represents to be replaced once or phenyl for several times by following group alternatively:
A) C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxy carbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8-cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base;
Wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl; C
1-C
6Alkoxyl group; Alternatively by C
1-C
6Alkyl replaces CONH once or twice
2Or SO
2NH
2SO
3H; CO
2H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
Thereby several the become keys wherein in these optional substituting groups form and condense saturated, unsaturated or aromatics homogeneity member ring systems or heterocyclic system; Perhaps
B) replaced once by following group alternatively or saturated, unsaturated or aromatic heterocycle system: the C of maximum 10 atoms for several times
1-C
6Alkyl; C
1-C
6Alkoxyl group; COOH; Alternatively by C
1-C
6Alkyl replaces CONH once or twice
2Or SO
2NH
2SO
3H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3Perhaps
C) hydroxyl; Thiol group; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3OCF
3CO
2H; SO
3H; CONH
2SO
2NH
2CONH
2Or SO
2NH
2, wherein amido functional group is selected from down more than the residue replacement once of group: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4Alkyl, and wherein at two-C
1-C
6Thereby alkyl residue can become key to form five-ring or six-ring under the situation of-alkyl-substituted-amino functional group; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Dibasic amino of following general formula (IV):
Wherein o represent 0 or 1 and W represent O, CH
2, or R
6Be selected from hydrogen atom and C
1-C
4The NR of alkyl
6And wherein the methylene group in general formula (IV) is selectively by C
1-C
4Alkyl, fluorine atom or chlorine atom replace once or twice;
Supplementary condition: Y does not represent not have the phenyl of replacement, if R
1, R
2And R
5The expression hydrogen atom, R
4Expression hydrogen atom, trifluoromethoxy, trifluoro butoxy, 3,3,5,5-tetramethyl-ring hexyloxy, benzyloxy, phenoxy group, phenyl, 2-dimethylamino ethoxy or 3-tolyloxy methyl, and R
3Expression hydrogen atom, trifluoromethoxy, trifluoro butoxy, 3; 3; 5,5-tetramethyl-ring hexyloxy, phenoxy group, 4-chlorophenoxy, cyclohexyl, phenyl, morpholine alkylsulfonyl, 3,3; 5-trimethylcyclohexyl amino-sulfonyl, 2; 2,6,6-tetramethyl piperidine-4-base amino-sulfonyl, 2-(di-isopropyl aminoethyl) sulfamyl, 4-methylpiperazine-1-base alkylsulfonyl, 3; 3-lupetidine carbonyl or 3,5-dichlorophenoxy, 2-dimethylamino ethoxy or 3-tolyloxy methyl.
More preferably Y represents to be replaced once or phenyl for several times: C by following group
1-C
6Alkyl; Phenyl; C
1-C
6Alkoxyl group; Hydroxyl; Fluorine atom; The chlorine atom; Bromine atoms; CF
3OCF
3Amino; Perhaps alternatively by C
1-C
6Alkyl replaces CONH once or twice
2Or SO
2NH
2, these optional C wherein
1-C
6Thereby alkyl residue can become key to form five-ring or six-ring.
Still more preferably m represent 0 and Y represent to be replaced once or twice phenyl by hydroxyl, fluorine atom, chlorine atom or bromine atoms.
Most preferably m represents 0 and the Y phenyl representing to be replaced in the 4-position by fluorine atom, the phenyl that is replaced in the 4-position by the chlorine atom, the phenyl that is replaced in 2-position and 4-position by fluorine atom, the phenyl that is replaced in 2-position and 4-position by the chlorine atom or the phenyl that is replaced in the 4-position by phenyl.
Preferred especially m is 0 in above-mentioned general formula (I); N is 0; Y represents by fluorine, chlorine or bromine replacement phenyl once or twice; And R
2To R
4In any one represents wherein R
7Be selected from hydrogen atom and C
1-C
4The OR of alkyl
7
In above-mentioned general formula (I) also very preferably m be 0; N is 0; The phenyl that Y represents to be replaced in the 4-position by fluorine atom, the phenyl that is replaced in the 4-position by the chlorine atom, the phenyl that is replaced in 2-position and 4-position by fluorine atom or the phenyl that is replaced in 2-position and 4-position by the chlorine atom; And R
2To R
4In any one represents wherein R
7Be selected from hydrogen atom and C
1-C
4The OR of alkyl
7
In above-mentioned general formula (I) also very preferably m be 0; N is 0; Y represents by fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice, and R
3, or R
3And R
4The expression hydroxyl.
In above-mentioned general formula (I) also very preferably m be 0; N is 0; The phenyl that Y represents to be replaced in the 4-position by fluorine atom, the phenyl that is replaced in the 4-position by the chlorine atom, the phenyl that is replaced in 2-position and 4-position by fluorine atom or the phenyl that is replaced in 2-position and 4-position by the chlorine atom, and R
3, or R
3And R
4The expression hydroxyl.
Preferred especially m is 0 in above-mentioned general formula (I); N is 0; Y represents by fluorine, chlorine or bromine replacement phenyl once or twice; And R
2To R
4In any one represents wherein R
7Be selected from hydrogen atom and C
1-C
4The OR of alkyl
7And R
1The expression fluorine atom.
Preferred especially m is 0 in above-mentioned general formula (I); N is 0; The phenyl that Y represents to be replaced in the 4-position by fluorine atom, the phenyl that is replaced in the 4-position by the chlorine atom, the phenyl that is replaced in 2-position and 4-position by fluorine atom or the phenyl that is replaced in 2-position and 4-position by the chlorine atom; And R
2To R
4In any one represents wherein R
7Be selected from hydrogen atom and C
1-C
4The OR of alkyl
7And R
1The expression fluorine atom.
Preferred especially m is 0 in general formula (I); N is 0; Y represents by fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice; R
3, or R
3And R
4The expression hydroxyl; And R
1The expression fluorine atom.
Preferred especially m is 0 in above-mentioned general formula (I); N is 0; The phenyl that Y represents to be replaced in the 4-position by fluorine atom, the phenyl that is replaced in the 4-position by the chlorine atom, the phenyl that is replaced in 2-position and 4-position by fluorine atom or the phenyl that is replaced in 2-position and 4-position by the chlorine atom; R
3, or R
3And R
4The expression hydroxyl; And R
1The expression fluorine atom.
In addition, also preferred in general formula (I), R
1To R
5Be selected from: methyl; The tertiary butyl; Phenyl; Methoxyl group; Oxyethyl group; Phenoxy group; Amino; Thiol group; Hydroxyl; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; Nitro; CF
3OCF
3Pyridine; CONH
2, SO
2NH
2, wherein amido functional group is selected from down more than the residue replacement once of group: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4Alkyl; Tetrazolium or triazole.
Also preferred R
1To R
5In any one be further to be replaced once or phenyl for several times: C by following group
1-C
6Alkoxyl group, COOH, SO
3H, amino, thiol group, hydroxyl, nitro, cyano group, fluorine, chlorine, bromine, iodine, CF
3Or OCF
3
Also preferred Y represents by following group at the ortho position and/or the phenyl of para-orientation: C in general formula (1)
1-C
6Alkoxyl group, C
6-C
10Aryloxy, hydroxyl, nitro, amino, CONH
2, SO
2NH
2, fluorine, chlorine or OCF
3
Even more preferably Y represent independently to be selected from down group substituting group at the ortho position and/or para-orientation once, the phenyl of twice or three times: methoxyl group, oxyethyl group, tert.-butoxy, phenoxy group, hydroxyl, nitro, CONH
2, SO
2NH
2, fluorine, chlorine or OCF
3
Also preferred Y represents by following group at the ortho position and/or the phenyl of para-orientation: C in general formula (1)
1-C
6Alkoxyl group, C
6-C
10Aryloxy, hydroxyl, nitro, CONH
2, SO
2NH
2, fluorine, chlorine or OCF
3
In general formula (I) also very preferably, R
1To R
5Be selected from: methyl, the tertiary butyl, phenyl, methoxyl group, oxyethyl group, phenoxy group, amino, thiol group, hydroxyl, cyano group, fluorine atom, chlorine atom, bromine atoms, nitro, CF
3, OCF
3, pyridine, CONH
2, SO
2NH
2, tetrazolium, triazole or further replaced once or phenyl for several times: C by following group
1-C
6Alkoxyl group, COOH, SO
3H, amino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Or OCF
3, and Y represents by following group at the ortho position and/or the phenyl of para-orientation: C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, hydroxyl, nitro, CONH
2, SO
2NH
2, fluorine atom, chlorine atom or OCF
3
In first embodiment very preferably, the present invention relates to the compound of a kind of general formula (I), perhaps acceptable salt or ester or prodrug on its steric isomer, the pharmacology,
R wherein
1Or R
5Expression hydrogen atom or fluorine atom;
R
2To R
4In any one expression hydroxyl and remaining other R residues be:
Hydrogen atom;
C
1-C
6Alkyl, C
3-C
8-cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxycarbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8-cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base, wherein each residue is replaced once by following group or for several times alternatively: C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, CO
2H, SO
3H, amino, C
1-C
6Alkylamino, two-C
1-C
6Alkylamino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3, or OCF
3
CO
2H；
SO
3H；
Amino;
The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl;
Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or R
6Be selected from hydrogen atom and C
1-C
6The NR of alkyl
6, and wherein the methylene group in general formula (II) alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice;
CONH
2；
SO
2NH
2；
CONH
2Or SO
2NH
2, wherein amido functional group is selected from down more than the residue replacement once of group: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
6Alkyl, and at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring;
Thiol group;
Hydroxyl;
Nitro;
Cyano group;
Fluorosulfonyl;
Be selected from the halogen of fluorine atom, chlorine atom, bromine atoms or iodine atom;
CF
3；
OCF
3Or
Replaced once by following group alternatively or saturated, unsaturated or aromatic heterocycle system: the C of maximum 10 atoms for several times
1-C
6Alkyl, C
1-C
6Alkoxyl group, COOH, SO
3H, amino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Or OCF
3
And R wherein
2To R
4Thereby in can become key to form more than two to condense saturated, unsaturated or aromatics homogeneity member ring systems or heterocyclic system arbitrarily;
N and m are 0; And
Y is replaced once or phenyl for several times: C by following group
1-C
6Alkyl; Phenyl; C
1-C
6Alkoxyl group; Hydroxyl; Fluorine atom; The chlorine atom; Bromine atoms; CF
3OCF
3Amino; Or alternatively by C
1-C
6Alkyl replaces CONH once or twice
2, these optional C wherein
1-C
6Thereby alkyl residue can become key to form five-ring or six-ring.
In second embodiment very preferably, the present invention relates to the compound of a kind of general formula (I), perhaps acceptable salt or ester or prodrug on its steric isomer, the pharmacology,
R wherein
1Or R
5Expression hydrogen atom or fluorine atom;
R
2To R
4In the amino and residue R residue of any one expression be:
Hydrogen atom;
C
1-C
6Alkyl, C
3-C
8-cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxycarbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8-cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base, wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, CO
2H, SO
3H, amino, C
1-C
6Alkylamino, two-C
1-C
6-alkylamino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Or OCF
3
CO
2H；
SO
3H；
Amino;
The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl;
Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or R
6Be selected from hydrogen atom and C
1-C
6The NR of alkyl
6, and wherein the methylene group in general formula (II) alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice;
CONH
2；
SO
2NH
2；
CONH
2Or SO
2NH
2, wherein amido functional group is selected from down more than the residue replacement once of group: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
6Alkyl, and at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring;
Thiol group;
Hydroxyl;
Nitro;
Cyano group;
Fluorosulfonyl;
Be selected from the halogen atom of fluorine atom, chlorine atom, bromine atoms, iodine atom;
CF
3；
OCF
3Perhaps
Replaced once by following group alternatively or saturated, unsaturated or aromatic heterocycle system: the C of maximum 10 atoms for several times
1-C
6Alkyl, C
1-C
6Alkoxyl group, COOH, SO
3H, amino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Or OCF
3
And R wherein
2To R
4Thereby in can become key to form more than two to condense saturated, unsaturated or aromatics homogeneity member ring systems or heterocyclic system arbitrarily;
N and m are 0; And
Y is replaced once or phenyl for several times: C by following group
1-C
6Alkyl; Phenyl; C
1-C
6Alkoxyl group; Hydroxyl; Fluorine atom; The chlorine atom; Bromine atoms; CF
3OCF
3Amino; Alternatively by C
1-C
6Alkyl replaces CONH once or twice
2, these optional C wherein
1-C
6Thereby alkyl residue can become key to form five-ring or six-ring.
In the 3rd embodiment very preferably, the present invention relates to the compound of a kind of general formula (I), perhaps acceptable salt or ester or prodrug on its steric isomer, the pharmacology,
R wherein
1Or R
5Expression hydrogen atom or fluorine atom;
R
3Or R
4In one be C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base, wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, CO
2H, SO
3H, amino, C
1-C
6Alkylamino, two-C
1-C
6-alkylamino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Or OCF
3
R
3Or R
4In another residue that is selected from down group replace once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl;
And R
2Be:
Hydrogen atom;
C
1-C
6Alkyl, C
3-C
8-cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxycarbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8-cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base, wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, CO
2H, SO
3H, amino, C
1-C
6Alkylamino, two-C
1-C
6-alkylamino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Or OCF
3
CO
2H；
SO
3H；
Amino;
The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl;
Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or R
6Be selected from hydrogen atom and C
1-C
6The NR of alkyl
6, and wherein the methylene group in general formula (II) alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice;
CONH
2；
SO
2NH
2；
CONH
2Or SO
2NH
2, wherein amido functional group is selected from down more than the residue replacement once of group: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
6Alkyl, and at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring;
Thiol group;
Hydroxyl;
Nitro;
Cyano group;
Fluorosulfonyl;
Be selected from the halogen atom of fluorine atom, chlorine atom, bromine atoms, iodine atom;
CF
3；
OCF
3Perhaps
Replaced once by following group alternatively or saturated, unsaturated or aromatic heterocycle system: the C of maximum 10 atoms for several times
1-C
6Alkyl, C
1-C
6Alkoxyl group, COOH, SO
3H, amino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Or OCF
3
N and m are 0; And
Y is replaced once or phenyl for several times: C by following group
1-C
6Alkyl; Phenyl; C
1-C
6Alkoxyl group; Hydroxyl; Fluorine atom; The chlorine atom; Bromine atoms; CF
3OCF
3Amino; Or alternatively by C
1-C
6Alkyl replaces CONH once or twice
2, these optional C wherein
1-C
6Thereby alkyl residue can become key to form five-ring or six-ring.
In these three preferred embodiments, further preferred Y is replaced once or phenyl for several times: C by following group at all
1-C
6Alkyl; Phenyl; C
1-C
6Alkoxyl group; Hydroxyl; Fluorine atom; The chlorine atom; Bromine atoms; CF
3OCF
3Amino; Perhaps alternatively by C
1-C
6Alkyl replaces CONH once or twice
2, these optional C wherein
1-C
6Thereby alkyl residue can become key to form five-ring or six-ring.
In these three preferred embodiments, further preferred Y is by hydroxyl, fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice at all.
At all in these three preferred embodiments, the phenyl that further preferred Y is replaced in the 4-position by fluorine atom or chlorine atom, the phenyl that is replaced in 2-position and 4-position by fluorine atom, the phenyl that is replaced in 2-position and 4-position by the chlorine atom or the phenyl that is replaced in the 4-position by phenyl.
Relate to compound self of the present invention aspect all in, meet as follows:
In the specific embodiment of the present invention at compound itself, the following compound of general formula (I) is excluded:
5-dodecyloxy-3-(4-Trifluoromethoxyphen-l)-3H-(1,3,4)-oxadiazoles-2-ketone
5-n-Hexadecane oxygen base-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-octyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-n-Hexadecane oxygen base-3-(3-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-n-Hexadecane oxygen base-3-(4-(4-chlorophenoxy)-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-octyloxy-3-phenyl-3H-(1,3,4)-oxadiazoles-2-ketone
5-octyloxy-3-(3-fluorophenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-n-Hexadecane oxygen base-3-(3-fluorophenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-n-Hexadecane oxygen base-3-(3-benzyloxy phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-n-Hexadecane oxygen base-3-phenyl-3H-(1,3,4)-oxadiazoles-2-ketone
5-n-Hexadecane oxygen base-3-(4-nitre phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-n-Hexadecane oxygen base-3-(4-methoxyphenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-n-Hexadecane oxygen base-3-(4-benzyloxy phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-oxygen in last of the ten Heavenly stems base-3-(4-Trifluoromethoxyphen-l)-3H-(1,3,4)-oxadiazoles-2-ketone
5-undecane oxygen base-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-tetradecyloxyaniline-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-tridecane oxygen base-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(2-(2-hexyloxy-oxyethyl group)-oxyethyl group)-3-(4-Trifluoromethoxyphen-l)-3H-(1,3,4)-oxadiazoles-2-ketone
5-((Z)-9-octadecylene oxygen)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(dodecyloxy-oxyethyl group)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(2-(4-fluorophenyl)-oxyethyl group)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-((3ss-cholestane-3-yl)-oxygen base)-3-(4-Trifluoromethoxyphen-l)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(2-butoxy-oxyethyl group)-3-(4-Trifluoromethoxyphen-l)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(7-phenyl-heptan oxygen base)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(20 dioxy base-oxyethyl group)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(2-(1-naphthyloxy)-oxyethyl group)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(the hot phenoxy group of 4-)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(3-phenoxy group-phenoxy group)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(dodecyloxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(dodecyloxy)-3-(3, the 4-dichlorophenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(dodecyloxy)-3-(3, the 5-dichlorophenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(dodecyloxy)-3-(3-methoxyl group-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(dodecyloxy)-3-(4-methoxyl group-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
In the specific embodiment of the present invention at compound itself, when m=0 and n=0, Y does not represent C
1-C
4Alkyl.
In addition, as m=0 and n=0, and Y is during for substituted phenyl ring alternatively, R
2Or R
4Do not represent substituting group C (=A)-N (B)-SO
2-NR
6R
7, wherein A represents O or S, B represents hydrogen atom, cyano group, C
1-C
6Alkyl, C
1-C
6Alkoxyl group-alkyl, C
3-C
7Cycloalkyl, C
3-C
6Alkylene, C
3-C
6Alkynyl or substituted alternatively phenmethyl derivative, and R
6And R
7Independently represent hydrogen atom or organic residue separately or represent organic ring structure altogether; When Y represents not have the phenyl of replacement, R
1To R
5Independent separately hydrogen atom, fluorine atom, chlorine atom, bromine atoms, iodine atom or the alkyl residue do not represented; R
2Or R
4Do not represent the pyrazole-3-yl derivative; And by R
1To R
5The phenyl ring and the Y that replace are not expressed as follows combination:
| By R 1To R 5The phenyl ring that replaces | Y |
| The 2-chloro-phenyl- | The 4-chloro-phenyl- |
| 2, the 3-3,5-dimethylphenyl | The 4-chloro-phenyl- |
| The 2,4 dichloro benzene base | The 4-chloro-phenyl- |
| 2-chloro-3-tolyl | The 4-chloro-phenyl- |
| 2, the 5-difluorophenyl | The 4-tolyl |
| 2-methoxyl group-4-chloro-phenyl- | The 4-chloro-phenyl- |
| The 2-chloro-phenyl- | The 4-tolyl |
| 2, the 6-dichlorophenyl | The 4-chloro-phenyl- |
| 2-(trifluoromethyl sulfydryl) phenyl | Phenyl |
| 2,3, the 4-trimethylphenyl | The 4-chloro-phenyl- |
| 2, the 5-difluorophenyl | The 4-bromophenyl |
| 2, the 4-3,5-dimethylphenyl | The 4-chloro-phenyl- |
| The 4-chloro-phenyl- | The 4-chloro-phenyl- |
| The 3-chloro-phenyl- | The 4-chloro-phenyl- |
| The 4-bromophenyl | The 4-chloro-phenyl- |
| The 2-chloro-phenyl- | The 4-bromophenyl |
| 2, the 5-difluorophenyl | The 4-chloro-phenyl- |
| The 4-chloro-phenyl- | The 4-bromophenyl |
| 3, the 5-3,5-dimethylphenyl | The 4-chloro-phenyl- |
| The 4-Trifluoromethoxyphen-l | The hot phenyl of 4- |
| The 4-Trifluoromethoxyphen-l | The 3-Phenoxyphenyl |
| 2,3-dihydro-2,2-dimethyl-7-benzofuryl | Phenyl |
In addition, work as m=0, n=0, and Y is when being optional substituted phenyl ring, Y does not represent not have the phenyl of replacement, if R
1, R
2And R
5The expression hydrogen atom, R
4Expression hydrogen atom, trifluoromethoxy, trifluoro butoxy, 3,3,5,5-tetramethyl-ring hexyloxy, benzyloxy, phenoxy group, phenyl, 2-dimethylamino ethoxy or 3-tolyloxy methyl, and R
3Expression hydrogen atom, trifluoromethoxy, trifluoro butoxy, 3; 3; 5,5-tetramethyl-ring hexyloxy, phenoxy group, 4-chlorophenoxy, cyclohexyl, phenyl, morpholine alkylsulfonyl, 3,3; 5-trimethylcyclohexyl amino-sulfonyl, 2; 2,6,6-tetramethyl piperidine-4-base amino-sulfonyl, 2-(di-isopropyl aminoethyl) sulfamyl, 4-methylpiperazine-1-base alkylsulfonyl, 3; 3-lupetidine carbonyl or 3,5-dichlorophenoxy, 2-dimethylamino ethoxy or 3-tolyloxy methyl.
In addition, work as m=1, n=0 and R
3During for trifluoromethoxy, Y does not represent not have the phenyl of replacement.
In some of the present invention optional embodiments, be expressed as C as n=0 and m=0 and as Y at compound self
1-C
6Alkyl and C
3-C
9During cycloalkyl, R
2To R
5Do not represent 2-oxygen-tetramethyleneimine-1-base, 2,5-dimethyl pyrrole-1-base or be connected to the substituting group of phenyl ring, wherein C by non-aromatics nitrogen
1-C
6Alkyl and C
3-C
9More than these two groups of cycloalkyl are all replaced once by following group alternatively: phenyl, C
1-C
4Alkoxyl group, S-C
1-C
4Alkyl, N (C
1-C
4Alkyl)
2, and wherein phenyl alternatively by halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, nitro or CF
3More than replacing once.
In some of the present invention optional embodiments at compound self, n represent 0 and m represent under 0 the situation, when substituent R as residual term
1To R
5In at least one expression be selected from substituting group, particularly F, Cl, Br, the CH of halogen
3, OCH
3, NO
2, CN, and when the expression Y phenyl ring by F, Cl, Br, CH
3, OCH
3, NO
2Or CN is when replacing, R
1Or R
5Do not represent to be selected from the substituting group of halogen, particularly F, Cl, NO
2, CH
3, OCH
3Or CF
3Or CN.
In some of the present invention optional embodiments at compound itself, n represent 0 and m represent that Y does not represent by phenoxy group or C under 0 the situation
6-C
12The phenyl that alkyl replaces.
In of the present invention optional embodiment at compound itself, n represent 0 and m represent that Y does not represent not have the phenyl of replacement under 0 the situation.
In some other optional embodiments of the present invention, under the situation of m=0 and n=0, work as R at compound itself
1To R
5When expression hydrogen atom or halogen atom or methyl, Y does not represent phenyl or low alkyl group.
In some of the present invention optional embodiments, represent C as n=0 and m=0 and as Y at compound self
7-C
22Alkyl, by C
4-C
20Alkoxyl group, C
6-C
10Aryl, C
6-C
10Aryloxy or C
4-C
12Alkoxy-C
2-C
4The C that alkoxyl group replaces
2-C
4Alkyl and Y represent C
7-C
20Alkylene, 3 β-cholestane-3-base or expression are by phenoxy group or C
6-C
12During phenyl that alkyl replaces, R
2To R
5Do not represent hydrogen atom, halogen atom, nitro, C
1-C
4Alkyl, C
1-C
9Alkoxyl group, trifluoromethyl, trifluoromethoxy or C
6-C
10Aryl C
1-C
4Alkoxyl group, C
6-C
10-aryloxy, C
6-C
10Aryl, C
3-C
8Cycloalkyl or O-C
3-C
8Cycloalkyl.In the of the present invention optional embodiment at compound itself, all these compounds can be replaced once or several by following group: under the situation of aryl, by C
1-C
9Alkyl, C
1-C
9Alkoxyl group, halogen and trifluoromethyl replace; Under the situation of cycloalkyl, by C
1-C
4Alkyl or C
6-C
10Aryl replaces; Under the situation of alkyl, by hydroxyl, two-C
1-C
4Alkylamino and fluorine atom replace.
In some other optional embodiments of the present invention, under the situation of m=0 and n=0, work as R at compound itself
1Or R
5The expression halogen atom; Alkyl with 1 to 4 carbon atom; Alkoxyl group with 1 to 4 carbon atom; Alkylthio with 1 to 4 carbon atom; Have the haloalkyl of 1 to 4 carbon atom and 1 to 5 halogen atom, halogen atom can be identical or different; Have the halogenated alkoxy of 1 to 4 carbon atom and 1 to 5 halogen atom, halogen atom can be identical or different; Perhaps have the halogenated alkylthio of 1 to 4 carbon atom and 1 to 5 halogen atom, halogen atom can be identical or different; And as remaining R
1To R
5In represent hydrogen atom more than one; Alkyl with 1 to 4 carbon atom; Alkoxyl group with 1 to 4 carbon atom; Alkylthio with 1 to 4 carbon atom; Have the haloalkyl of 1 to 4 carbon atom and 1 to 5 halogen atom, halogen atom can be identical or different; Have the halogenated alkoxy of 1 to 4 carbon atom and 1 to 5 halogen atom, halogen atom can be identical or different; Perhaps have the halogenated alkylthio of 1 to 4 carbon atom and 1 to 5 halogen atom, halogen atom can be identical or different; Alkylenedioxy group with 1 or 2 carbon atom; Have the halo alkylenedioxy group of 1 or 2 carbon atom and 1 to 4 halogen atom, halogen atom can be identical or different; Halogen atom; Cyano group; Nitro; Amino; Single alkylamino and dialkylamino with 1 to 4 each alkyl of carbon atom; Alkyl carbonyl with 2 to 4 carbon atoms; Carbalkoxy with 2 to 4 carbon atoms; Alkyl sulphonyl with 1 to 4 carbon atom; Aryl sulfonyl with 6 or 10 aryl carbon atoms; When phenyl, naphthyl, phenoxy group, naphthyloxy, thiophenyl or naphthalene sulfenyl, Y does not represent the phenyl that replaced by following group: the alkyl with 1 to 4 carbon atom; Alkoxyl group with 1 to 4 carbon atom; Alkylthio with 1 to 4 carbon atom; Have the haloalkyl of 1 to 4 carbon atom and 1 to 5 halogen atom, halogen atom can be identical or different; Have the halogenated alkoxy of 1 to 4 carbon atom and 1 to 5 halogen atom, halogen atom can be identical or different; Perhaps have the halogenated alkylthio of 1 to 4 carbon atom and 1 to 5 halogen atom, halogen atom can be identical or different; Alkylenedioxy group (alkylenedioxy) with 1 or 2 carbon atom; Have the halo alkylenedioxy group of 1 or 2 carbon atom and 1 to 4 halogen atom, halogen atom can be identical or different; Cyano group; Nitro; Alkyl carbonyl with 2 to 4 carbon atoms; Carbalkoxy with 2 to 4 carbon atoms; Alkyl sulphonyl with 1 to 4 carbon atom; Aryl sulfonyl with 6 or 10 aryl carbon atoms; Phenyl, naphthyl, phenoxy group, naphthyloxy, thiophenyl or naphthalene sulfenyl.
In some of the present invention optional embodiments at compound self, n represent 0 and m represent under 0 the situation, when remaining substituent R
1To R
5In at least one expression be selected from substituting group, particularly F, Cl, Br, the CH of halogen atom
3, OCH
3, NO
2, CN, and when the expression Y phenyl ring by F, Cl, Br, CH
3, OCH
3, NO
2Or CN is when replacing, R
1Or R
5Do not represent to be selected from the substituting group of halogen atom, particularly F, Cl, NO
2, CH
3, OCH
3Or CF
3Or CN.
In some of the present invention optional embodiments, work as R at compound itself
1, R
2And R
5Expression is during hydrogen atom or work as R
1, R
4And R
5During the expression hydrogen atom, and when m=0 and n=0, Y does not represent to be replaced once or C for several times by phenyl alternatively
1-C
6Alkyl or C
3-C
9Cycloalkyl, wherein phenyl can be replaced once successively by following residue or several: halogen atom, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, nitro, CF
3Perhaps O-C
1-C
4Alkyl, S-C
1-C
4Alkyl, N (C
1-C
4Alkyl)
2
In of the present invention optional embodiment, work as R at compound itself
1Or R
5Expression hydrogen atom and when m=1 and n=0, Y are not represented to be replaced once by phenyl alternatively or the C of several
1-C
6Alkyl or C
3-C
9Cycloalkyl, wherein phenyl can be replaced once successively by following residue or several: halogen atom, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, nitro, CF
3Perhaps O-C
1-C
4Alkyl, S-C
1-C
4Alkyl, N (C
1-C
4Alkyl)
2
On the other hand, the invention still further relates to the use of the pharmacophoric group of following structure (III),
Be used to suppress the preparation of the compound of FAAH, and be used for the treatment of conditions that influenced energetically by the inhibition of fatty amide hydrolase (FAAH), refer to the treatment of disease especially for above-mentioned medical science.
On the other hand, the invention still further relates to the compound of the pharmacophoric group that comprises following structural formula (III),
Be used for the inhibition of FAAH, and be used for the treatment of conditions that influenced energetically by the inhibition of fatty amide hydrolase (FAAH), refer to the treatment of disease especially for above-mentioned medical science.
In the application's meaning, term " pharmacophoric group " will be understood that to the structure or the part of requisite molecular basis unit of FAAH enzyme interacting or molecule.The pharmacophoric group that can be regarded as general formula (III) can further be replaced.
On the other hand, the invention still further relates to a kind of preparation method as any described compound in claim 1 to 17 and 24 to 79, its formula of (IV) thus compound become oxadiazole ketone member ring systems by cyclisation shape,
Wherein
R
1To R
5Independent separately expression:
Hydrogen atom;
C
1-C
6Alkyl, C
3-C
8-cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxycarbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8-cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base, wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, CO
2H, SO
3H, amino, C
1-C
6Alkylamino, two C
1-C
6Alkylamino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Or OCF
3
CO
2H；
SO
3H；
Amino;
The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl;
Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or R
6Be selected from hydrogen atom and C
1-C
6The NR of alkyl
6, and wherein the methylene group in general formula (II) alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice;
CONH
2；
SO
2NH
2；
CONH
2Or SO
2NH
2, wherein the amido functional group residue that is selected from down group replaces once or twice: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
6Alkyl, and at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring;
Thiol group;
Hydroxyl;
Nitro;
Cyano group;
Fluorosulfonyl;
Be selected from the halogen atom of fluorine atom, chlorine atom, bromine atoms, iodine atom;
CF
3；
OCF
3Perhaps
Replaced once by following group alternatively or saturated, unsaturated or aromatic heterocycle system: the C of maximum 10 atoms for several times
1-C
6Alkyl, C
1-C
6Alkoxyl group, COOH, SO
3H, amino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Or OCF
3
And R wherein
1To R
5Thereby in can become key to form more than two to condense saturated, unsaturated or aromatics homogeneity member ring systems or heterocyclic system arbitrarily;
M represents 0,1,2,3,4,5 or 6;
Y represents::
A) hydrogen atom;
B) C
1-C
18-alkyl, single unsaturated or how unsaturated C
2-C
18Alkylene, C
3-C
8Cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxy carbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8Cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Saturated, the unsaturated or aromatic heterocycle system of aryl sulphur oxygen base or maximum 10 atoms, wherein each group is selectively replaced once or several by following group:
B1) C
1-C
6Alkyl, C
3-C
8Cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxy carbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6-alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8Cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base; Wherein each group is selectively replaced once or several: C by following group
1-C
6Alkyl; C
1-C
6Alkoxyl group; CONH
2SO
2NH
2CONH
2Or SO
2NH
2, wherein amido functional group is by C
1-C
6Alkyl replaces once or twice; SO
3H; CO
2H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
Wherein, thus several substituting groups b1) can become key to form to condense saturated, unsaturated or aromatics homogeneity member ring systems or heterocyclic system;
Perhaps
B2) hydroxyl; Thiol group; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3CO
2H; SO
3H; OCF
3CONH
2SO
2NH
2CONH
2Or SO
2NH
2, wherein amido functional group is selected from C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
6The residue of alkyl replaces once or twice, and wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Dibasic amino of perhaps following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or R
6Be selected from hydrogen atom and C
1-C
6The NR of alkyl
6, and wherein the methylene group in general formula (II) alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice;
Perhaps
B3) saturated, the unsaturated or aromatic heterocycle system of maximum 10 atoms, this heterocyclic system are replaced once or several: C by following group alternatively
1-C
6Alkyl; C
1-C
6Alkoxyl group; COOH; CONH
2SO
2NH
2CONH
2Or SO
2NH
2, wherein amido functional group is by C
1-C
6Alkyl replaces once or twice; SO
3H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
C) SO
3H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; CONH
2SO
2NH
2CONH
2Or SO
2NH
2, wherein amido functional group is selected from C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4The residue of alkyl replaces once or twice, and wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorosulfonyl; Be selected from the halogen atom of fluorine atom, chlorine atom, bromine atoms or iodine atom; CF
3Or OCF
3
The cyclisation step that is preferred for Xing Cheng oxadiazole ketone member ring systems is finished by carbonyl chloride, carbonyl dimidazoles or carbonic ether.
The carbonic ether that is fit to is C particularly
1-C
4Alkyl carbonate.
Carbonyl chloride and carbonyl dimidazoles are the most preferably reagent of finishing cyclisation.
Preferred in above-mentioned general formula (IV), R
1To R
5Independent separately expression hydrogen atom; Hydroxyl; C
1-C
6Alkyl, C
6-C
10Aryl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
6Alkoxyl group, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, alternatively by C
1-C
6Alkyl or C
6-C
10Aryl replaces CONH once or twice
2Or SO
2NH
2Amino, C
1-C
4Alkylamino, two C
1-C
4Alkylamino, hydroxyl, fluorine atom, chlorine atom, bromine atoms, CF
3Or OCF
3Amino; Be selected from C
1-C
6Alkyl, C
6-C
10The residue of aryl replaces once above amino; Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or R
6Be selected from hydrogen atom and C
1-C
4The NR of alkyl
6, and wherein the methylene group in general formula (II) alternatively by C
1-C
4Alkyl, fluorine atom or chlorine atom replace once or twice; CONH
2SO
2NH
2CONH
2Or SO
2NH
2, wherein amido functional group is selected from C alternatively
1-C
6Alkyl or C
6-C
10More than the residue of aryl replaces once; Fluorine atom; The chlorine atom; Bromine atoms; CF
3Or OCF
3
Further preferred R in above-mentioned general formula (IV)
1To R
5In expression fluorine atom or chlorine atom more than.R most preferably
1Or R
5In one the expression fluorine atom.
Further preferred in general formula (IV), R
1To R
5In represent hydroxyl more than one; C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
6Alkoxyl group, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, alternatively by C
1-C
6Alkyl or C
6-C
10Aryl replaces CONH once or twice
2Or SO
2NH
2Amino, C
1-C
4Alkylamino, two-C
1-C
4Alkylamino, hydroxyl, fluorine atom, chlorine atom, bromine atoms, CF
3Perhaps OCF
3
More preferably R
2, R
3Or R
4In one the expression hydroxyl; C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
6Alkoxyl group, each group is alternatively by C
1-C
4Alkyl, C
1-C
4Alkoxyl group, CONH
2Or SO
2NH
2Replace once or for several times, wherein CONH
2Or SO
2NH
2Alternatively by C
1-C
6Alkyl or C
6-C
10Aryl replaces once or twice; Amino, C
1-C
4Alkylamino, two-C
1-C
4Alkylamino, hydroxyl, fluorine atom, chlorine atom or bromine atoms.
Further preferred R in above-mentioned general formula (IV)
1To R
5In expression more than amino; Be selected from C
1-C
6Alkyl, C
6-C
10The residue of aryl replaces once above amino; Dibasic amino of perhaps following general formula (II)
Wherein o represents 0 or 1, and W represents O, CH
2, or R
6Be selected from hydrogen atom and C
1-C
4The NR of alkyl
6, and wherein the methylene group in general formula (II) alternatively by C
1-C
4Alkyl, fluorine atom or chlorine atom replace once or twice.
More preferably R
2, R
3Or R
4In an expression amino; Be selected from C
1-C
6Alkyl, C
6-C
10The residue of aryl replaces amino once or twice; Dibasic amino of perhaps following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or R
6Be selected from hydrogen atom and C
1-C
4The NR of alkyl
6, and wherein the methylene group in general formula (II) alternatively by C
1-C
4Alkyl, fluorine atom or chlorine atom replace once or twice.
Further preferred n represents 0 in above-mentioned general formula (IV); M represents 0,1,2,3,4,5 or 6; And Y represents C
3-C
6Cycloalkyl or C
6-C
10Aryl, wherein each group is replaced once or several by following group alternatively:
A) C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
4Alkoxyl group,
Wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl; C
1-C
6Alkoxyl group; Alternatively by C
1-C
6Alkyl replaces CONH once or twice
2Or SO
2NH
2SO
3H; CO
2H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
Perhaps
B) hydroxyl; Thiol group; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3OCF
3CO
2H; SO
3H; Alternatively by C
1-C
6Alkyl replaces CONH once or twice
2Or SO
2NH
2, wherein amino these optional C
1-C
6Thereby alkyl residue can become key to form five-ring or six-ring; Amino; By C
1-C
6Alkyl or phenyl replaces once or amino for several times; Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or R
6Be selected from hydrogen atom and C
1-C
4The NR of alkyl
6, and wherein the methylene group in general formula (II) alternatively by C
1-C
4Alkyl, fluorine atom or chlorine atom replace once or twice;
Perhaps
C) replaced once by following group alternatively or saturated, unsaturated or aromatic heterocycle system: the C of maximum 10 atoms for several times
1-C
6Alkyl; C
1-C
6Alkoxyl group; COOH; Alternatively by C
1-C
6Alkyl replaces CONH once or twice
2Or SO
2NH
2, these optional C wherein
1-C
6Alkyl residue can become key to form five-ring or six-ring; SO
3H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
More preferably n represents 0; M represents 0 or 1; And Y represents phenyl ring system, naphthalene nucleus system or pyridine ring system.
More preferably Y is replaced once or several: C by following group
1-C
4Alkyl; Phenyl; C
1-C
4Alkoxyl group; Hydroxyl; Fluorine atom; The chlorine atom; Bromine atoms; CF
3OCF
3Alternatively by C
1-C
4Alkyl replaces CONH once or twice
2Or SO
2NH
2, these optional C of ammonia wherein
1-C
4Thereby alkyl residue can become key to form five-ring or six-ring; Perhaps amino.
More preferably m represent 0 and Y represent to be replaced once or twice phenyl by hydroxyl, fluorine atom, chlorine atom or bromine atoms.
Most preferably m represents 0; The phenyl that Y represents to be replaced in the 4-position by fluorine atom, the phenyl that is replaced in the 4-position by the chlorine atom, the phenyl that is replaced in 2-position and 4-position by fluorine atom, the phenyl that is replaced in 2-position and 4-position by the chlorine atom or the phenyl that is replaced in the 4-position by phenyl.
Preferred especially m is 0 in above-mentioned general formula (IV); N is 0; The Y table is by fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice; And R
2To R
4In any one the expression R
7Be selected from hydrogen atom and C
1-C
4The OR of alkyl
7
In above-mentioned general formula (IV) also very preferably m be 0; N is 0; The phenyl that Y represents to be replaced in the 4-position by fluorine atom, the phenyl that is replaced in the 4-position by the chlorine atom, the phenyl that is replaced in 2-position and 4-position by fluorine atom or the phenyl that is replaced in 2-position and 4-position by the chlorine atom; And R
2To R
4In any one the expression R
7Be selected from hydrogen atom and C
1-C
4The OR of alkyl
7
Also preferred m is 0 in general formula (IV); N is 0; Y represents by fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice; And R
3, or R
3And R
4The expression hydroxyl.
In above-mentioned general formula (IV) also very preferably m be 0; N is 0; The phenyl that Y represents to be replaced in the 4-position by fluorine atom, the phenyl that is replaced in the 4-position by the chlorine atom, the phenyl that is replaced in 2-position and 4-position by fluorine atom, the phenyl that is replaced in 2-position and 4-position by the chlorine atom; And R
3, or R
3And R
4The expression hydroxyl.
Preferred especially m is 0 in above-mentioned general formula (IV); N is 0; Y represents by fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice; And R
2To R
4In any one the expression R
7Be selected from hydrogen atom and C
1-C
4The OR of alkyl
7And R
1The expression fluorine atom.
Preferred especially m is 0 in above-mentioned general formula (IV); N represents 0; And the phenyl that Y represents to be replaced in the 4-position by fluorine atom, the phenyl that is replaced in the 4-position by the chlorine atom, the phenyl that is replaced in 2-position and 4-position by fluorine atom or the phenyl that is replaced in 2-position and 4-position by the chlorine atom; R
2To R
4In any one the expression R
7Be selected from hydrogen atom and C
1-C
4The OR of alkyl
7And R
1The expression fluorine atom.
Preferred especially m is 0 in general formula (IV); N is 0; Y represents by fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice; And R
3, or R
3And R
4The expression hydroxyl; And R
1The expression fluorine atom.
Preferred especially m is 0 in general formula (IV); N is 0; The phenyl that Y represents to be replaced in the 4-position by fluorine atom, the phenyl that is replaced in the 4-position by the chlorine atom, the phenyl that is replaced in 2-position and 4-position by fluorine atom, the phenyl that is replaced in 2-position and 4-position by the chlorine atom; And R
3, or R
3And R
4The expression hydroxyl; And R
1The expression fluorine atom.
Next, the present invention describes by following representation example:
Embodiment 1:
5-phenoxy group-3-(4-pyridyl-3-yl) phenyl-1,3,4-oxadiazole-2 (3H)-ketone
A) under argon shield, Phenyl Chloroformate 99 (2.412g, 15.41mmol) dropwise join through ice-cooled stirring (6.87g, (3.13g is 14mmol) in the solution for (4-bromophenyl) hydrazine in mixture 87mmol) at NMP (20mL) and pyridine.Be reflected at 0 ℃ and stirred 30 minutes down, be heated to room temperature then and stirred 1 hour.Reaction mixture water alkene is released and is extracted with EtOAc.Organic phase is water and salt water washing respectively.Through MgSO
4Filter after the drying and evaporate, obtain 5.5g yellow oil phenyl-2-(4-bromophenyl) hydrazinecarboxylate, leave standstill crystallization then.
B) 20% carbonyl chloride solution in toluene (22.6mL, 43mmol) dropwise join above-mentioned intermediate product (5.5g) and pyridine (7.37g, 83mmol) in ice-cooled mixture.Reaction mixture stirred 30 minutes under cooling, at room temperature stirred then 1 hour.So argon gas bubbles in reaction mixture, then release at 0 ℃ of following water alkene.Be separated two, and organic phase is used 2N HCl solution, water and salt water washing respectively.Stirred organic phase 30 minutes with charcoal (charcoal), filter with short silicon-dioxide pad then.After solvent evaporation, thereby raw product provides 1.938g white solid 3-(4-bromophenyl)-5-phenoxy group-1,3,4-oxadiazole-2 (3H)-ketone by DCM/IPA mixture recrystallization.(productive rate in above-mentioned two steps is 32.5%).
C) pyridin-3-yl boric acid (0.31g, 2.52mmol) and salt of wormwood (0.647g 4.68mmol) joins 3-(4-the bromophenyl)-5-phenoxy group-1,3 in glycol dimethyl ether (20mL) and water (3mL) through stirring, (0.6g is 1.8mmol) in the solution for 4-oxadiazole-2 (3H)-ketone.Once obtaining solution, just add Pd (PPh
3)
4(0.104g 0.09mmol) and with mixture heated 3 hours down at 85 ℃, then it was cooled to room temperature.Under reduced pressure, remove and desolvate, and resistates is separated between 20%iPrOH-DCM and water.Thereby filtering mixt helps the separation of layer, and MgSO is used in organic phase water and salt water washing then then
4Drying, and on activated carbon, filter.After stirring 10 minutes, mixture filters with short silica dioxide gel/diatomite stopper, thereby and evaporated filtrate remove light green oil, leave standstill curing.By ethyl alcohol recrystallization, thereby provide shallow green powder 5-phenoxy group-3-(4-pyridyl-3-yl) phenyl-1,3,4-oxadiazole-2 (3H)-ketone (0.165g, 27.7%), its fusing point is 146-147 ℃.
Embodiment 2
5-(benzyloxy)-3-(3-bromophenyl)-1,3,4-oxadiazole-2 (3H)-ketone
A) under argon shield; 50% chloroformic acid benzyl esters (8.40g in toluene; 24.61mmol) dropwise join (3-bromophenyl) hydrazine hydrochloride in 40mLNMP through ice-cooled stirring (5.00g, 22.37mmol) and pyridine (8.85g is in solution 112mmol).Be reflected at 0 ℃ and stirred 30 minutes down, be heated to room temperature then and stirred 1 hour.Reaction mixture is poured in the frozen water; Filtering precipitate, wash with water and in EtOAc through MgSO
4Dry.The evaporation of solvent provides 6.77g yellow solid phenmethyl-2-(3-bromophenyl) hydrazinecarboxylate (productive rate: 94%).
B) (26.6mL 50.6mmol) joins dropwise that (8.57g is in mixture 110mmol) through ice-cooled phenmethyl-2-(3-bromophenyl) hydrazinecarboxylate (6.77g) and pyridine 20% carbonyl chloride solution in toluene.Reaction mixture stirred 30 minutes under cooling, at room temperature stirred then 1 hour.So argon gas bubbles in reaction mixture and releases at 0 ℃ of following water alkene.Be separated two, and organic phase is used 2N HCl solution, water and salt water washing respectively.Stirred organic phase 30 minutes with charcoal, filter with short silicon-dioxide pad then.After solvent evaporation, thereby raw product provides 4.76g beige solid 5-benzyloxy-3-(3-bromophenyl)-1,3 by ethyl alcohol recrystallization, and 4-oxadiazole-2 (3H)-ketone, its fusing point (m.p.) are 89-90 ℃ of (productive rate: 65%).
Embodiment 3
5-(2-bromopyridine base-3-base oxygen base)-3-(4-tolyl)-1,3,4-oxadiazole-2 (3H)-ketone
A) through 1 hour; the 2-bromopyridine base in DCM (50mL)-3-alcohol (3.48g; 20mmol) and pyridine (2.108g; 26.7mmol) mixture under nitrogen protection portion-wise addition to (52.6mL is 100mmol) in the solution of (20% solution in toluene) through the ice-cooled carbonyl chloride in DCM (25mL).Reaction is heated to room temperature and extra the stirring two hours, and nitrogen bubbled in reaction mixture 30 minutes then.Thereby evaporation is dry under vacuum condition, with the methylbenzene azeotropic of 100mL and dry under vacuum.Obtain grey hygroscopic powder 2-bromopyridine base-3-base chloro-formic ester (6.59g, 93%).
B) under nitrogen protection; 2-bromopyridine base-3-base chloro-formic ester (4.23g; 12.0mmol) portion-wise addition to (4-methoxyphenyl) hydrazine hydrochloride in the NMP of 15mL through ice-cooled stirring (1.746g, 10.0mmol) and pyridine (3.95g, solution 50mmol).Be reflected at 0 ℃ and stirred 30 minutes down, be heated to room temperature then and stirred 1 hour.Reaction mixture is poured in the frozen water; Mixture is with the EtOAc extraction and through MgSO
4Dry.Obtain yellow oil after solvent evaporation, this yellow oil process sherwood oil: EtOAc=2: the column chromatography of 1 mixture is purified, thereby 1.09g white solid 2 (4-methoxyphenyl) hydrazine carboxylic acid 2-bromopyridine base-3-base ester (productive rate: 32.2%) is provided.
C) 20% carbonyl chloride solution in toluene (4.0mL, 7.6mmol) dropwise join through ice-cooled 2-(4-methoxyphenyl) hydrazine carboxylic acid 2-bromopyridine base-3-base ester (1.071g, 3.17mmol) and pyridine (1.303g is in mixture 16.47mmol).Reaction mixture stirred 30 minutes under cooling, at room temperature stirred then 1.5 hours.So nitrogen bubbles in reaction mixture and releases at 0 ℃ of following water alkene.Be separated two, and water extracts with DCM.Mix organic phase through MgSO
4Dry also filtration.After evaporation, rough 5-(2-bromopyridine base-3-base oxygen base)-3-(4-methoxyphenyl)-1,3,4-oxadiazole-2 (3H)-ketone are via sherwood oil: EtOAc=2: the column chromatography of 1 mixture is purified.Productive rate: 75mg beige powder, 6.50%; Fusing point m.p.:116.5-117.5 ℃.
Embodiment 4
5-(4-bromo-2-methoxyl group phenoxy group)-3-phenyl-1,3,4-oxadiazole-2 (3H)-ketone
A) the N in toluene (9mL), accelerine (2.424g, 20.00mmol) dropwise join through the 4-of ice-cooled stirring bromo-2-methoxyphenol (4.06g, 20mmol) and carbonyl chloride (11.58mL is in solution 22.00mmol).Reaction was at room temperature stirred 3 hours.So nitrogen bubbled in reaction mixture 30 minutes; And quench with ice.Organic phase is used 1N HCl solution and water washing respectively.Through MgSO
4Toluene is removed by vacuum in dry back, and obtains oily chloroformic acid 4-bromo-2-methoxyl group phenyl ester.Productive rate 4.10g, 77%.
B) chloroformic acid 4-bromo-2-methoxyl group phenyl ester (3.19g, 12.0mmol) portion-wise addition to the phenylhydrazine in the NMP at 15mL of ice-cooled stirring (1.081g, 10.0mmol) and pyridine (3.95g is in solution 50mmol).Reaction was at room temperature stirred 1 hour.Then, be poured in the mixture of ice and 1N HCl; Filtering precipitate washes with water, and vacuum-drying.By smashing to pieces, obtain white powder 2-phenylhydrazine carboxylic acid 4-bromo-2-methoxyphenyl ester with sherwood oil.Productive rate: 3.38g.
C) 20% carbonyl chloride solution in toluene (11.98mL, 22.78mmol) dropwise join through ice-cooled 2-phenylhydrazine carboxylic acid 4-bromo-2-methoxyl group phenyl ester (3.20g, 9.49mmol) and pyridine (3.90g is in mixture 49.4mmol).Reaction mixture stirred 15 minutes under cooling, at room temperature stirred then 45 minutes.So nitrogen bubbles in reaction mixture and releases at 0 ℃ of following water alkene.Be separated two, and organic phase is used 1N HCl and water washing respectively.At process MgSO
4After the drying, pass through solvent removed in vacuo.Pass through sherwood oil: EtOAc=10: the column chromatography purification 5-of 1 mixture (4-bromo-2-methoxyl group phenoxy group)-3-phenyl-1,3,4-oxadiazole-2 (3H)-ketone.Productive rate: 1.198g white powder, 34.8%; Fusing point m.p.:77-78 ℃
Embodiment 5:
5-(4-chlorophenoxy)-3-(4-hydroxyphenyl)-1,3,4-oxadiazole-2 (3H)-ketone
A) at room temperature, (13.89mL, (6g, in solution 34.4mmol), and gained solution is cooled to 0 ℃ 172mmol) dropwise to join the hydrochloric acid 4-methoxy phenylhydrazine ester in N-N-methyl-2-2-pyrrolidone N-(48mL) through stirring pyridine.So dropwise add chloroformic acid 4-chlorobenzene ester (5.29mL, 37.8mmol).Gained solution stirred 30 minutes down at 0 ℃, was heated to room temperature then and stirred 1 hour.Reaction mixture poured in ice/water stirred 1 hour.Filtering precipitate, and wash with water, dry then.Thereby provide white solid 2-(4-methoxyphenyl) hydrazine carboxylic acid 4-chlorobenzene ester, (5.74g, 57%) by the Virahol recrystallization.
B) at room temperature, (8.25mL, (5.74g, in solution 19.61mmol), and gained solution is cooled to 0 ℃ 102mmol) to join the 2-in methylene dichloride (150mL) (4-p-methoxy-phenyl) hydrazine carboxylic acid 4-chlorobenzene ester through stirring pyridine.Dropwise be added in then 20% carbonyl chloride solution in the toluene (24.76mL, 47.1mmol).The gained mixture stirred 30 minutes down at 0 ℃, was heated to room temperature then and stirred 1 hour.Nitrogen bubbled in mixture 30 minutes, was cooled to 0 ℃ and water alkene then and released.Separate each phase, and organic phase is used 2N HCl, water and salt water washing respectively, dry then (MgSO
4) and through active carbon filtration.After stirring 15 minutes, filter suspension liquid through silicon-dioxide and diatomaceous short pad, evaporated filtrate, and the gained yellow solid is by twice in Virahol recrystallization, thereby provide white solid 5-(4-chlorophenoxy)-3-(4-methoxyphenyl)-1,3,4-oxadiazole-2 (3H)-ketone (3.14g, 50%).
C) under nitrogen protection; will be through the 5-in methylene dichloride (30mL) (4-the chlorophenoxy)-3-(4-methoxyphenyl)-1 of stirring; 3; 4-oxadiazole-2 (3H)-ketone (3.14g; 9.85mmol) solution is cooled to-80 ℃ (suspension liquid); and dropwise add boron tribromide (1.863mL, 19.70mmol).Gained lightpink solution stirred 5 minutes down at-80 ℃, was heated to room temperature then and stirred 2 hours.Reaction mixture is cooled to 0 ℃ and also adds ice/water carefully.Filter the gained throw out, wash with water and drying.By the Virahol recrystallization, thereby provide white solid 5-(4-chlorophenoxy)-3-(4-hydroxyphenyl)-1,3,4-oxadiazole-2 (3H)-ketone (2.2g, 73%), m.p.:163.5-164.5 ℃ of its fusing point.
Embodiment 6:
3-(3-aminophenyl)-5-(2,4 difluorobenzene oxygen base)-1,3,4-oxadiazole-2 (3H)-ketone
A) at room temperature, (2.13mL, (1g is in solution 5.27mmol) 26.4mmol) dropwise to join hydrochloric acid 3-nitrophenyl hydrazine ester in N-N-methyl-2-2-pyrrolidone N-(8mL) through stirring pyridine.The gained mixture is cooled to 0 ℃, and dropwise add chloroformic acid 2,4 difluorobenzene ester (1.22g, 6.33mmol).The gained mixture stirred 30 minutes down at 0 ℃, at room temperature stirred then 1 hour, so be poured into ice/waterborne.The mixture ethyl acetate extraction, and organic extract is used 2N HCl, water and salt water washing respectively, dry then (MgSO
4) filter and evaporation, thereby yellow oil 2-(3-nitre phenyl) hydrazine carboxylic acid's 2,4 difluorobenzene ester (1.6g, 100%) is provided.
B) at room temperature, (2.312mL, (1.7g, 5.50mmol) in the solution, and solution is cooled to 0 ℃ 28.6mmol) dropwise to join 2-(3-nitre phenyl) hydrazine carboxylic acid's 2,4 difluorobenzene ester in methylene dichloride (30mL) pyridine.Dropwise be added in then 20% carbonyl chloride solution in the toluene (6.94mL, 13.19mmol).Gained pink colour suspension liquid stirred 30 minutes down at 0 ℃, was heated to room temperature then and stirred 1 hour.Bubbled 30 minutes in the comfortable mixture of nitrogen, be cooled to 0 ℃ and water alkene then and release.Separate each phase, and organic phase 2N HCl, water and salt water washing, dry then (MgSO
4), filter and evaporation.By chromatography (petrol ether/ethyl acetate: 6/1 to 4/1) purification gained yellow oil.Converge the part and the evaporation of purification thing, leave standstill solidified pink colour oil thereby provide.By heptane and diethyl ether recrystallization, thereby provide white solid 5-(2,4 difluorobenzene oxygen base)-3-(3-nitre phenyl)-1,3,4-oxadiazole-2 (3H)-ketone (260g, 14%).
C) under nitrogen protection and at room temperature; join the 5-in methyl alcohol (20mL) (2,4 difluorobenzene oxygen base)-3-(3-nitre phenyl)-1,3 with 10% at the palladium on the carbon (25mg) through stirring; (251mg is in suspension liquid 0.749mmol) for 4-oxadiazole-2 (3H)-ketone.Hydrogen bubbled in reaction mixture 1 hour.Reaction mixture filters with diatomaceous short pad, and evaporated filtrate.The gained yellow oil is by column chromatography (petrol ether/ethyl acetate: 6/1 to 4/1) purify.Converge homogeneous part and evaporation, and the gained light yellow solid is by the Virahol recrystallization, thereby light yellow solid 3-(3-aminophenyl)-5-(2 is provided, 4-two fluorophenoxies)-1,3,4-oxadiazole-2 (3H)-ketone (128mg, 56%), its fusing point m.p. is 122-123 ℃.
Embodiment 7:
3-(4-(1H-pyrroles-1-yl) phenyl)-5-(2,4 difluorobenzene oxygen base)-1,3,4-oxadiazole-2 (3H)-ketone
Will be through the 3-in acetate (10mL) (4-the aminophenyl)-5-(2 of stirring, 4-two fluorophenoxies)-1,3,4-oxadiazole-2 (3H)-ketone (203mg, 0.665mmol) and 2, (0.108mL, solution 0.832mmol) heated 1 hour down at 95 ℃ the 5-dimethoxy-tetrahydrofuran, made it become dark red solution.Mixture is cooled to room temperature and evaporating solvent.Toluene is added to resistates, and revaporization.Resistates is smashed to pieces with ebullient ethanol, filters when it is heat, and uses washing with alcohol.After drying, obtain sorrel solid 3-(4-(1H-pyrroles-1-yl) phenyl)-5-(2,4 difluorobenzene oxygen base)-1,3,4-oxadiazole-2 (3H)-ketone (109mg, 46%), its fusing point m.p. is 181-182 ℃.
Embodiment 8
3-(3 '-methoxyl group phenylbenzene-4-yl)-5-phenoxy group-1,3,4-oxadiazole-2 (3H)-ketone
Under nitrogen protection; with tetrakis triphenylphosphine palladium (0) (91mg; 0.079mmol) join 3-(4-the bromophenyl)-5-phenoxy group-1 in glycol dimethyl ether (20mL) and water (10mL) through stirring; 3; 4-oxadiazole-2 (3H)-ketone (526mg; 1.58mmol), 3-methoxyphenyl boric acid (336mg, 2.21mmol) and salt of wormwood (567mg is in suspension liquid 4.10mmol).The gained mixture stirred 3 hours down at 85 ℃, then it was cooled to room temperature.Evaporating solvent, and resistates separated between methylene dichloride and water.Separate organic phase, and water and salt water washing, dry then (MgSO
4) and through active carbon filtration.After stirring 10 minutes, suspension liquid filters with the short pad of silica dioxide gel/diatomite, thereby and evaporated filtrate stay oil and leave standstill curing.By methylene dichloride/ethyl alcohol recrystallization, thereby provide white crystal 3-(3 '-methoxy phenylbenzene-4-yl)-5-phenoxy group-1,3,4-oxadiazole-2 (3H)-ketone (182mg, 32%), its fusing point is 102-103 ℃.
Embodiment 9:
5-(2,4 difluorobenzene oxygen base)-3-(4-hydroxyphenyl)-1,3,4-oxadiazole-2 (3H)-ketone
A) at room temperature, (13.89mL, (6g, in solution 34.4mmol), and gained solution is cooled to 0 ℃ 172mmol) dropwise to join the hydrochloric acid 4-methoxy phenylhydrazine ester in N-N-methyl-2-2-pyrrolidone N-(48mL) through stirring pyridine.Dropwise add then chloroformic acid 2,4 difluorobenzene ester (7.94g, 41.2mmol).Gained solution stirred 30 minutes down at 0 ℃, was heated to room temperature then and stirred 2 hours.Pour into reaction mixture in ice/water and stirred 1 hour.The mixture ethyl acetate extraction, and organic extract is used 2N HCl, water and salt water washing respectively, dry then (MgSO
4) filter and on gac, filter.After stirring 15 minutes, suspension liquid filters with silica dioxide gel and the short pad of diatomite.Evaporated filtrate, and the gained yellow oil is by the Virahol crystallization, thus white solid 2-(4-methoxyphenyl) hydrazine carboxylic acid's 2,4 difluorobenzene ester (3.82g, 38%) is provided.
B) at room temperature, (5.46mL, (3.82g, 12.98mmol) in the solution, and gained solution is cooled to 0 ℃ 67.5mmol) dropwise to join the 2-in methylene dichloride (120mL) (4-methoxyphenyl) hydrazine carboxylic acid's 2,4 difluorobenzene ester through stirring pyridine.Dropwise be added in then 20% carbonyl chloride solution in the toluene (16.39mL, 31.2mmol).The gained orange solution stirred 30 minutes down at 0 ℃, was heated to room temperature then and stirred 1 hour.Nitrogen bubbled in reaction mixture 30 minutes, was cooled to 0 ℃ and water alkene then and released.Be separated two, and organic phase is with 2N HCl, water and salt water washing, dry then (MgSO
4), and through active carbon filtration.After stirring 30 minutes, filter suspension liquid with silica dioxide gel and diatomaceous short pad.Evaporated filtrate, and the gained light yellow solid is by the Virahol crystallization, thus white solid 5-(2,4 difluorobenzene oxygen base)-3-(4-methoxyphenyl)-1,3,4-oxadiazole-2 (3H)-ketone (1.77g, 43%) are provided.
C) under nitrogen protection, will be through the 5-in methylene dichloride (5mL) (2,4 difluorobenzene oxygen the base)-3-(4-methoxyphenyl)-1 of stirring; 3, and 4-oxadiazole-2 (3H)-ketone (241mg, 0.753mmol) solution is cooled to-80 ℃; and dropwise add boron tribromide (0.142mL, 1.505mmol).Gained solution stirred 5 minutes down at-80 ℃, was heated to room temperature then and stirred 1 hour.Reaction mixture is cooled to 0 ℃ and quench by adding entry carefully then.Mixture is used in the 30% Virahol extraction in the methylene dichloride, and organic layer water and salt water washing, dry then (MgSO
4), filter and evaporation.The gained pale solid is by the Virahol crystallization, thereby white solid 5-(2,4 difluorobenzene oxygen base)-3-(4-hydroxyphenyl)-1,3,4-oxadiazole-2 (3H)-ketone (158mg, 69%), m.p.:174.5-176 ℃ of its fusing point are provided.
Embodiment 10:
5-(4-chlorophenoxy)-3-(2-fluoro-4-hydroxyphenyl)-1,3,4-oxadiazole-2 (3H)-ketone
A) at room temperature, a salt of wormwood (15.40g, 111mmol) join the 3-fluoro-4-nitrophenols in acetone (100mL) through stirring (5g, 31.8mmol) in the solution, then dropwise add methyl-sulfate (6.04mL, 63.7mmol).The yellow suspension liquid of gained refluxes and stirred 2 hours.Reaction mixture is cooled to room temperature, filtration then, and evaporated filtrate.The gained yellow liquid is by column chromatography (petrol ether/ethyl acetate: 9/1) purify.Converge and evaporate the homogeneous part, and the gained yellow oil is by diethyl ether/sherwood oil crystallization, thereby pale yellow crystals 2-fluoro-4-methoxyl group-1-oil of mirbane (2.81g, 52%) is provided.
B) under nitrogen protection and at room temperature, (2.76g is 16.13mmol) in the solution join the 2-fluoro-4-methoxyl group-1-oil of mirbane in methyl alcohol (50mL) through stirring at 10% palladium (276mg) on the carbon.Hydrogen bubbled in reaction mixture 1 hour, so suspension liquid filters with the short pad of diatomite.Evaporated filtrate, and the gained reddish oil is smashed to pieces with sherwood oil.Filtering also, thereby dry gained orange solids provides 2-fluoro-4-methyl oxyaniline (2.2g, 97%).
C) will be at the Sodium Nitrite (1.121g in the water (6.96mL), 16.25mmol) solution dropwise join the 2-fluoro-4-anisidine (2.13g in concentrated hydrochloric acid (13.97mL) under-10 ℃ through stirring, 15.09mmol) in the solution, keep below-10 ℃ temperature simultaneously.The gained mixture stirred 1 hour down at-10 ℃.So (2.90mL, solution 34.8mmol) keep below-5 ℃ temperature simultaneously dropwise to drip tin chloride (II) dihydrate in concentrated hydrochloric acid (11.61mL).Reaction mixture stirred 1 hour down at-5 ℃, was heated to room temperature then.Filter the beige suspension liquid, filter cake is soluble in water, and make gained solution be alkalescence by adding the 3N aqueous sodium hydroxide solution.Then, use the dichloromethane extraction mixture, and water and salt water washing mixed extracts; Dry then (MgSO
4), filter and evaporation.Gained is dark red-and brown solid is by by diethyl ether/sherwood oil crystallization, thus deep pink solid (2-fluoro-4-methoxyphenyl) hydrazine (1.24g, 53%) is provided.
D) at room temperature, (3.16mL, (1.22g, 7.81mmol) in the solution, and gained solution is cooled to 0 ℃ 39.1mmol) dropwise to join (2-fluoro-4-methoxyphenyl) hydrazine in N-N-methyl-2-2-pyrrolidone N-(10mL) through stirring pyridine.So, dropwise add chloroformic acid 4-chlorobenzene ester (1.640mL, 11.72mmol).Gained solution stirred 30 minutes down at 0 ℃, was heated to room temperature then and stirred 1 hour.Reaction mixture poured in ice/water stirred 1 hour.Filtering precipitate, and wash with water, dry then, thus beige solid 2-(2-fluoro-4-methoxyphenyl) is provided hydrazine carboxylic acid 4-chlorobenzene ester (2.5g, 100%).
E) at room temperature, (3.38mL, (2.5g, 8.05mmol) in the solution, and gained solution is cooled to 0 ℃ 41.8mmol) dropwise to join the 2-in methylene dichloride (40mL) (2-fluoro-4-methoxyphenyl) hydrazine carboxylic acid 4-chlorobenzene ester through stirring pyridine.Dropwise be added in then 20% carbonyl chloride solution in the toluene (10.16mL, 19.31mmol).The red suspension liquid of gained stirred 30 minutes down at 0 ℃, was heated to room temperature then and stirred 1 hour.Being cooled to before 0 ℃ and water alkene releases, nitrogen was bubbled in reaction mixture 30 minutes.Separate each phase, and organic phase 2N HCl, water and salt water washing.Dry (MgSO
4) organic layer, and with it through active carbon filtration, and stirred 30 minutes.Suspension liquid filters with silica dioxide gel and the short pad of diatomite.Evaporated filtrate, and the gained yellow solid is by Virahol crystallization twice, thus light beige solid 5-(4-fluorophenoxy)-3-(2-fluoro-4-methoxyphenyl)-1,3,4-oxadiazole-2 (3H)-ketone (1.2g, 44%) are provided.
F) under nitrogen protection, will be through the 5-in methylene dichloride (40mL) (4-the chlorophenoxy)-3-(2-fluoro-4-methoxyphenyl)-1,3 of stirring; 4-oxadiazole-2 (3H)-ketone (1.2g; 3.56mmol) solution is cooled to-80 ℃, and dropwise add boron tribromide (0.674mL, 7.13mmol).Gained solution stirred 5 minutes down at-80 ℃, was heated to room temperature then and stirred 5 hours.Reaction mixture is cooled to 0 ℃ and quench by adding entry carefully then.Be added in the mixture of 30% Virahol in the methylene dichloride, and separate each phase.Water extracts with methylene dichloride, and mixed extracts water and salt water washing.Dry (MgSO
4), filter and the evaporation organic layer.Be dissolved in the gained green solid in the hot Virahol and the filtration insoluble material.Evaporated filtrate, and resistates is by methylene dichloride/sherwood oil crystallization, thus the deep pink solid is provided.This solid is dissolved in the methylene dichloride, and adds activated carbon.After stirring 15 minutes, suspension liquid filters with silica dioxide gel and the short pad of diatomite.Thereby evaporated filtrate reduces liquor capacity, and adds PE.Gained solid filtering, also dry with petroleum ether, thus pale solid 5-(4-chlorophenoxy)-3-(2-fluoro-4-hydroxyphenyl)-1,3,4-oxadiazole-2 (3H)-ketone (379mg, 33%), m.p:180-182 ℃ of its fusing point are provided.
Embodiment 11:
Hydrochloric acid 3-(4-amino-3-methoxyphenyl)-5-(2,4 difluorobenzene oxygen base)-1,3,4-oxadiazole-2 (3H)-ketone salt
A) at room temperature, methyl-iodide (11.94mL, 191mmol) dropwise join the 5-fluoro-2-nitrophenols in acetone (318mL) through stirring (10g, 63.7mmol) and salt of wormwood (17.59g is in suspension liquid 127mmol).Reaction mixture at room temperature stirred 4 days, underpressure distillation acetone subsequently, and resistates separated between water and ethyl acetate.Water layer neutralizes with concentrated hydrochloric acid.Separate organic layer, and water and salt water washing, drying (MgSO
4), filter and evaporation, thereby pale solid is provided, described solid is by Virahol/methylene dichloride recrystallization, thereby pale solid 4-fluoro-2-methoxyl group-1-oil of mirbane (9.6g, 88%) is provided.
B) at room temperature, (5.96mL, (7g is 40.9mmol) in the solution 123mmol) dropwise to add the 4-fluoro-2-methoxyl group-1-oil of mirbane in ethanol (84mL) through stirring hydrazine hydrate.Solution becomes yellow, becomes bright orange (brightorange) then.Reaction mixture stirred 2 hours down at 100 ℃, will be cooled to 0 ℃ then.By the filtering separation yellow mercury oxide, and use cold washing with alcohol.Mother liquid evaporation to half volume, is cooled to 0 ℃ then, thereby forms more throw outs.The collecting precipitation thing, and use cold washing with alcohol.Mixed sediment, thus (3-methoxyl group-4-nitre phenyl) hydrazine (4.18g, 56%) is provided.
C) under 0 ℃, chloroformic acid 2,4 difluorobenzene ester (4.63g, 24.02mmol) dropwise join (3-methoxyl group-4-nitre phenyl) hydrazine in NMP (40mL) through stirring (4g, 21.84mmol) and pyridine (8.83mL is in solution 109mmol).Reaction mixture stirred 15 minutes down at 0 ℃, at room temperature stirred then 45 minutes.Then solution is poured in the mixture of ice/1N HCl solution.Product extracts with ethyl acetate, extracts with methylene dichloride/Virahol then.Mix organic layer salt water washing, drying (MgSO
4), filter and evaporation, thereby orange oil is provided.Through column chromatography (silicon-dioxide; Petrol ether/ethyl acetate=2: 1, then=1: 1), thereby orange oil/solid 2-(3-methoxyl group-4-nitre phenyl) is provided hydrazine carboxylic acid's 2,4 difluorobenzene ester (5.84g, 79%).
D) under 0 ℃, 20% carbonyl chloride solution (21.74mL in toluene, 41.3mmol) dropwise join the 2-in methylene dichloride (115mL) (3-methoxyl group-4-nitre phenyl) hydrazine carboxylic acid 2 through stirring, 4-difluoro phenyl ester (5.84g, 17.21mmol) and pyridine (7.24mL is in solution 90mmol).Gained solution becomes garnet and stirred 15 minutes down at 0 ℃, at room temperature stirs then 45 minutes.Air bubbled in solution 10 minutes, added entry then under 0 ℃.Separate organic layer, and, follow water and salt water washing, dry then (MgSO with 1N HCl washing
4), filter and evaporation, thereby garnet oil is provided.Through column chromatography (sherwood oil/methylene dichloride=2: 1, then=1: 1), yellow solid is provided, described yellow solid is by Virahol/methylene dichloride recrystallization, thereby provide 5-(2,4 difluorobenzene oxygen base)-3-(3-methoxyl group-4-nitre phenyl)-1,3,4-oxadiazole-2 (3H)-ketone (722mg, 11.5%).
E) under nitrogen protection and at room temperature; join the 5-in methyl alcohol (15mL) (2,4 difluorobenzene oxygen base)-3-(3-methoxyl group-4-nitre phenyl)-1,3 with 10% at the palladium on the carbon (18.5mg) through stirring; (200mg is in solution 0.548mmol) for 4-oxadiazole-2 (3H)-ketone.Under atmosphere of hydrogen, reaction mixture at room temperature stirred 3 hours.In addition, add 10% palladium (9mg) on Pd/carbon catalyst, and under atmosphere of hydrogen and at room temperature, reaction mixture stirred further 2 hours.Solution filters with the short pad of diatomite, and diatomite washs with ethyl acetate.Evaporated filtrate, thus brown solid is provided, and described brown solid is by the Virahol recrystallization, thereby beige solid (124mg) is provided.Before the 2N HCl in dropwise being added in ether (2mL), described solid is put into ethyl acetate (5mL), and be cooled to 0 ℃.Filter formed throw out, and also dry with the ethyl acetate washing, thus beige solid hydrochloric acid 3-(4-amino-3-methoxyphenyl)-5-(2 is provided, 4-two fluorophenoxies)-1,3,4-oxadiazole-2 (3H)-ketone salt (120mg, 90%), its fusing point is m.p.:186-188 ℃.
Embodiment 12:
3-(4-amino-3-(2-methoxy ethoxy) phenyl)-5-(2,4 difluorobenzene oxygen base)-1,3,4-oxadiazole-2 (3H)-ketone
A) at room temperature, sodium iodide (0.191g, 1.273mmol) join the 5-fluoro-2-nitrophenols in DMF (102mL) through stirring (4g, 25.5mmol), salt of wormwood (10.56g, 76mmol) (5.10mL is in suspension liquid 56.0mmol) with 1-chloro-2-methoxy ethane.Reaction mixture is 80 ℃ of following stirred overnight.In addition, (6.38mL, 70.0mmol), and reaction mixture stirred 4 hours at 80 ℃ to add 1-chloro-2-methoxy ethane.Add entry and ethyl acetate, and separate organic layer.Water layer neutralizes with 1N HCl, and uses ethyl acetate extraction.Mix organic layer salt water washing, drying (MgSO
4), filter and evaporation, thereby yellow oil is provided.Through column chromatography (petrol ether/ethyl acetate=6: 1), thereby provide limpid oily 4-fluoro-2-(2-methoxy ethoxy)-1-oil of mirbane (2.26g, 39%)
B) at room temperature, (1.531mL, (2.26g is 10.50mmol) in the solution 31.5mmol) to join 4-fluoro-2-(2-the methoxy ethoxy)-1-oil of mirbane in ethanol (21.43mL) through stirring hydrazine hydrate.Reaction mixture stirred 3 hours down at 85 ℃.Solution is cooled to 0 ℃ then, thereby causes sedimentary formation.By the filtering separation solid, and use cold washing with alcohol.With mother liquid evaporation half, be cooled to 0 ℃ then to original volume.By the throw out of filtering separation formation, and use cold washing with alcohol.The mixed sediment of (3-(2-methoxy ethoxy)-4-nitre phenyl) hydrazine (1.75g, 73%) just is used in the next step without further purification.
C) under 0 ℃, (1.631g 8.47mmol) dropwise joins (3-(2-methoxy ethoxy)-4-nitre phenyl) hydrazine (1.75g in NMP (14mL) through stirring chloroformic acid 2,4 difluorobenzene ester, 7.70mmol) and pyridine (3.11mL is in solution 38.5mmol).Reaction mixture stirred 20 minutes down at 0 ℃, at room temperature stirred then 1 hour.Then solution is poured on the mixture of 1N HCl/ ice.After stirring 30 minutes, add ethyl acetate and separate organic layer, then with 1N HCl, water and salt water washing.Dry then (MgSO
4) and evaporate organic layer, thereby stay orange oil.The process column chromatography (petrol ether/ethyl acetate=2: 1, then=1: 1, then=1: 2), thereby orange oil is provided.Gained oil dissolves in ethyl acetate, and washes with water.Organic layer (the MgSO that is dried
4), filter and evaporation, thereby orange foam 2-(3-(2-methoxy ethoxy)-4-nitre phenyl) is provided hydrazine carboxylic acid's 2,4 difluorobenzene ester (1.54g, 52%).
D) under 0 ℃, toluene solution (the 5.07mL of carbonyl chloride 20%, 9.64mmol) dropwise join the 2-in methylene dichloride (27mL) (3-(2-methoxy ethoxy)-4-nitre phenyl) hydrazine carboxylic acid 2 through stirring, 4-difluoro phenyl ester (1.54g, 4.02mmol) and pyridine (1.690mL is in solution 20.89mmol).The gained dark red solution stirred 15 minutes down at 0 ℃, at room temperature stirred then 1 hour.Under 0 ℃, add entry, and separate organic layer, then with 1N HCl washing, then water and salt water washing.Dry (MgSO
4), filter and the evaporation organic layer, thereby stay red oil.Through column chromatography (petrol ether/ethyl acetate=6: 1, then=4: 1), thereby provide brown solid, described brown solid is by Virahol/methylene dichloride recrystallization, thereby provide beige solid 5-(2,4 difluorobenzene oxygen base)-3-(3-(2-methoxy ethoxy)-4-nitre phenyl)-1,3,4-oxadiazole-2 (3H)-ketone (539mg, 33%).
E) at room temperature, join the 5-in methyl alcohol (18mL) (2,4 difluorobenzene oxygen base)-3-(3-(2-methoxy ethoxy)-4-nitre phenyl)-1,3 with 10% at the palladium on the carbon (35mg) through stirring, (267mg is in solution 0.652mmol) for 4-oxadiazole-2 (3H)-ketone.Under atmosphere of hydrogen, reaction mixture at room temperature stirred 1 hour.Mixture filters with the short pad of diatomite, and diatomite washs with ethyl acetate.Thereby evaporated filtrate provides orange oil.The process column chromatography (petrol ether/ethyl acetate=4: 1, then=2: 1), thereby the orange oil of crystalline at room temperature is provided.Gained oil is by Virahol/methylene dichloride recrystallization, thereby beige solid 3-(4-amino-3-(2-methoxy ethoxy) phenyl)-5-(2,4 difluorobenzene oxygen base)-1 is provided, 3,4-oxadiazole-2 (3H)-ketone (118mg, 45%), m.p.:74-75 ℃ of its fusing point.
Embodiment 13:
3-(3-amino-4-methoxyphenyl)-5-(2,4 difluorobenzene oxygen base)-1,3,4-oxadiazole-2 (3H)-ketone
A) with 5-(2,4 difluorobenzene oxygen base)-3-(4-methoxyphenyl)-1,3,4-oxadiazole-2 (3H)-ketone (500mg, 1.561mmol) join be cooled to 0 ℃ in the nitrosonitric acid (5mL) that brute force stirs.The yellow suspension liquid of gained stirred 5 minutes down at 0 ℃, was heated to room temperature then and stirred 30 minutes.Reaction mixture is poured in ice/water, and filter, wash with water, dry gained throw out, thereby light yellow solid 5-(2,4 difluorobenzene oxygen base)-3-(4-methoxyl group-3-nitre phenyl)-1,3,4-oxadiazole-2 (3H)-ketone (533mg, 93%) are provided.
B) at room temperature, join the 5-in methyl alcohol (20mL) (2,4 difluorobenzene oxygen base)-3-(4-methoxyl group-3-nitre phenyl)-1,3 through stirring with 10% at the palladium on the carbon (52mg), (520mg is 1.424mmol) in the suspension liquid for 4-oxadiazole-2 (3H)-ketone.Hydrogen bubbled in mixture 2 hours, so remove by filter catalyzer via the short pad of diatomite.Evaporated filtrate, and the filbert solid of gained is dissolved in the methylene dichloride.Add gac, and before filtering, stirred suspension liquid 15 minutes with silica dioxide gel and the short pad of diatomite.Evaporated filtrate, and the gained yellow solid is by the Virahol recrystallization, thus orange solids 3-(3-amino-4-methoxyphenyl)-5-(2,4 difluorobenzene oxygen base)-1,3,4-oxadiazole-2 (3H)-ketone (280mg, 59%), m.p.:101 ℃ of its fusing point are provided.
Embodiment 14:
5-(2,4 difluorobenzene oxygen base)-3-(4-methoxyl group-3-(1H-pyrroles-1-yl) phenyl)-1,3,4-oxadiazole-2 (3H)-ketone
Will be through the 3-in acetate (5mL) (3-amino-4-the methoxyphenyl)-5-(2 of stirring, 4-two fluorophenoxies)-1,3, (162 milligrams of 4-oxadiazoles-2 (3H)-ketone, 0.483mmol) and 2, (0.077mL, solution 0.598mmol) heated 1 hour down at 90 ℃ the 5-dimethoxy-tetrahydrofuran, was cooled to room temperature then.Reduced pressure is gone down and is desolventized, and toluene is added in the resistates, and revaporization.Resistates is added in the methylene dichloride, and before filtering with the short pad of silica/silicon algae soil, stirs 30 minutes with gac.Thereby evaporated filtrate stays at the oil that adds the ether after fixing.By the Virahol recrystallization, thereby provide light orange solid 5-(2,4 difluorobenzene oxygen base)-3-(4-methoxyl group-3-(1H-pyrroles-1-yl) phenyl)-1,3,4-oxadiazole-2 (3H)-ketone (137mg, 73%), m.p.:136 ℃ of its fusing point.
Table 1 shows the additional compounds according to the similarity method preparation.For solid material, fusing point is provided.For oil, the NMR data are provided in table 2.
Table 1
The NMR data that are used for the oil that obtains are as shown in table 2 below.The NMR spectrum is with being recorded on Bruker Avance DPX 400 spectrometers as interior target solvent.Deliver data in the following order: about chemical shift (ppm), proton number, multiplicity (br: broad peak; D: bimodal; M: multimodal; S: unimodal; Three peaks) and coupling constant (Hz) t:.
Table 2
The FAAH external activity is determined according to following method:
The freezing brain that use is taken out from the Wei Sita mouse (no cerebellum), and each brain is with the MgCl of Potter Elvejhem (impacting 8 times with 500rpm) at 15mL, 1mM
2, 20nM HEPES (pH7.0) in homogenize.Under 4 ℃ (Beckman, 70Ti rotor), homogenate under 36000g centrifugal 20 minutes.Granule resuspending in the 15mL same buffer, and under the same conditions by centrifugal.Resuspending granule in the 15mL same buffer, and under 4 ℃, 36000g after centrifugal 20 minutes, with it 37 ℃ of hatchings 15 minutes down.Then, each is at 15mL, 3mM MgCl
2, resuspending among 1mMEDTA, the 50mM Tris (pH 7.4), and determine protein with the BioRad protein analysis (than Aura) of use BSA (50-250 μ g/mL) typical curve.With this film suspension (membrane suspensions) five equilibrium and be stored under-80 ℃.
FAAH is active to use AEA (to be used in the thanomin part of molecule
3H comes mark) as substrate and measure to form
3H-thanomin form is determined.In 1mM EDTA, 10mM Tris (pH 7.6) and 10 μ M or 100mM compound, reaction mixture (200 μ l cumulative volume) comprises: the BSA of the AEA of 2 μ M (3H-AEA of the AEA+5nM of 2 μ M), 0.1% FAF, 5 μ g protein.Compound stock solution (10mM) to be tested prepares in 100%DMSO, and DMSO concentration is 0.1% in test.15 minutes preincubation after dates under 37 ℃, the adding by substrate solution (the radiolabeled EAE+BSA of cold EAE+) begins reaction.Before the adding termination reaction by 400 μ l gac suspension liquids (stirring the 8g charcoal in the HCI of 32mL, 0.5M continuously), reaction was carried out 10 minutes.After 30 minute incubation period of at room temperature stirring, charcoal precipitates by centrifugal in Eppendorf centrifuge (under 13000rpm 10 minutes).Before in it being assigned to 24 porose disc, 200 μ l supernatant liquids are added in the 800 μ l Optiphase Supermix flicker cocktail.Count per minute (cpm) is determined in Microbeta TriLux scintillometer (10 minutes counting or up to σ=2).
In each test, there are blank group (blank) (no protein, be usually less than 200cpm) and control group (control) (not having compound).Result as the percentage ratio that deducts blank group control group is afterwards reported in table 3.
Table 3
Determine to be suppressed active according to following method by FAAH in the body in the animal tissues of administration compound of the present invention.
Treatment of animals
The animal that is used for this experiment is the male NMRI mouse (weight is 27-44g) from Interfauna Ib é rica (Spain).Under the controlled environment condition (12 hours bright/dark cycles, and room temperature is 22 ± 1 ℃), keep five mouse of every cage.Allow to search for food arbitrarily food and drinking water, and described experiment the time carries out all in the daytime.
Animal via by oral route by the BIA compound (8mL/kg of administration 30mg/kg; Be suspended in 0.5% carboxymethyl cellulose (CMC) or be dissolved in compound in the water), (Perfectum U.S.A) uses 8ml//kg, 0.5%CMC (control group) perhaps to use animal-feed stainless steel curved needle.Before animal dead 15 minutes use Sodital 60mg/kg through intraperitoneal administration with Animal Anesthesia.Take out the liver fragment, left lung and not with the brain of cerebellum, and put it into and comprise the film damping fluid (MgCl of 3mM
2, 1mM the Tris HCl of EDTA, 50mM, pH value 7.4) Plastic Bottle in.Before analyzing, tissue is stored under-30 ℃.
Except surpassing 18 hours time cycle, before compound administration, animal is taken away food by overnight fasted in that morning of administration, and is giving drug compound on the same day afternoon.Then, only give animal water.
All animal programs are carried out under the situation that strictly observes " pact is protected in the vertebrate Europe that is used to protect experiment usefulness and other scientific research purposes to use " (86/609 CEE) and " Portugal's rules " (" Portuguese legislation ") (Decreto-Lei 129/92, Portarias 1005/92e 1131/97).The quantity of used animal is that the minimum of abideing by regulation in force and science integrity may be counted.
Reagent and solution
Arachidonic thanomin [thanomin-1-3H-] (40-60Ci/mmol) obtains from American Radiochemicals company.Every other reagent obtains from Sigma-Aldrich company.Optiphase Supermix obtains from Perkin Elmer company, and gac obtains from Sigma-Aldrich company.
Tissue preparation
Be organized on ice and thawed, and at the film damping fluid (MgCl of 3mM of 10 volumes
2, 1mM the Tris HCl of EDTA, 50mM, pH 7.4) in, homogenize with Potter-Elvejhem (brain-under 500rpm, impact 8 times) or with one among the Heidolph Diax (liver-impact 2 times in the 5th position continues 20 seconds, whenever impacts and once pauses 30 seconds).
With BioRad protein analysis method (BioRad company), use BSA (50-250 μ g/ml) typical curve to measure the total protein in the tissue.
Enzyme is analyzed (Enzymatic assay)
In EDTA, the 10mM Tris (pH7.6) of 1mM, reaction mixture (cumulative volumes of 200 μ l) comprises: the AEA of 2 μ M be (AEA+5nM's of 2 μ M
3H-AEA), the BSA of 0.1% FAF, 15 μ g (brain) protein, 5 μ g (liver) protein or 50 μ g (lung) protein.Carry out 15 minutes preincubation after date under 37 ℃, reaction is by adding substrate solution (the radiolabeled AEA+BSA of cold AEA+) beginning.By add 400 μ l gac suspension liquids (the HCl of 32mL, 0.5M in stir the 8g charcoal continuously) before the termination reaction, 10 minutes (to brain and lung) or 7 minutes (to liver) are carried out in reaction.After at room temperature stirring the incubation period carry out 30 minutes, charcoal precipitates by centrifugal in Eppendorf centrifuge (under 13000rpm 10 minutes).Before in it being assigned to 24 porose disc, 200 μ l supernatant liquids are added in the Optiphase Supermix flicker cocktail of 800 μ l.Count per minute (cpm) is measured in Microbeta TriLux scintillometer.
In each test, the blank group of preparation (no protein).
The percentage composition of remaining enzymic activity calculates by deduct blank group with control group (no compound).
Institute's record in result such as the table 4.
Table 4
Apparent from as above test, compound of the present invention has the highly inhibited of beyond thought FAAH, all these compound characteristics are: 5-O-replaces 3-N-phenyl-1,3,4-oxadiazole ketone structural unit, these compounds are expected to become the treatment that is used for the medical conditions relevant with FAAH or the material standed for of prophylactic agent.In addition, described beyond thought FAAH is highly inhibited not only external but also be tangible in vivo.
In addition, with central nervous system (CNS) in specific activity than the time, in the body data more also show to have 5-O-and replace 3-N-phenyl-1,3, the FAAH of the compound of 4-oxadiazole ketone structural unit suppresses activity and has optionally feature of periphery.
Above-mentioned data for large-scale high-activity compound show, the 5-O of following structural formula (III) replaces 3-N-phenyl-1,3,4-oxadiazole ketone tectonic element is to be used for the efficient pharmacophoric group that FAAH suppresses, thereby the substituent selection that allows to be present on this pharmacophoric group has highly variable.
Be to be understood that the present invention can make amendment within the scope of the appended claims.
Claims (90)
1. compound that is used to suppress the general formula (I) of fatty amide hydrolase (FAAH), perhaps acceptable salt or ester or its prodrug on its steric isomer, its pharmacology,
Wherein
R
1To R
5Independent separately expression:
Hydrogen;
C
1-C
6Alkyl, C
3-C
8Cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxy carbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8Cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base, wherein each group is selectively replaced once or several by following group
C
1-C
6Alkyl; C
1-C
6Alkoxyl group; C
6-C
10Aryloxy; CO
2H; SO
3H; CONH
2SO
2NH
2The residue that amido functional group is selected from down group replaces once above CONH
2Or SO
2NH
2: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4Alkyl, and at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
CO
2H；
SO
3H；
Amino;
The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl;
Dibasic amino of general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen atom and C
1-C
6Alkyl, wherein the methylene group in general formula (II) is selectively by C
1-C
6-alkyl, fluorine atom or chlorine atom replace once or twice;
CONH
2；
SO
2NH
2；
Amido functional group is selected from down the residue replacement CONH once or twice of group
2Or SO
2NH
2: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
6Alkyl is wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring;
Thiol group;
Hydroxyl;
Nitro;
Cyano group;
Fluorosulfonyl;
Be selected from the halogen atom of fluorine atom, chlorine atom, bromine atoms or iodine atom;
CF
3；
OCF
3Perhaps
Saturated, the unsaturated or aromatic heterocycle system of maximum 10 atoms, this heterocyclic system are replaced once or several by following group alternatively:
C
1-C
6-alkyl; C
1-C
6-alkoxyl group; COOH; SO
3H; CONH
2SO
2NH
2The residue that amido functional group is selected from down group replaces once above CONH
2Or SO
2NH
2: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4Alkyl is wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
R wherein
1To R
5Thereby can become key to form more than two to condense saturated, unsaturated or aromatics homogeneity member ring systems or heterocyclic system arbitrarily;
N represents 0 or 1; M represents 0,1,2,3,4,5 or 6;
X represents O or S;
Y represents:
A) hydrogen atom;
B) C
1-C
18Alkyl, single unsaturated or how unsaturated C
2-C
18Alkylene, C
3-C
8Cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxy carbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8Cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Saturated, the unsaturated or aromatic heterocycle system of aryl sulphur oxygen base or maximum 10 atoms, wherein each group is selectively replaced once or several by following group:
B1) C
1-C
6Alkyl, C
3-C
8Cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxy carbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8Cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base; Wherein each group is selectively replaced once or several: C by following group
1-C
6Alkyl; C
1-C
6Alkoxyl group; CONH
2SO
2NH
2Amido functional group is by C
1-C
6Alkyl replaces CONH once or twice
2Or SO
2NH
2SO
3H; CO
2H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
Wherein, several substituting groups in b1) can become key to form to condense saturated, unsaturated or aromatics homogeneity member ring systems or heterocyclic system;
Perhaps
B2) hydroxyl; Thiol group; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3CO
2H; SO
3H; OCF
3CONH
2SO
2NH
2Amido functional group is selected from C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
6The residue of alkyl replaces CONH once or twice
2Or SO
2NH
2, wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Dibasic amino of perhaps following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen atom and C
1-C
6Alkyl, its
Methylene group in the formula of (II) is alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice; Perhaps
B3) saturated, the unsaturated or aromatic heterocycle system of maximum 10 atoms, this heterocyclic system are replaced once or several: C by following group alternatively
1-C
6Alkyl; C
1-C
6Alkoxyl group; COOH; SO
3H; CONH
2SO
2NH
2Amido functional group is selected from C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4The residue of alkyl replaces once above CONH
2Or SO
2NH
2, wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby described alkyl residue can become key to form five-ring or six-ring; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
C) SO
3H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; CONH
2SO
2NH
2Amido functional group is selected from C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
6The residue of alkyl replaces CONH once or twice
2Or SO
2NH
2, wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorosulfonyl; Be selected from the halogen atom of fluorine atom, chlorine atom or iodine atom; CF
3Or OCF
3
2. compound as claimed in claim 1 is characterized in that R
1To R
5Independent separately expression:
Hydrogen atom;
Hydroxyl;
C
1-C
6Alkyl, C
6-C
10Aryl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
6Alkoxyl group, C
1-C
6-alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, wherein each group is alternatively by C
1-C
6Alkyl, C
1-C
6Alkoxyl group, amino, C
1-C
6Alkylamino, two-C
1-C
6Alkylamino, hydroxyl, fluorine atom, chlorine atom, bromine atoms, cyano group, CF
3Or OCF
3Replace once or for several times;
Amino;
Be selected from C
1-C
6Alkyl, C
6-C
10The residue of aryl replaces once above amino;
Be selected from C alternatively
1-C
6Alkyl, amino, fluorine atom, chlorine atom or CF
3More than one residue the 1-pyrryl, 2-pyrryl or the 3-pyrryl that replace;
Perhaps dibasic amino of general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen and C
1-C
6Alkyl, wherein the methylene group in general formula (II) is alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice;
CONH
2；
SO
2NH
2；
CONH
2Or SO
2NH
2, wherein amido functional group is selected from C
1-C
6Alkyl or C
6-C
10The residue of aryl replaces once or twice;
Fluorine atom;
The chlorine atom;
Bromine atoms;
CF
3Or
OCF
3。
3. compound as claimed in claim 1 or 2 is characterized in that R
1To R
5In represent hydrogen atom, fluorine atom or chlorine atom more than one.
4. compound as claimed in claim 3 is characterized in that R
1Or R
5Expression hydrogen atom or fluorine atom.
5. as any described compound in the claim 1 to 4, it is characterized in that R
1To R
5In represent hydroxyl more than one; Perhaps
C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
6Alkoxyl group, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, amino, C
1-C
6Alkylamino, two-C
1-C
6Alkylamino, alternatively by C
1-C
6Alkyl or C
6-C
10Aryl replaces CONH once or twice
2Or SO
2NH
2, hydroxyl, fluorine atom, chlorine atom, bromine atoms, cyano group, CF
3Or OCF
3
6. compound as claimed in claim 5 is characterized in that R
2, R
3Or R
4In an expression:
Hydroxyl; Perhaps
C
1-C
6Alkoxyl group, C
6-C
10Aryloxy or C
6-C
10Aryl-C
1-C
6Alkoxyl group, wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, amino, C
1-C
6Alkylamino, two-C
1-C
6Alkylamino, alternatively by C
1-C
6Alkyl or C
6-C
10Aryl replaces CONH once or twice
2Or SO
2NH
2, hydroxyl, fluorine atom, chlorine atom or bromine atoms.
7. as any described compound in the claim 1 to 6, it is characterized in that R
1To R
5In more than one the expression:
Amino;
Be selected from C
1-C
6Alkyl, C
6-C
10The residue of aryl replaces once above amino; Perhaps
Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen and C
1-C
6Alkyl, wherein the methylene group in general formula (II) is alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice.
8. compound as claimed in claim 7 is characterized in that R
2, R
3Or R
4In an expression:
Amino;
Be selected from C
1-C
6Alkyl, C
6-C
10The residue of aryl replaces amino once or twice; Perhaps
Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen and C
1-C
6Alkyl, wherein the methylene group in general formula (II) is alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice.
9. as any described compound in the claim 1 to 8, it is characterized in that n represents 0; M represents 0,1,2,3,4,5 or 6; Y represents C
3-C
6Cycloalkyl or C
6-C
10Aryl, wherein each group is replaced once or several by following group alternatively:
A) C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
4Alkoxyl group, wherein each group is replaced once or several by following group alternatively:
C
1-C
6Alkyl; C
1-C
6Alkoxyl group; COOH; CONH
2SO
2NH
2By C
1-C
6Alkyl or C
6-C
10Aryl replaces CONH once or twice
2Or SO
2NH
2SO
3H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
Perhaps
B) hydroxyl; Thiol group; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3OCF
3CO
2H; SO
3H; CONH
2SO
2NH
2CONH
2Or SO
2NH
2, wherein amido functional group is selected from down more than the residue replacement once of group: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4Alkyl, and at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; By C
1-C
6Alkyl or phenyl replaces once or amino for several times; Dibasic amino of following general formula (II);
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen atom and C
1-C
4Alkyl, wherein the methylene group in general formula (II) is alternatively by C
1-C
4Alkyl, fluorine atom or chlorine atom replace once or twice;
Perhaps
C) replaced once by following group alternatively or saturated, the unsaturated or aromatic heterocycle system of maximum 10 atoms for several times:
C
1-C
6Alkyl; C
1-C
6Alkoxyl group; COOH; CONH
2SO
2NH
2By C
1-C
6Alkyl or C
6-C
10Aryl replaces CONH once or twice
2Or SO
2NH
2SO
3H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
10. compound as claimed in claim 9 is characterized in that n represents 0; M represents 0 or 1; Y represents phenyl, 1-naphthyl, 2-naphthyl, 2-pyridyl, 3-pyridyl or 4-pyridyl ring system.
11. compound as claimed in claim 10 is characterized in that, Y is replaced once or several: C by following group
1-C
6Alkyl; Phenyl; C
1-C
6Alkoxyl group; Hydroxyl; Fluorine atom; The chlorine atom; Bromine atoms; CF
3OCF
3Amino; Or alternatively by C
1-C
6Alkyl replaces CONH once or twice
2Or SO
2NH
2, these optional C wherein
1-C
6Thereby alkyl residue can become key to form five-ring or six-ring.
12. compound as claimed in claim 11 is characterized in that m represents 0, Y represents by hydroxyl, fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice.
13. compound as claimed in claim 11, it is characterized in that, m represents 0, and Y is illustrated in phenyl that the 4-position replaced by fluorine atom or chlorine atom, the phenyl that is replaced by fluorine atom in 2-position and 4-position, the phenyl that is replaced by the chlorine atom in 2-position and 4-position or the phenyl that is replaced by phenyl in the 4-position.
14. compound as claimed in claim 1 is characterized in that, m is 0; N is 0; Y represents by fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice; R
2To R
4Any one the expression OR
7, R wherein
7Be selected from hydrogen atom and C
1-C
6Alkyl.
15. compound as claimed in claim 14 is characterized in that, the phenyl that Y is illustrated in phenyl that the 4-position replaced by fluorine atom or chlorine atom, the phenyl that is replaced by fluorine atom in 2-position and 4-position or is replaced by the chlorine atom in 2-position and 4-position.
16., it is characterized in that R as claim 14 or 15 described compounds
1Or R
5Expression hydrogen atom or fluorine atom.
17., it is characterized in that R as any described compound in the claim 14 to 16
2Or R
3And R
4The expression hydroxyl.
18. one kind as any described compound in the claim 1 to 17, is used for treatment for diseases, described illness is subjected to positive influence because of the inhibition of FAAH.
19. compound as claimed in claim 18, it is characterized in that described illness is selected from: pain, dizzy, vomiting and gastric disorder causing nausea, the disturbance of food intake, nerve and spiritual pathology, acute or chronic neurodegenerative disease, epilepsy, somnopathy, cardiovascular disorder, cancer, immune system disorder, parasite, virus or bacterial infectious disease, inflammation, osteoporosis, eye conditions, lung's illness and gastrointestinal illness.
20. the purposes as any described compound in the claim 1 to 17 is used to suppress FAAH.
21. the purposes as any described compound in the claim 1 to 17 is used for treatment for diseases, described illness is subjected to positive influence because of the inhibition of FAAH.
22. the purposes as any described compound in the claim 1 to 17 is used to make the treatment for diseases medicine, described illness is subjected to positive influence because of the inhibition of FAAH.
23. as claim 21 or 22 described purposes, it is characterized in that described illness is selected from: pain, dizzy, vomiting and gastric disorder causing nausea, the disturbance of food intake, nerve and spiritual pathology, acute or chronic neurodegenerative disease, epilepsy, somnopathy, cardiovascular disorder, cancer, immune system disorder, parasite, virus or bacterial infectious disease, inflammation, osteoporosis, eye conditions, lung's illness and gastrointestinal illness.
24. the compound of a general formula (I), perhaps acceptable salt or ester or its prodrug on its steric isomer, its pharmacology,
Wherein
R
1To R
5Independent separately expression:
Hydrogen;
C
1-C
6Alkyl, C
3-C
8-cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxy carbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8-cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base, wherein each group is replaced once or several by following group alternatively:
C
1-C
6Alkyl; C
1-C
6Alkoxyl group; C
6-C
10Aryloxy; CO
2H; SO
3H; CONH
2SO
2NH
2The residue that amido functional group is selected from down group replaces once above CONH
2Or SO
2NH
2: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4Alkyl, and at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
CO
2H；
SO
3H；
Amino;
The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl;
Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen atom and C
1-C
6Alkyl, wherein the methylene group in general formula (II) is alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice;
CONH
2；
SO
2NH
2；
Amido functional group is selected from down the residue replacement CONH once or twice of group
2Or SO
2NH
2: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
6Alkyl, and at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring;
Thiol group;
Hydroxyl;
Nitro;
Cyano group;
Fluorosulfonyl;
Be selected from the halogen atom of fluorine atom, chlorine atom, bromine atoms or iodine atom;
CF
3；
OCF
3Perhaps
Replaced once by following group alternatively or saturated, the unsaturated or aromatic heterocycle system of maximum 10 atoms for several times:
C
1-C
6Alkyl; C
1-C
6Alkoxyl group; COOH; SO
3H; CONH
2SO
2NH
2The residue that amido functional group is selected from down group replaces once above CONH
2Or SO
2NH
2: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4Alkyl, and at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
And R wherein
1To R
5Thereby in can become key to form more than two to condense saturated, unsaturated or aromatics homogeneity member ring systems or heterocyclic system arbitrarily;
N represents 0 or 1; M represents 0,1,2,3,4,5 or 6;
X represents O or S;
Y represents:
A) hydrogen;
B) C
1-C
18Alkyl, single unsaturated or how unsaturated C
2-C
18Alkylene, C
3-C
8Cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxy carbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8Cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Saturated, the unsaturated or aromatic heterocycle system of aryl sulphur oxygen base or maximum 10 atoms, wherein each group is selectively replaced once or several by following group:
B1) C
1-C
6Alkyl, C
3-C
8Cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxy carbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8Cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base; Wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl; C
1-C
6Alkoxyl group; CONH
2SO
2NH
2Amido functional group is by C
1-C
6Alkyl replaces CONH once or twice
2Or SO
2NH
2SO
3H; CO
2H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
Wherein, a plurality of substituting groups in b1) can become key to form to condense saturated, unsaturated or aromatics homogeneity member ring systems or heterocyclic system;
Perhaps
B2) hydroxyl; Thiol group; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3CO
2H; SO
3H; OCF
3CONH
2SO
2NH
2Amido functional group is selected from C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
6The residue of alkyl replaces CONH once or twice
2Or SO
2NH
2, wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Dibasic amino of perhaps following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen atom and C
1-C
6Alkyl, wherein the methylene group in general formula (II) is alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice;
Perhaps
B3) saturated, the unsaturated or aromatic heterocycle system of maximum 10 atoms, this heterocyclic system are replaced once or several: C by following group alternatively
1-C
6Alkyl; C
1-C
6Alkoxyl group; COOH; SO
3H; CONH
2SO
2NH
2Amido functional group is selected from C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4The residue of alkyl replaces once above CONH
2Or SO
2NH
2, wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby described alkyl residue can become key to form five-ring or six-ring; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
C) SO
3H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; CONH
2SO
2NH
2Amido functional group is selected from C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
6The residue of alkyl replaces CONH once or twice
2Or SO
2NH
2, wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorosulfonyl; Be selected from the halogen atom of fluorine atom, chlorine atom or iodine atom; CF
3Or OCF
3
N represent 0 and m represent that supplementary condition are under 0 the situation:
A) R
2Or R
4Do not represent substituting group C (=A)-N (B)-SO
2-NR
6R
7, wherein A represents O or S, B represents hydrogen atom, cyano group, C
1-C
6Alkyl, C
1-C
6Alkoxyalkyl, C
3-C
7Cycloalkyl, C
3-C
6Alkylene, C
3-C
6Alkynyl or substituted alternatively phenmethyl derivative, R
6And R
7Independently represent hydrogen atom or organic residue separately or represent organic ring structure altogether;
B) when Y represents not have the phenyl of replacement, R
1To R
5Do not represent hydrogen atom, fluorine atom, chlorine atom, bromine atoms, iodine atom or alkyl independently of one another;
C) R
2Or R
4Do not represent the pyrazole-3-yl derivative; And
D) by R
1To R
5The phenyl ring and the Y that replace are not expressed as follows combination:
And n represent 0 and m represent that other supplementary condition are: if R under 1 the situation
1, R
2And R
5The expression hydrogen atom, R
4Expression hydrogen atom, trifluoromethoxy, trifluoro butoxy, 3,3,5,5-tetramethyl-ring hexyloxy, benzyloxy, phenoxy group, phenyl, 2-dimethylamino ethoxy or 3-tolyloxy methyl, and R
3Expression hydrogen atom, trifluoromethoxy, trifluoro butoxy, 3,3,5,5-tetramethyl-ring hexyloxy, phenoxy group, 4-chlorophenoxy, cyclohexyl, phenyl, morpholine alkylsulfonyl, 3,3,5-trimethylcyclohexyl amino-sulfonyl, 2,2,6,6-tetramethyl piperidine-4-base amino-sulfonyl, 2-(di-isopropyl aminoethyl) amino-sulfonyl, 4-methylpiperazine-1-base alkylsulfonyl, 3,3-lupetidine carbonyl or 3,5-dichlorophenoxy, 2-dimethylamino ethoxy or 3-tolyloxy methyl, Y does not represent not have the phenyl of replacement so;
And under the situation of m=0 and n=0, further supplementary condition are that Y does not represent C
1-C
4Alkyl;
And other supplementary condition are: described compound is not one of following compound:
5-phenoxy group-3-phenyl-(1,3,4)-oxadiazoles-2-ketone
5-dodecyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-n-Hexadecane oxygen base-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-octyloxy-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-n-Hexadecane oxygen base-3-(3-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-n-Hexadecane oxygen base-3-(4-(4-chlorophenoxy)-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-octyloxy-3-phenyl-3H-(1,3,4)-oxadiazoles-2-ketone
5-octyloxy-3-(3-fluorophenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-n-Hexadecane oxygen base-3-(3-fluorophenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-n-Hexadecane oxygen base-3-(3-benzyloxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-n-Hexadecane oxygen base-3-phenyl-3H-(1,3,4)-oxadiazoles-2-ketone
5-n-Hexadecane oxygen base-3-(4-nitro-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-n-Hexadecane oxygen base-3-(4-methoxyl group-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-n-Hexadecane oxygen base-3-(4-benzyloxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-oxygen in last of the ten Heavenly stems base-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-undecane oxygen base-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-tetradecyloxyaniline-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-tridecane oxygen base-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(2-(2-hexyloxy-oxyethyl group)-oxyethyl group)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-((Z)-9-octadecylene oxygen)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(dodecyloxy-oxyethyl group)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(2-(4-fluorophenyl)-oxyethyl group)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-((3ss-cholestane-3-yl)-oxygen base)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(2-butoxy-oxyethyl group)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(7-phenyl-heptan oxygen base)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(docosane oxygen base-oxyethyl group)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(2-(1-naphthyloxy)-oxyethyl group)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(the hot phenoxy group of 4-)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(3-phenoxy group-phenoxy group)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(dodecyloxy)-3-(4-trifluoromethoxy-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(dodecyloxy)-3-(3, the 4-dichlorophenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(dodecyloxy)-3-(3, the 5-dichlorophenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(dodecyloxy)-3-(3-methoxyl group-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone
5-(dodecyloxy)-3-(4-methoxyl group-phenyl)-3H-(1,3,4)-oxadiazoles-2-ketone.
25. compound as claimed in claim 24 is characterized in that, R
1To R
5Independent separately expression:
Hydrogen atom;
Hydroxyl;
C
1-C
6Alkyl, C
6-C
10Aryl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
6Alkoxyl group, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, amino, C
1-C
6Alkylamino, two C
1-C
6Alkylamino, hydroxyl, fluorine atom, chlorine atom, bromine atoms, cyano group, CF
3Perhaps OCF
3
Amino;
Be selected from C
1-C
6Alkyl, C
6-C
10The residue of aryl replaces once above amino;
Be selected from C alternatively
1-C
6Alkyl, amino, fluorine atom, chlorine atom or CF
3An above residue 1-pyrryl, 2-pyrryl or the 3-pyrryl that replace;
Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen atom and C
1-C
6Alkyl, the methylene group in its formula of (II) is alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice;
CONH
2；
SO
2NH
2；
Amido functional group is selected from C
1-C
6Alkyl or C
6-C
10The residue of aryl replaces CONH once or twice
2Or SO
2NH
2
Fluorine atom;
The chlorine atom
Bromine atoms;
CF
3Perhaps
OCF
3。
26., it is characterized in that R as claim 24 or 25 described compounds
1To R
5In represent hydrogen atom, fluorine atom or chlorine atom more than one.
27. compound as claimed in claim 26 is characterized in that, R
1Or R
5Expression hydrogen atom or fluorine atom.
28., it is characterized in that R as any described compound in the claim 24 to 27
1To R
5In more than one the expression:
Hydroxyl; Perhaps
C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
6Alkoxyl group, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, amino, C
1-C
6Alkylamino, two C
1-C
6Alkylamino, alternatively by C
1-C
6Alkyl or C
6-C
10Aryl replaces CONH once or twice
2Or SO
2NH
2, hydroxyl, fluorine atom, chlorine atom, bromine atoms, cyano group, CF
3Or OCF
3
29. compound as claimed in claim 28 is characterized in that, R
2, R
3Or R
4In an expression:
Hydroxyl; Perhaps
C
1-C
6Alkoxyl group, C
6-C
10Aryloxy or C
6-C
10Aryl-C
1-C
6Alkoxyl group, wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, amino, C
1-C
6Alkylamino, two C
1-C
6Alkylamino, alternatively by C
1-C
6Alkyl or C
6-C
10Aryl replaces CONH once or twice
2Or SO
2NH
2, hydroxyl, fluorine atom, chlorine atom or bromine atoms.
30., it is characterized in that R as any described compound in the claim 24 to 29
1To R
5In more than one the expression:
Amino;
Be selected from C
1-C
6Alkyl, C
6-C
10The residue of aryl replaces once above amino; Perhaps
Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen atom and C
1-C
6Alkyl, wherein the methylene group in general formula (II) is alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice.
31. compound as claimed in claim 30 is characterized in that, R
2, R
3Or R
4In an expression:
Amino;
Be selected from C
1-C
6Alkyl, C
6-C
10The residue of aryl replaces amino once or twice; Perhaps
Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen atom and C
1-C
6Alkyl, wherein the methylene group in general formula (II) is alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice.
32., it is characterized in that n represents 0 as any described compound in the claim 24 to 31; M represents 0,1,2,3,4,5 or 6; Y represents C
3-C
6Cycloalkyl or C
6-C
10Aryl, wherein each group is replaced once or several by following group alternatively:
A) C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
4Alkoxyl group, wherein each group is replaced once or several by following group alternatively:
C
1-C
6Alkyl; C
1-C
6Alkoxyl group; COOH; CONH
2SO
2NH
2By C
1-C
6Alkyl or C
6-C
10Aryl replaces CONH once or twice
2Or SO
2NH
2SO
3H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
Perhaps
B) hydroxyl; Thiol group; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3OCF
3CO
2H; SO
3H; CONH
2SO
2NH
2The residue that amido functional group is selected from down group replaces once above CONH
2Or SO
2NH
2: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4Alkyl is wherein at two C
1-C
6Under the situation of alkyl-substituted amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; By C
1-C
6Alkyl or phenyl replaces once or amino for several times; Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen atom and C
1-C
4Alkyl, wherein the methylene group in general formula (II) is alternatively by C
1-C
4Alkyl, fluorine atom or chlorine atom replace once or twice;
Perhaps
C) replaced once by following group alternatively or saturated, the unsaturated or aromatic heterocycle system of maximum 10 atoms for several times:
C
1-C
6Alkyl; C
1-C
6Alkoxyl group; COOH; CONH
2SO
2NH
2By C
1-C
6Alkyl or C
6-C
10Aryl replaces CONH once or twice
2Or SO
2NH
2SO
3H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
33. compound as claimed in claim 32 is characterized in that n represents 0; M represents 0 or 1; Y represents phenyl, 1-naphthyl, 2-naphthyl, 2-pyridyl, 3-pyridyl or 4-pyridyl ring system.
34. compound as claimed in claim 33 is characterized in that, Y is replaced once or several: C by following group
1-C
6Alkyl; Phenyl; C
1-C
6Alkoxyl group; Hydroxyl; Fluorine atom; The chlorine atom; Bromine atoms; CF
3OCF
3Amino; Or alternatively by C
1-C
6Alkyl replaces CONH once or twice
2Or SO
2NH
2, these optional C wherein
1-C
6Thereby alkyl residue can become key to form five-ring or six-ring.
35. compound as claimed in claim 34 is characterized in that m represents 0, Y represents by hydroxyl, fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice.
36. compound as claimed in claim 34, it is characterized in that, m represents 0, and Y is illustrated in phenyl that the 4-position replaced by fluorine atom or chlorine atom, the phenyl that is replaced by fluorine atom in 2-position and 4-position, the phenyl that is replaced by the chlorine atom in 2-position and 4-position or the phenyl that is replaced by phenyl in the 4-position.
37. compound as claimed in claim 24 is characterized in that, m is 0; N is 0; Y represents by fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice; R
2To R
4In any one the expression OR
7, R wherein
7Be selected from hydrogen atom and C
1-C
6Alkyl.
38. compound as claimed in claim 37 is characterized in that, the phenyl that Y is illustrated in phenyl that the 4-position replaced by fluorine atom or chlorine atom, the phenyl that is replaced by fluorine atom in 2-position and 4-position or is replaced by the chlorine atom in 2-position and 4-position.
39. the compound described in claim 37 or 38 is characterized in that R
1Or R
5Expression hydrogen atom or fluorine atom.
40., it is characterized in that R as any described compound in the claim 37 to 39
2Or R
3And R
4The expression hydroxyl.
41. the compound of a general formula (I), perhaps acceptable salt or ester or its prodrug on its steric isomer, its pharmacology,
Wherein
R
1To R
5Independent separately expression:
Hydrogen;
C
1-C
6Alkyl, C
3-C
8Cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxy carbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8Cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base, wherein each group is selectively replaced once or several by following group:
C
1-C
6-alkyl; C
1-C
6-alkoxyl group; C
6-C
10-aryloxy; CO
2H; SO
3H; CONH
2SO
2NH
2The residue that amido functional group is selected from down group replaces once above CONH
2Or SO
2NH
2: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4Alkyl is wherein at two-C
1-C
6Under the situation of-alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; The thiol group base; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
CO
2H；
SO
3H；
Amino;
The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl;
Dibasic amino of general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen atom and C
1-C
6-alkyl,, wherein the methylene group in general formula (II) is selectively by C
1-C
6-alkyl, fluorine atom or chlorine atom replace once or twice;
CONH
2；
SO
2NH
2；
Amido functional group is selected from down the residue replacement CONH once or twice of group
2Or SO
2NH
2: C
1-C
6-alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
6Alkyl is wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring;
Thiol group;
Hydroxyl;
Nitro;
Cyano group;
Fluorosulfonyl;
Be selected from the halogen atom of fluorine atom, chlorine atom, bromine atoms or iodine atom;
CF
3；
OCF
3Perhaps
Saturated, the unsaturated or aromatic heterocycle system of maximum 10 atoms, this heterocyclic system are replaced once or several by following group alternatively:
C
1-C
6-alkyl; C
1-C
6-alkoxyl group; COOH; SO
3H; CONH
2SO
2NH
2The residue that amido functional group is selected from down group replaces once above CONH
2Or SO
2NH
2: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10-aryl-C
1-C
4Alkyl is wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
And, R wherein
1To R
5Thereby can become key to form more than two to condense saturated, unsaturated or aromatics homogeneity member ring systems or heterocyclic system arbitrarily;
N represents 0; M represents 0;
Y represents to be replaced once or phenyl for several times by following group alternatively:
A) C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxy carbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8-cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base;
Wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl; C
1-C
6Alkoxyl group; Alternatively by C
1-C
6Alkyl replaces CONH once or twice
2Or SO
2NH
2SO
3H; CO
2H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
Thereby several the become keys wherein in these optional substituting groups form and condense saturated, unsaturated or aromatics homogeneity member ring systems or heterocyclic system; Perhaps
B) replaced once by following group alternatively or saturated, unsaturated or aromatic heterocycle system: the C of maximum 10 atoms for several times
1-C
6Alkyl; C
1-C
6Alkoxyl group; COOH; Alternatively by C
1-C
6Alkyl replaces CONH once or twice
2Or SO
2NH
2SO
3H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3Perhaps
C) hydroxyl; Thiol group; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3OCF
3CO
2H; SO
3H; CONH
2SO
2NH
2The residue that amido functional group is selected from down group replaces once above CONH
2Or SO
2NH
2: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4Alkyl is wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Dibasic amino of following general formula (IV):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen atom and C
1-C
4Alkyl, wherein the methylene group in general formula (IV) is alternatively by C
1-C
4Alkyl, fluorine atom or chlorine atom replace once or twice;
Supplementary condition are:
A) R
2Or R
4Do not represent substituting group C (=A)-N (B)-SO
2-NR
6R
7, wherein A represents O or S, B represents hydrogen atom, cyano group, C
1-C
6Alkyl, C
1-C
6Alkoxyalkyl, C
3-C
7Cycloalkyl, C
3-C
6Alkylene, C
3-C
6Alkynyl or substituted alternatively phenmethyl derivative, and R
6And R
7Independently represent hydrogen atom or organic residue separately or represent organic ring structure altogether;
B) when Y represents not have the phenyl of replacement, R
1To R
5Do not represent hydrogen atom, fluorine atom, chlorine atom, bromine atoms, iodine atom or alkyl independently of one another;
C) R
2Or R
4Do not represent the pyrazole-3-yl derivative; And
D) by R
1To R
5The phenyl ring and the Y that replace are not expressed as follows combination:
42. compound as claimed in claim 41 is characterized in that, R
1To R
5Independent separately expression:
Hydrogen atom;
Hydroxyl;
C
1-C
6Alkyl, C
6-C
10Aryl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
6Alkoxyl group, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, amino, C
1-C
6Alkylamino, two C
1-C
6Alkylamino, hydroxyl, fluorine atom, chlorine atom, bromine atoms, cyano group, CF
3Perhaps OCF
3
Amino;
Be selected from C
1-C
6Alkyl, C
6-C
10The residue of aryl replaces once above amino;
Be selected from C alternatively
1-C
6Alkyl, amino, fluorine atom, chlorine atom or CF
3An above residue 1-pyrryl, 2-pyrryl or the 3-pyrryl that replace;
Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen atom and C
1-C
6Alkyl, wherein the methylene group in general formula (II) is alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice;
CONH
2；
SO
2NH
2；
Amido functional group is selected from C
1-C
6Alkyl or C
6-C
10The residue of aryl replaces CONH once or twice
2Or SO
2NH
2
Fluorine atom;
The chlorine atom
Bromine atoms;
CF
3Perhaps
OCF
3。
43., it is characterized in that R as claim 41 or 42 described compounds
1To R
5In represent hydrogen atom, fluorine atom or chlorine atom more than one.
44. compound as claimed in claim 43 is characterized in that, R
1Or R
5Expression hydrogen atom or fluorine atom.
45., it is characterized in that R as any described compound in the claim 41 to 44
1To R
5In more than one the expression:
Hydroxyl; Perhaps
C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
6Alkoxyl group, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, amino, C
1-C
6Alkylamino, two C
1-C
6Alkylamino, alternatively by C
1-C
6Alkyl or C
6-C
10Aryl replaces CONH once or twice
2Or SO
2NH
2, hydroxyl, fluorine atom, chlorine atom, bromine atoms, cyano group, CF
3Or OCF
3
46. compound as claimed in claim 45 is characterized in that, R
2, R
3Or R
4In an expression: hydroxyl; Perhaps C
1-C
6Alkyl, C
6-C
10Aryloxy or C
6-C
10Aryl-C
1-C
6Alkoxyl group, wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, amino, C
1-C
6Alkylamino, two C
1-C
6Alkylamino, alternatively by C
1-C
6Alkyl or C
6-C
10Aryl replaces CONH once or twice
2Or SO
2NH
2, hydroxyl, fluorine atom, chlorine atom or bromine atoms.
47., it is characterized in that R as any described compound in the claim 41 to 46
1To R
5In more than one the expression:
Amino;
Be selected from C
1-C
6Alkyl, C
6-C
10The residue of aryl replaces once above amino; Perhaps
Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen atom and C
1-C
6Alkyl, wherein the methylene group in general formula (II) is alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice.
48. compound as claimed in claim 47 is characterized in that, R
2, R
3Or R
4In an expression amino; Be selected from C
1-C
6Alkyl, C
6-C
10The residue of aryl replaces amino once or twice; Dibasic amino of perhaps following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen atom and C
1-C
6Alkyl, wherein the methylene group in general formula (II) is alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice.
49., it is characterized in that Y represents to be replaced once or phenyl for several times by following group as any described compound in the claim 41 to 48:
A) C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
6Alkoxyl group, wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl; C
1-C
6Alkoxyl group; SO
3H; CO
2H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl; C
1-C
6Alkyl carbonyl; C
6-C
10Aromatic carbonyl; C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3CONH
2SO
2NH
2OCF
3Perhaps amido functional group is by C
1-C
6Alkyl replaces CONH once or twice
2Or SO
2NH
2
Perhaps
B) hydroxyl; Thiol group; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3OCF
3CO
2H; SO
3H; CONH
2SO
2NH
2Perhaps amido functional group is by following group replacement CONH once or twice
2Or SO
2NH
2: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl is wherein at two-C
1-C
6Under the situation of alkyl-substituted amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; By C
1-C
6Alkyl or phenyl replaces once or amino for several times; Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen atom and C
1-C
6Alkyl, wherein the methylene group in general formula (II) is alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice;
Perhaps
C) replaced once by following group alternatively or saturated, unsaturated or aromatic heterocycle system: the C of maximum 10 atoms for several times
1-C
6Alkyl; C
1-C
6Alkoxyl group; COOH; CONH
2SO
2NH
2Amido functional group can be become key to form the C of five-ring or six-ring
1-C
6Alkyl replaces CONH once or twice
2Or SO
2NH
2SO
3H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
50. compound as claimed in claim 49 is characterized in that, Y represents to be replaced once or phenyl for several times: C by following group
1-C
6Alkyl; Phenyl; C
1-C
6Alkoxyl group; Hydroxyl; Fluorine atom; The chlorine atom; Bromine atoms; CF
3OCF
3Amino; Or alternatively by C
1-C
6Alkyl replaces CONH once or twice
2, these optional C wherein
1-C
6Alkyl residue can become key to form five-ring or six-ring.
51. compound as claimed in claim 50 is characterized in that, Y is by hydroxyl, fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice.
52. compound as claimed in claim 50, it is characterized in that Y is the phenyl that replaced by fluorine atom or chlorine atom in the 4-position, the phenyl that is replaced by fluorine atom in 2-position and 4-position, the phenyl that is replaced by the chlorine atom in 2-position and 4-position or the phenyl that is replaced by phenyl in the 4-position.
53. compound as claimed in claim 41 is characterized in that, Y is by fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice; R
2To R
4In any one the expression OR
7, R wherein
7Be selected from hydrogen atom and C
1-C
6Alkyl.
54. compound as claimed in claim 53 is characterized in that, Y is the phenyl that replaced by fluorine atom or chlorine atom in the 4-position, the phenyl that is replaced by fluorine atom in 2-position and 4-position or the phenyl that replaced by the chlorine atom in 2-position and 4-position.
55., it is characterized in that R as claim 53 or 54 described compounds
1Or R
5Expression fluorine atom or hydrogen atom.
56., it is characterized in that R as any described compound in the claim 53 to 55
3, or R
3And R
4The expression hydroxyl.
57. the compound of a general formula (I), perhaps acceptable salt or ester or its prodrug on its steric isomer, its pharmacology,
R wherein
1Or R
5Expression hydrogen atom or fluorine atom;
R
2To R
4In any one expression hydroxyl and other remaining R residues be:
Hydrogen atom;
C
1-C
6Alkyl, C
3-C
8-cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxycarbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8-cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base, wherein each residue is replaced once or several: C by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, CO
2H, SO
3H, amino, C
1-C
6Alkylamino, two-C
1-C
6Alkylamino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3, or OCF
3
CO
2H；
SO
3H；
Amino;
The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl;
Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen atom and C
1-C
6Alkyl, wherein the methylene group in general formula (II) is alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice;
CONH
2；
SO
2NH
2；
The residue that amido functional group is selected from down group replaces once or CONH for several times
2Or SO
2NH
2: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
6Alkyl is wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring;
Thiol group;
Hydroxyl;
Nitro;
Cyano group;
Fluorosulfonyl;
Be selected from the halogen atom of fluorine atom, chlorine atom, bromine atoms or iodine atom;
CF
3；
OCF
3Or
Replaced once by following group alternatively or saturated, unsaturated or aromatic heterocycle system: the C of maximum 10 atoms for several times
1-C
6Alkyl, C
1-C
6Alkoxyl group, COOH, SO
3H, amino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Or OCF
3
And R wherein
2To R
4Thereby in can become key to form more than two to condense saturated, unsaturated or aromatics homogeneity member ring systems or heterocyclic system arbitrarily;
N and m are 0; And
Y is replaced once or phenyl for several times: C by following group
1-C
6Alkyl; Phenyl; C
1-C
6Alkoxyl group; Hydroxyl; Fluorine atom; The chlorine atom; Bromine atoms; CF
3OCF
3Amino; Or alternatively by C
1-C
6Alkyl replaces CONH once or twice
2, these optional C wherein
1-C
6Thereby alkyl residue can become key to form five-ring or six-ring.
58. the compound of a general formula (I), perhaps acceptable salt or ester or its prodrug on its steric isomer, its pharmacology,
R wherein
1Or R
5Expression hydrogen atom or fluorine atom;
R
2To R
4In other amino and remaining R residues of any one expression be:
Hydrogen atom;
C
1-C
6Alkyl, C
3-C
8-cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxycarbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8-cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base, wherein each group is alternatively by C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, CO
2H, SO
3H, amino, C
1-C
6Alkylamino, two-C
1-C
6-alkylamino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Or OCF
3Replace once or for several times;
CO
2H；
SO
3H；
Amino;
The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl;
Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen atom and C
1-C
6Alkyl, wherein the methylene group in general formula (II) is alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice;
CONH
2；
SO
2NH
2；
The residue that amido functional group is selected from down group replaces once or CONH for several times
2Or SO
2NH
2: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
6Alkyl is wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring;
Thiol group;
Hydroxyl;
Nitro;
Cyano group;
Fluorosulfonyl;
Be selected from the halogen atom of fluorine atom, chlorine atom, bromine atoms, iodine atom;
CF
3；
OCF
3Perhaps
Replaced once by following group alternatively or saturated, unsaturated or aromatic heterocycle system: the C of maximum 10 atoms for several times
1-C
6Alkyl, C
1-C
6Alkoxyl group, COOH, SO
3H, amino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Or OCF
3
And R wherein
2To R
4Thereby in can become key to form more than two to condense saturated, unsaturated or aromatics homogeneity member ring systems or heterocyclic system arbitrarily;
N and m are 0; And
Y is replaced once or phenyl for several times: C by following group
1-C
6Alkyl; Phenyl; C
1-C
6Alkoxyl group; Hydroxyl; Fluorine atom; The chlorine atom; Bromine atoms; CF
3OCF
3Amino; Or alternatively by C
1-C
6Alkyl replaces CONH once or twice
2, these optional C wherein
1-C
6Thereby alkyl residue can become key to form five-ring or six-ring.
59. the compound of a general formula (I), perhaps acceptable salt or ester or its prodrug on its steric isomer, its pharmacology,
R wherein
1Or R
5Expression hydrogen atom or fluorine atom;
R
3Or R
4In one be C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base, wherein each group is alternatively by C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, CO
2H, SO
3H, amino, C
1-C
6Alkylamino, two-C
1-C
6-alkylamino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Or OCF
3Replace once or for several times;
R
3Or R
4In another residue that is selected from down group replace once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl;
R
2Be:
Hydrogen atom;
C
1-C
6Alkyl, C
3-C
8-cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxycarbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8-cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base, wherein each group is alternatively by C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, CO
2H, SO
3H, amino, C
1-C
6Alkylamino, two-C
1-C
6-alkylamino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Or OCF
3Replace once or for several times;
CO
2H；
SO
3H；
Amino;
The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl;
Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen atom and C
1-C
6Alkyl, wherein the methylene group in general formula (II) is alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice;
CONH
2；
SO
2NH
2；
The residue that amido functional group is selected from down group replaces once or CONH for several times
2Or SO
2NH
2: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
6Alkyl is wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring;
Thiol group;
Hydroxyl;
Nitro;
Cyano group;
Fluorosulfonyl;
Be selected from the halogen atom of fluorine atom, chlorine atom, bromine atoms, iodine atom;
CF
3；
OCF
3Perhaps
Replaced once by following group alternatively or saturated, unsaturated or aromatic heterocycle system: the C of maximum 10 atoms for several times
1-C
6Alkyl, C
1-C
6Alkoxyl group, COOH, SO
3H, amino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Or OCF
3
N and m are 0; And
Y is replaced once or phenyl for several times: C by following group
1-C
6Alkyl; Phenyl; C
1-C
6Alkoxyl group; Hydroxyl; Fluorine atom; The chlorine atom; Bromine atoms; CF
3OCF
3Amino; Or alternatively by C
1-C
6Alkyl replaces CONH once or twice
2, these optional C wherein
1-C
6Thereby alkyl residue can become key to form five-ring or six-ring.
60., it is characterized in that Y is replaced once or phenyl for several times: C by following group as any described compound in the claim 57 to 59
1-C
6Alkyl; Phenyl; C
1-C
6Alkoxyl group; Hydroxyl; Fluorine atom; The chlorine atom; Bromine atoms; CF
3OCF
3Amino; Perhaps alternatively by C
1-C
6Alkyl replaces CONH once or twice
2, these optional C wherein
1-C
6Thereby alkyl residue can become key to form five-ring or six-ring.
61. compound as claimed in claim 60 is characterized in that, Y is by hydroxyl, fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice.
62. compound as claimed in claim 60, it is characterized in that Y is the phenyl that replaced by fluorine atom or chlorine atom in the 4-position, the phenyl that is replaced by fluorine atom in 2-position and 4-position, the phenyl that is replaced by the chlorine atom in 2-position and 4-position or the phenyl that is replaced by phenyl in the 4-position.
63. the compound of a general formula (I),
Wherein
R
1To R
5Independent separately expression:
Hydrogen;
C
1-C
6Alkyl, C
3-C
8-cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxy carbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8-cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base, wherein each group is replaced once or several by following group alternatively:
C
1-C
6Alkyl; C
1-C
6Alkoxyl group; C
6-C
10Aryloxy; CO
2H; SO
3H; CONH
2SO
2NH
2The residue that amido functional group is selected from down group replaces once above CONH
2Or SO
2NH
2: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4Alkyl is wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
CO
2H；
SO
3H；
Amino;
The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl;
Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen atom and C
1-C
6Alkyl, wherein the methylene group in general formula (II) is alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice;
CONH
2；
SO
2NH
2；
Amido functional group is selected from down the residue replacement CONH once or twice of group
2Or SO
2NH
2: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
6Alkyl is wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring;
Thiol group;
Hydroxyl;
Nitro;
Cyano group;
Fluorosulfonyl;
Be selected from the halogen atom of fluorine atom, chlorine atom, bromine atoms or iodine atom;
CF
3；
OCF
3Perhaps
Replaced once by following group alternatively or saturated, the unsaturated or aromatic heterocycle system of maximum 10 atoms for several times:
C
1-C
6Alkyl; C
1-C
6Alkoxyl group; COOH; SO
3H; CONH
2SO
2NH
2The residue that amido functional group is selected from down group replaces once above CONH
2Or SO
2NH
2: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4Alkyl is wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
And R wherein
1To R
5Thereby in can become key to form more than two to condense saturated, unsaturated or aromatics homogeneity member ring systems or heterocyclic system arbitrarily;
N represents 0; M represents 1;
Y represents to be replaced once or phenyl for several times by following group alternatively:
A) C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxy carbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8-cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base;
Wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl; C
1-C
6Alkoxyl group; Alternatively by C
1-C
6Alkyl replaces CONH once or twice
2Or SO
2NH
2SO
3H; CO
2H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
Thereby several the become keys wherein in these optional substituting groups form and condense saturated, unsaturated or aromatics homogeneity member ring systems or heterocyclic system; Perhaps
B) replaced once by following group alternatively or saturated, unsaturated or aromatic heterocycle system: the C of maximum 10 atoms for several times
1-C
6Alkyl; C
1-C
6Alkoxyl group; COOH; Alternatively by C
1-C
6Alkyl replaces CONH once or twice
2Or SO
2NH
2SO
3H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
4Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3Perhaps
C) hydroxyl; Thiol group; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3OCF
3CO
2H; SO
3H; CONH
2SO
2NH
2The residue that amido functional group is selected from down group replaces once above CONH
2Or SO
2NH
2: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4Alkyl is wherein at two-C
1-C
6Under the situation of-alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Dibasic amino of following general formula (IV):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen atom and C
1-C
4Alkyl, wherein the methylene group in general formula (IV) is selectively by C
1-C
4Alkyl, fluorine atom or chlorine atom replace once or twice; Supplementary condition are: if R
1, R
2And R
5The expression hydrogen atom, R
4Expression hydrogen atom, trifluoromethoxy, trifluoro butoxy, 3,3,5,5-tetramethyl-ring hexyloxy, benzyloxy, phenoxy group, phenyl, 2-dimethylamino ethoxy or 3-tolyloxy methyl, and R
3Expression hydrogen atom, trifluoromethoxy, trifluoro butoxy, 3; 3; 5; 5-tetramethyl-ring hexyloxy, phenoxy group, 4-chlorophenoxy, cyclohexyl, phenyl, morpholine alkylsulfonyl, 3; 3; 5-trimethylcyclohexyl amino-sulfonyl, 2; 2; 6; 6-tetramethyl piperidine-4-base amino-sulfonyl, 2-(di-isopropyl aminoethyl) sulfamyl, 4-methylpiperazine-1-base alkylsulfonyl, 3; 3-lupetidine carbonyl or 3,5-dichlorophenoxy, 2-dimethylamino ethoxy or 3-tolyloxy methyl, Y does not represent not have the phenyl of replacement so.
64., it is characterized in that R as the described compound of claim 63
1To R
5Independent separately expression:
Hydrogen atom;
Hydroxyl;
C
1-C
6Alkyl, C
6-C
10-aryl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
6Alkoxyl group, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, wherein each group is alternatively by C
1-C
6Alkyl, C
1-C
6Alkoxyl group, amino, C
1-C
6Alkylamino, two-C
1-C
6-alkylamino, hydroxyl, fluorine atom, chlorine atom, bromine atoms, cyano group, CF
3Or OCF
3Replace once or for several times;
Amino;
Be selected from C
1-C
6Alkyl, C
6-C
10The residue of aryl replaces once above amino;
Be selected from C alternatively
1-C
6Alkyl, amino, fluorine atom, chlorine atom or CF
3An above residue 1-pyrryl, 2-pyrryl or the 3-pyrryl that replace;
Dibasic amino of general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen and C
1-C
6Alkyl, wherein the methylene group in general formula (II) is alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice;
CONH
2；
SO
2NH
2；
Amido functional group is selected from C
1-C
6Alkyl or C
6-C
10The residue of aryl replaces CONH once or twice
2Or SO
2NH
2
Fluorine atom;
The chlorine atom;
Bromine atoms;
CF
3Or
OCF
3。
65., it is characterized in that R as claim 63 or 64 described compounds
1To R
5In represent hydrogen atom, fluorine atom or chlorine atom more than one.
66., it is characterized in that R as the described compound of claim 65
1Or R
5Expression hydrogen atom or fluorine atom.
67., it is characterized in that R as any described compound in the claim 63 to 66
1To R
5In represent hydroxyl more than one; Perhaps
C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
6Alkoxyl group, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Arylsulfonyl, wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, amino, C
1-C
6Alkylamino, two-C
1-C
6Alkylamino, alternatively by C
1-C
6Alkyl or C
6-C
10Aryl replaces CONH once or twice
2Or SO
2NH
2, hydroxyl, fluorine atom, chlorine atom, bromine atoms, cyano group, CF
3Or OCF
3
68., it is characterized in that R as the described compound of claim 67
2, R
3Or R
4In one the expression hydroxyl; Perhaps C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
6Alkoxyl group, wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, amino, C
1-C
6Alkylamino, two-C
1-C
6Alkylamino, alternatively by C
1-C
6Alkyl or C
6-C
10Aryl replaces CONH once or twice
2Or SO
2NH
2, hydroxyl, fluorine atom, chlorine atom or bromine atoms.
69., it is characterized in that R as any described compound in the claim 63 to 68
1To R
5In expression more than amino;
Be selected from C
1-C
6Alkyl, C
6-C
10The residue of aryl replaces once above amino; Perhaps
Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen and C
1-C
6Alkyl, wherein the methylene group in general formula (II) is alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice.
70., it is characterized in that R as the described compound of claim 69
2, R
3Or R
4In an expression amino;
Be selected from C
1-C
6Alkyl, C
6-C
10The residue of aryl replaces amino once or twice;
Dibasic amino of perhaps following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen and C
1-C
6Alkyl, wherein the methylene group in general formula (II) is alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice.
71., it is characterized in that Y represents to be replaced once or phenyl for several times by following group as any described compound in the claim 63 to 70:
A) C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
6Alkoxyl group, wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl; C
1-C
6Alkoxyl group; SO
3H; CO
2H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl; C
1-C
6Alkyl carbonyl; C
6-C
10Aromatic carbonyl; C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3CONH
2SO
2NH
2OCF
3Perhaps amido functional group is by C
1-C
6Alkyl replaces CONH once or twice
2Or SO
2NH
2
Perhaps
B) hydroxyl; Thiol group; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3OCF
3CO
2H; SO
3H; CONH
2SO
2NH
2Perhaps amido functional group is by following group replacement CONH once or twice
2Or SO
2NH
2: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl is wherein at two-C
1-C
6Under the situation of alkyl-substituted amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; By C
1-C
6Alkyl or phenyl replaces once or amino for several times; Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen atom and C
1-C
6Alkyl, wherein the methylene group in general formula (II) is alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice;
Perhaps
C) replaced once by following group alternatively or saturated, unsaturated or aromatic heterocycle system: the C of maximum 10 atoms for several times
1-C
6Alkyl; C
1-C
6Alkoxyl group; COOH; CONH
2SO
2NH
2Amido functional group can be become key to form the C of five-ring or six-ring
1-C
6Alkyl replaces CONH once or twice
2Or SO
2NH
2SO
3H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
72., it is characterized in that Y represents to be replaced once or phenyl for several times: C by following group as the described compound of claim 71
1-C
6Alkyl; Phenyl; C
1-C
6Alkoxyl group; Hydroxyl; Fluorine atom; The chlorine atom; Bromine atoms; CF
3OCF
3Amino; Perhaps alternatively by C
1-C
6Alkyl replaces CONH once or twice
2, these optional C wherein
1-C
6Alkyl residue can become key to form five-ring or six-ring.
73., it is characterized in that Y is by hydroxyl, fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice as the described compound of claim 71.
74. as the described compound of claim 72, it is characterized in that Y is the phenyl that replaced by fluorine atom or chlorine atom in the 4-position, the phenyl that is replaced by fluorine atom in 2-position and 4-position, the phenyl that is replaced by the chlorine atom in 2-position and 4-position or the phenyl that is replaced by phenyl in the 4-position.
75., it is characterized in that Y is by fluorine atom, chlorine atom or bromine atoms replacement phenyl once or twice as the described compound of claim 63; R
2To R
4In any one the expression OR
7, R wherein
7Be selected from hydrogen atom and C
1-C
6Alkyl.
76., it is characterized in that Y is the phenyl that replaced by fluorine atom or chlorine atom in the 4-position, the phenyl that is replaced by fluorine atom in 2-position and 4-position or the phenyl that replaced by the chlorine atom in 2-position and 4-position as the described compound of claim 75
77., it is characterized in that R as claim 75 or 76 described compounds
1Or R
5Expression fluorine atom or hydrogen atom.
78., it is characterized in that R as any described compound in the claim 75 to 77
3, or R
3And R
4The expression hydroxyl.
79. a compound that comprises the pharmacophoric group of following structure (III),
Be used for the inhibition of fatty amide hydrolase (FAAH).
80. a pharmaceutical composition, it comprises as acceptable carrier on any described compound and the pharmacology in the claim 24 to 79.
81. one kind as any described compound in the claim 24 to 79, as medicament.
82. one kind as any described compound in the claim 24 to 78, is used for the inhibition of fatty amide hydrolase (FAAH).
83. one kind as any described compound in the claim 24 to 79, is used for treatment for diseases, described illness is subjected to influencing energetically because of the inhibition of fatty amide hydrolase (FAAH).
84. as the described compound of claim 83, it is characterized in that described illness is selected from: pain, dizzy, vomiting and gastric disorder causing nausea, the disturbance of food intake, nerve and spiritual pathology, acute or chronic neurodegenerative disease, epilepsy, somnopathy, cardiovascular disorder, cancer, immune system disorder, parasite, virus or bacterial infectious disease, inflammation, osteoporosis, eye conditions, lung's illness and gastrointestinal illness.
85. the purposes as any described compound in the claim 24 to 79 is used for the inhibition of fatty amide hydrolase (FAAH).
86. the purposes as any described compound in the claim 24 to 79 is used for treatment for diseases, described illness is subjected to influencing energetically because of the inhibition of fatty amide hydrolase (FAAH).
87. the purposes of the pharmacophoric group of following structure (III),
Be used for the preparation of treatment for diseases with compound, described illness is subjected to influencing energetically because of the inhibition of fatty amide hydrolase (FAAH).
88. as claim 86 or 87 described purposes, it is characterized in that described illness is selected from: pain, dizzy, vomiting and gastric disorder causing nausea, the disturbance of food intake, nerve and spiritual pathology, acute or chronic neurodegenerative disease, epilepsy, somnopathy, cardiovascular disorder, cancer, immune system disorder, parasite, virus or bacterial infectious disease, inflammation, osteoporosis, eye conditions, lung's illness and gastrointestinal illness.
89. preparation method as any described compound in claim 1 to 17 and 24 to 79; it is characterized in that; general formula (IV) thus compound by cyclisation Xing Cheng oxadiazole ketone member ring systems, supplementary condition are: products therefrom is not the compound of failed call protection in the claim 24
Wherein
R
1To R
5Independent separately expression:
Hydrogen atom;
C
1-C
6Alkyl, C
3-C
8-cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxycarbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8-cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base, wherein each group is replaced once or several: C by following group alternatively
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, CO
2H, SO
3H, amino, C
1-C
6Alkylamino, two C
1-C
6Alkylamino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Or OCF
3
CO
2H；
SO
3H；
Amino;
The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl;
Dibasic amino of following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen atom and C
1-C
6Alkyl, wherein the methylene group in general formula (II) is alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice;
CONH
2；
SO
2NH
2；
Amido functional group is selected from down the residue replacement CONH once or twice of group
2Or SO
2NH
2: C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
6Alkyl is wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring;
Thiol group;
Hydroxyl;
Nitro;
Cyano group;
Fluorosulfonyl;
Be selected from the halogen atom of fluorine atom, chlorine atom, bromine atoms, iodine atom;
CF
3；
OCF
3Perhaps
Replaced once by following group alternatively or saturated, unsaturated or aromatic heterocycle system: the C of maximum 10 atoms for several times
1-C
6Alkyl, C
1-C
6Alkoxyl group, COOH, SO
3H, amino, thiol group, hydroxyl, nitro, cyano group, fluorine atom, chlorine atom, bromine atoms, iodine atom, CF
3Or OCF
3
And R wherein
1To R
5Thereby in can become key to form more than two to condense saturated, unsaturated or aromatics homogeneity member ring systems or heterocyclic system arbitrarily;
M represents 0,1,2,3,4,5 or 6;
Y represents:
A) hydrogen atom;
B) C
1-C
18-alkyl, single unsaturated or how unsaturated C
2-C
18Alkylene, C
3-C
8Cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxy carbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8Cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Saturated, the unsaturated or aromatic heterocycle system of aryl sulphur oxygen base or maximum 10 atoms, wherein each group is selectively replaced once or several by following group:
B1) C
1-C
6Alkyl, C
3-C
8Cycloalkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
6-C
10Aryl-C
1-C
8Alkoxyl group, C
1-C
6Carbalkoxy, C
6-C
10Aryloxy carbonyl, C
6-C
10Aryl-C
1-C
8Carbalkoxy, C
1-C
6-alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
6-C
10Aryl-C
1-C
8Alkyl carbonyl, C
1-C
6Alkane carboxyl, C
6-C
10Virtue carboxyl, C
1-C
6Alkane sulfydryl, C
6-C
10Aromatic thiohydroxy, C
1-C
6Alkane sulfydryl carbonyl, C
3-C
8Cycloalkanes sulfydryl carbonyl, C
6-C
10Aromatic thiohydroxy carbonyl, C
1-C
6Alkane sulfydryl carboxyl, C
6-C
10Aromatic thiohydroxy carboxyl, C
1-C
6Alkyl sulphonyl, C
6-C
10Aryl sulfonyl, C
1-C
6Alkyl sulfide oxygen base, C
6-C
10Aryl sulphur oxygen base; Wherein each group is selectively replaced once or several: C by following group
1-C
6Alkyl; C
1-C
6Alkoxyl group; CONH
2SO
2NH
2Amido functional group is by C
1-C
6Alkyl replaces CONH once or twice
2Or SO
2NH
2SO
3H; CO
2H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
Wherein, thus several substituting groups b1) can become key to form to condense saturated, unsaturated or aromatics homogeneity member ring systems or heterocyclic system;
Perhaps
B2) hydroxyl; Thiol group; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3CO
2H; SO
3H; OCF
3CONH
2SO
2NH
2Amido functional group is selected from C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
6The residue of alkyl replaces CONH once or twice
2Or SO
2NH
2, wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Dibasic amino of perhaps following general formula (II):
Wherein o represents 0 or 1, and W represents O, CH
2, or NR
6, R wherein
6Be selected from hydrogen atom and C
1-C
6Alkyl, wherein the methylene group in general formula (II) is alternatively by C
1-C
6Alkyl, fluorine atom or chlorine atom replace once or twice;
Perhaps
B3) saturated, the unsaturated or aromatic heterocycle system of maximum 10 atoms, this heterocyclic system are replaced once or several: C by following group alternatively
1-C
6Alkyl; C
1-C
6Alkoxyl group; COOH; CONH
2SO
2NH
2Amido functional group is by C
1-C
6Alkyl replaces CONH once or twice
2Or SO
2NH
2SO
3H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
6Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorine atom; The chlorine atom; Bromine atoms; The iodine atom; CF
3Perhaps OCF
3
C) SO
3H; Amino; The residue that is selected from down group replaces once above amino: C
1-C
6Alkyl, C
6-C
10Aryl, C
6-C
10Aryl-C
1-C
8Alkyl, C
1-C
6Alkyl carbonyl, C
6-C
10Aromatic carbonyl, C
1-C
6Alkyl sulphonyl and C
6-C
10Aryl sulfonyl; CONH
2SO
2NH
2Amido functional group is selected from C
1-C
6Alkyl, C
6-C
10Aryl or C
6-C
10Aryl-C
1-C
4The residue of alkyl replaces CONH once or twice
2Or SO
2NH
2, wherein at two-C
1-C
6Under the situation of alkyl-substituted-amino functional group, thereby alkyl residue can become key to form five-ring or six-ring; Thiol group; Hydroxyl; Nitro; Cyano group; Fluorosulfonyl; Be selected from the halogen atom of fluorine atom, chlorine atom, bromine atoms or iodine atom; CF
3Or OCF
3
90., it is characterized in that Yong finishes by carbonyl chloride, carbonyl dimidazoles or carbonic ether in the cyclisation of Xing Cheng oxadiazole ketone member ring systems as the described preparation method of claim 89.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US930207P | 2007-12-27 | 2007-12-27 | |
| US61/009,302 | 2007-12-27 | ||
| PCT/PT2008/000054 WO2009084970A1 (en) | 2007-12-27 | 2008-12-23 | 5-o-substituted 3-n-phenyl-1,3,4-oxadiazolones for medical use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101959881A true CN101959881A (en) | 2011-01-26 |
Family
ID=40361548
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008801276810A Pending CN101959881A (en) | 2007-12-27 | 2008-12-23 | The 5-O-that is used for medical use replaces 3-N-phenyl-1,3,4-oxadiazole ketone |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP2238131A1 (en) |
| JP (1) | JP2011507952A (en) |
| KR (1) | KR20100111691A (en) |
| CN (1) | CN101959881A (en) |
| AR (1) | AR069970A1 (en) |
| AU (1) | AU2008344032A1 (en) |
| BR (1) | BRPI0821482A2 (en) |
| CA (1) | CA2710743A1 (en) |
| CL (1) | CL2008003895A1 (en) |
| IL (1) | IL206419A0 (en) |
| MX (1) | MX2010006995A (en) |
| TW (1) | TW200932732A (en) |
| WO (1) | WO2009084970A1 (en) |
| ZA (1) | ZA201005306B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| TW201028406A (en) * | 2008-12-23 | 2010-08-01 | Bial Portela & Ca Sa | 5-O-substituted 3-N-aryl-1,3,4-oxadiazolones for medical use |
| AR076687A1 (en) * | 2009-05-18 | 2011-06-29 | Infinity Pharmaceuticals Inc | ISOXAZOLINS AS INHIBITORS OF THE AMIDAHIDROLASA OF FATTY ACIDS AND PHARMACEUTICAL COM-POSITIONS CONTAINING THEM |
| WO2010151160A1 (en) * | 2009-06-24 | 2010-12-29 | Bial - Portela & Ca., S.A. | O-substituted 3-n-heteroaryl-1,3,4-oxadiazolones for medical use |
| US20130150346A1 (en) | 2010-01-08 | 2013-06-13 | Quest Ventures Ltd. | Use of FAAH Inhibitors for Treating Parkinson's Disease and Restless Legs Syndrome |
| WO2011123719A2 (en) | 2010-03-31 | 2011-10-06 | Ironwood Pharmaceuticals, Inc. | Use of faah inhibitors for treating abdominal, visceral and pelvic pain |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3931843A1 (en) * | 1989-09-23 | 1991-04-04 | Bayer Ag | SUBSTITUTED 1,3,4-OXA (THIA) DIAZOLINONE PROCESS FOR THEIR PREPARATION AND THEIR USE OF THE CONTROL OF ENDOPARASITES |
| DE19942354A1 (en) * | 1999-09-04 | 2001-03-08 | Aventis Pharma Gmbh | Substituted 3-phenyl-5-alkoxi-1,3,4-oxdiazol-2-one, their manufacture and use in medicinal products |
| WO2003043997A1 (en) * | 2001-11-15 | 2003-05-30 | Eli Lilly And Company | Peroxisome proliferator activated receptor alpha agonists |
| DE10208987A1 (en) * | 2002-02-28 | 2003-09-11 | Aventis Pharma Gmbh | Substituted 3-phenyl-5-alkoxy-1,3,4-oxidiazol-2-ones, their preparation and use in drugs |
| US20090111778A1 (en) * | 2005-11-18 | 2009-04-30 | Richard Apodaca | 2-Keto-Oxazoles as Modulators of Fatty Acid Amide Hydrolase |
-
2008
- 2008-12-23 CN CN2008801276810A patent/CN101959881A/en active Pending
- 2008-12-23 AR ARP080105707A patent/AR069970A1/en unknown
- 2008-12-23 AU AU2008344032A patent/AU2008344032A1/en not_active Abandoned
- 2008-12-23 KR KR1020107015516A patent/KR20100111691A/en not_active Application Discontinuation
- 2008-12-23 MX MX2010006995A patent/MX2010006995A/en not_active Application Discontinuation
- 2008-12-23 TW TW097150238A patent/TW200932732A/en unknown
- 2008-12-23 CA CA2710743A patent/CA2710743A1/en not_active Abandoned
- 2008-12-23 WO PCT/PT2008/000054 patent/WO2009084970A1/en active Application Filing
- 2008-12-23 CL CL2008003895A patent/CL2008003895A1/en unknown
- 2008-12-23 BR BRPI0821482-4A patent/BRPI0821482A2/en not_active IP Right Cessation
- 2008-12-23 EP EP08866782A patent/EP2238131A1/en not_active Withdrawn
- 2008-12-23 JP JP2010540610A patent/JP2011507952A/en not_active Withdrawn
-
2010
- 2010-06-16 IL IL206419A patent/IL206419A0/en unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| ZA201005306B (en) | 2011-04-28 |
| EP2238131A1 (en) | 2010-10-13 |
| IL206419A0 (en) | 2010-12-30 |
| MX2010006995A (en) | 2010-08-18 |
| AR069970A1 (en) | 2010-03-03 |
| WO2009084970A1 (en) | 2009-07-09 |
| AU2008344032A1 (en) | 2009-07-09 |
| CA2710743A1 (en) | 2009-07-09 |
| BRPI0821482A2 (en) | 2015-07-14 |
| AU2008344032A8 (en) | 2010-08-19 |
| JP2011507952A (en) | 2011-03-10 |
| TW200932732A (en) | 2009-08-01 |
| CL2008003895A1 (en) | 2010-06-25 |
| KR20100111691A (en) | 2010-10-15 |
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Open date: 20110126 |