CN1871235A - Azabicyclic-substituted fused heteroaryl compounds for the treatment of disease - Google Patents
Azabicyclic-substituted fused heteroaryl compounds for the treatment of disease Download PDFInfo
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- CN1871235A CN1871235A CN 02824179 CN02824179A CN1871235A CN 1871235 A CN1871235 A CN 1871235A CN 02824179 CN02824179 CN 02824179 CN 02824179 A CN02824179 A CN 02824179A CN 1871235 A CN1871235 A CN 1871235A
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- pyridine
- carboxylic acid
- acid amides
- azabicyclic
- oct
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
The invention provides compounds of Formula (I), wherein Azabicyclo is formulas (II-VII), W is formulas (VIII-X). These compounds may be in the form of pharmaceutical salts or compositions, racemic mixtures, or pure enantiomers thereof. The compounds of Formula I are useful in pharmaceuticals in which alpha 7 is known to be involved.
Description
Invention field
NAChR (nAChRs) plays an important role in central nervous system (CNS) activity.Particularly, known they relate to cognition, study, mood, emotion and neuroprotective.As if nAChR has broad variety, and the different effect of performance in regulating the CNS function of various acceptor.Nicotine influences all these acceptors and has various active.Disadvantageously, not all these activity are all expected.In fact, at least a unwanted nicotine characteristic is that its habituation characteristic and the ratio of validity and security is lower.The present invention relates to a kind of method molecule, this molecule to the effect of α 7nAChRs greater than its effect to other the most close members of this part-gate receptor family.Therefore, the invention provides active drug molecule compound with less side effect.
Background of invention
The normally good and effective drug targets of cell surface receptor.NAChRs comprises the part-gated ion channel of a big class control nervous activity and brain function.These acceptors have the pentamer structure.In Mammals, this gene family is made up of nine α and four β subunits, is assembled into the multiple receptor subtype with different pharmacological actions jointly.Vagusstoff is the endogenous conditioning agent of all these receptor subtypes, and nicotine non-selectively activates all nAChRs.
α 7 nAChR are a kind of acceptor systems that are proved to be to the target that is difficult to be used to test.Natural α 7nAChR usually can not be in most of mammal cell lines stably express (Cooper and Millar, J.Neurochem., 1997,68 (5): 2140-51).Another feature that makes the functional selection of α 7 nAChR become challenge is acceptor rapid deactivation (100 milliseconds).This rapid deactivation has greatly limited the functional selection that is used for measuring channel activity.
Recently, Eisele etc. indicate by α 7 nAChR N end ligand binding domain (Eisele etc., Nature, 366 (6454), p479-83,1993), and 5-HT
3The mosaic type acceptor that acceptor C-stomidium formation structural domain forms is expressed in the XenoPus ovocyte and is well kept nicotinic agonist susceptibility simultaneously.Eisele etc. have used the N-end and the mouse 5-HT of bird (bird) α 7 nAChR acceptors
3The C-end of gene.But under physiological condition, α 7 nAChR are calcium channel and 5-HT
3R is sodium and potassium channel.Really, instruction such as Eisele bird α 7 nAChR/ mouse 5-HT
3R is different fully with natural α 7 nAChR performance, and bore portion does not conduct calcium ion and in fact blocked by calcium ion.WO00/73431A2 has reported a kind of analysis condition, 5-HT under this condition
3R can conduct calcium ion.This analytical procedure can be used to screen the agonist activity of this receptor.
United States Patent (USP) 6,054,464 disclose and can be used for treatment, especially for the carbamic azabicyclic ester class of treatment or the imbalance of prevention psychataxia and intellectual damage, and intermediate and the purposes of intermediate in synthetic.
United States Patent (USP) 5,977,144 disclose Ben Yajiaji-and the composition of Chinese cassia tree subunit-neonicotine and utilize said composition treatment nicotine hypotype brain acceptor defect or the malfunction disease that is associated.These compositions act on α 7 receptor subtypes, the less or not effect to the activation of α 4 β 2 or other receptor subtypes.
United States Patent (USP) 5,599,937 disclose the assorted fragrant rubane that is used for the treatment of the disease relevant with muscarinic function of receptors.
United States Patent (USP) 5,561,149 disclose single or two ring carbocyclic rings or heterocyclic carboxylic acid, ester or acid amides or imidazolyl carbazole is being used for preparing the psychataxia that is suitable for treating pressure correlation, is being used to increase vigilance, is being used for the treatment of rhinitis or serotonin-imbalance that causes and/or with other active medicine Combined Preparation to increase its bioavailability or to be used for the purposes of the medication preparation of nasal administration.
United States Patent (USP) 5,543,426 disclose some 3,7-disubstituted indole compound is used for the treatment of the purposes of dysthymia disorders or awareness imbalance.
United States Patent (USP) 5,434,161 disclose as serotonin energy 5-HT
3Antagonist imidazole and pyridine.
United States Patent (USP) 5,362,740 disclose the Dihydrobenzofuranes carboxylic acid amides, can be used for treatment CNS imbalance in the Mammals, but except the mobility imbalance, and/or vomiting and/or pain, and/or migraine.
United States Patent (USP) 5,352,685 disclose thieno-[3,2-b] pyridine derivate, can be effective to prevent and syndrome that the hypofunction of therapeutic treatment peristole causes, for example pained, abdominal distension sensation, appetite stimulator, the offending sensation of epigastrium, stomachache, feel sick, for example acute and chronic gastritis, stomach and duodenal ulcer that potential disease such as vomiting causes, stomach neurosis, gastroptosis etc.
United States Patent (USP) 5,342,845 disclose indole derivatives and medicine.The compound of this disclosure of the Invention can be used as gastrointestinal movement active regulator, anti-migraine medicine, tranquilizer or anti anxiety agent thing effectively and and be used for dementia or postural hypotension.
United States Patent (USP) 5,322,951 disclose some 1-(2,3-dihydro-indoles) carbonyl intermediates, can be used for preparing 1-(2, the 3-the dihydro)-1-carboxylic acid amides end product with 5-HT M-receptor antagonist activity.
United States Patent (USP) 5,272,154 disclose 3,7-substituted indole and indazole compound and comprise their pharmaceutical composition and disclose and can be used for treating moral ataxia.
United States Patent (USP) 5,217,975 disclose the Azabicyclic compound that is used for the treatment of dementia.
United States Patent (USP) 5,039,680 disclose the prevention or alleviate the dependent 5-HT of dependency inductor
3Antagonist.
United States Patent (USP) 5,001,133 disclose and have been the substituted benzoic acid heterocycleamide and the ester of serotonin M antagonist.
United States Patent (USP) 4,985,437 disclose some compound as serotonine (5-HT) at 5-HT
3The purposes of receptor antagonist is used for the treatment of awareness lack of proper care for example attention and memory deficit and dull-witted situation.
United States Patent (USP) 4,983,600 disclose as 5-HT
3The heterogeneous ring compound of antagonist.
United States Patent (USP) 4,973,594 disclose as serotonine (5-HT) at 5-HT
3The compound of receptor antagonist is used for the treatment of the purposes of dysthymia disorders.
United States Patent (USP) 4,937,247 disclose and have had 5HT
3The 1-acyl group indazole of antagonistic activity.
United States Patent (USP) 4,935,511 disclose benzoxazine and benzo oxa-nitrogen heterocyclic heptantriene carboxylic acid amides 5-HT
3Antagonist properties comprises that CNS, vomiting suppress and the short locomotor activity of stomach, and it is without any significant D
2Receptors bind avidity.
United States Patent (USP) 4,921,982 disclose the 5-halo-2 of the intermediate that can be used as the 5-HT3 antagonist, 3-dihydro-2,2-dimethyl benzofuran-7-carboxylic acid.
United States Patent (USP) 4,920,219 disclose replace saturated and undersaturated indoles quinoline and benzo-aza cycloheptatriene carboxylic acid amides with and as 5-HT
3The useful purposes of antagonist has the short locomotor activity of CNS and stomach, does not have any significant D
2Receptors bind character.
United States Patent (USP) 4,920,127 disclose substituted indole and as 5-HT
3The purposes of receptor antagonist.
United States Patent (USP) 4,910,193 disclose the treatment of gastro intestinal disorders.
United States Patent (USP) 4,888,353 disclose the carboxylic acid amides as antiemetic or antipsychotic drug.
United States Patent (USP) 4,882,327 disclose some has 5-HT
3The heterocyclic N-of receptor antagonist activity replaces carboxylic acid amides.
United States Patent (USP) 4,845,092 discloses the method that Mammals comprises visceral pain in the human body for the treatment of.
United States Patent (USP) 4,835,162 disclose nicotinic agonist and the antagonist as smoking suppressant.
United States Patent (USP) 4,822,795 disclose pharmaceutically useful ester and acid amides.
United States Patent (USP) 4,803,199 disclose the peperidine of pharmaceutically useful heterocyclic acid esters and acid amides or alkylidene group bridging as serotonin M antagonist.
United States Patent (USP) 4,798,829 disclose 1-azabicyclic [3.2.2] nonane derivatives, and having the stomach motion increases active and/or vomiting inhibition activity and/or 5-HT receptor antagonist activity.
United States Patent (USP) 4,797,406 disclose that acid amides and ester comprise the piperidines of bridging and as serotonin M antagonist.
United States Patent (USP) 4,721,720 disclose a kind of method for the treatment of vomiting, anxiety disorder and/or irritable bowel syndrome.
United States Patent (USP) 4,612, the 319 quinoline alkylamides that disclose bridging, comprise them composition with and using method.
United States Patent (USP) 4,605,652 disclose and a kind ofly improve one's memory or correct the insufficient method of memory deficit, utilize aryl amido group (and aryl thioamides base)-azabicyclic alkane, with and medicinal acid addition salt, hydrate and alcohol adduct.
WO01/60821A1 discloses novel dibenzyl carboxylic acid amides and their purposes in treatment, in particular for the prophylactic treatment of psychotic disorder and intellectual damage disease.
WO01/36417A1 discloses novel N-azabicyclic-amide derivatives and therepic use, especially for the prophylactic treatment of mental disorder and intellectual damage imbalance.
WO00/73431A2 discloses two kinds of binding analysis, is used for directly measuring compound to α 7nAChR and 5-HT
3R avidity and selectivity.These applied in any combination functional and binding analysis can be used to be identified as the compound of selectivity α 7 nAChR agonists.
WO99/20633 discloses has 5-HT
3/ 5-HT
4The benzoazine derivative of receptor antagonist activity.
WO97/35860 discloses the novel benzimidazole derivatives derivative, to these serotoninergic 5-HT
3/ 5-HT
4Acceptor has avidity.
WO96/33186 discloses as 5-HT
4The substituted-dihydro benzofuran derivative of agonist.
WO95/27490 discloses the 5-hydroxytryptamine antagonist (5-HT that is used for the treatment of fibromyalgia
3).
WO95/04742 discloses the tropyl 7-azaindole-3-yl-carboxamides as antitussive.
WO92/10494 discloses and has been 5-HT
3The new compound of receptor antagonist.
WO91/17161 discloses as 5-HT
3The isoquinoline 99.9 acid amides and the ester of receptor antagonist.
WO91/09593 discloses 5-HT
3Antagonist be used for the treatment of relevant with myocardium unstable feel sick, bradyrhythmia or hypopiesia.
WO90/14347A at chemical abstracts 1991:143, discloses the N-quinuclidinyl-indoles carboxamide derivative as antiemetic with the form of digest in 158.
EP512350A2 discloses 3-(indyl-2-carboxamide groups) quinine alkali, and being used for the treatment of with susceptibility superfluous to serotonin or that increase is the disease of feature, and psychosis is for example felt sick, vomiting, dull-witted or other cognitive disorderss, migraine, diabetes.Described compound can be used to control anxiety disorder, aggressiveness, dysthymia disorders and pain.These compounds openly can be used as serotonin 5-HT
3Antagonist.
EP496064A1 discloses a kind of method for preparing the substituted benzene benzofuran derivs.Described compound openly can be used as 5-HT
3Receptor antagonist.
EP483836A1 discloses pyrazolo [1,5-a] pyridine-3-carboxylic acid derivative, its preparation method and comprise their 5-hydroxytryptamine receptor antagonists as activeconstituents.
DE3810552A1 disclose indyl-, benzo [b] thienyl-, benzo [b] furancarboxylic acid or 4-amino-2 methoxyl group-benzoic ester and acid amides and N heterocyclic or N-hetero-bicyclic alcohol or amine.Disclosed these compounds have the particularly activity of migraine of inhibition of pain, as anti-arrhythmic, be used for the treatment of gastrointestinal disturbance, stomach disorder, stomach ulcer, gall-bladder, spastic colon, Crohn disease, ulcerative colitis, carcinoid syndrome, polytype diarrhoea.These compounds also openly can quicken stomach emptying, control gastroduodenal and gastroesophageal reflux, oesophagus motion disorder, HH, cardiac insufficiency, gastric hypotonus, paralytic ileus, manic depressive psychosis and other psychosis.These compounds also openly can be used for disease, the aging of pressure correlation, and the snuffing receipts that increase other drug, for example, are used for the treatment of vomiting.
At Bioorg.﹠amp; Among Med.Chen.Lett.11 (2001) 319-321,5-HT
3Antagonist tropisetron (ICS205-930) has been discussed as alpha 7 nicotinic acceptor portion agonist effectively and optionally.
At Behavoral Brain Res., brain alpha 7 nicotinic acceptor has been discussed for being used for the treatment of the sick critical treatment target of Alzheimer (family name) among 113 (2000) 169-181, utilize the DMXBA that is known as GTS-21.
At Bioorg.﹠amp; Among Med.Chem.Lett.9 (1999) 1895-1900, the muscarinic M1 agonist of finding high reactivity, functionally selective has been discussed.
At Bioorg.﹠amp; Among Med.Chem.Lett.4 (1994) 695-698, pyrazolo [1, a] pyridine and pyrazolo [1,5-b] pyridazine have been discussed as 5-HT
3Antagonist.
At Eur.J Med.Chena., 34 (1999) 415-422, benzimidazolyl-2 radicals-carboxylic acid amide and ester have been discussed the 5-HT that can be used as the new texture type
3Part.
Summary of the invention
The invention discloses the compound of formula I:
Formula I
Wherein Azabicyclo is
W is
Condition is-C (=X)-chemical bond between group and the W group can connect as at R
3, R
6And R
15Any in the W group that provides becomes on the key carbon atom;
X is O or S;
R
0Be H, low alkyl group, replacement low alkyl group or junior alkyl halides;
Each R
1Be H, alkyl, cycloalkyl, haloalkyl, substituted-phenyl or substituted naphthyl;
Each R
2Be alkyl, cycloalkyl, aryl, F, Cl, Br, the I of alkyl, haloalkyl, replacement, or R
2Do not exist, condition is k
2, k
5Or k
6Be 0;
R
2-3Alkyl, haloalkyl, F, Cl, Br or I for H, alkyl, replacement;
k
2Be 0 or 1;
k
5And k
6Independently 0,1 or 2;
A---A '---A " is N (R
4)-C (R
3)=C (R
3), N=C (R
3)-C (R
15)
2, C (R
3)=C (R
3)-N (R
4), C (R
3)
2-N (R
4)-C (R
3)
2, C (R
15)
2-C (R
3)=N, N (R
4)-C (R
3)
2-C (R
3)
2, C (R
3)
2-C (R
3)
2-N (R
4), O-C (R
3)=C (R
3), O-C (R
3)
2-C (R
3)
2, C (R
3)
2-O-C (R
3)
2, C (R
3)=C (R
3)-O, C (R
3)
2-C (R
3)
2-O, S-C (R
3)=C (R
3), S-C (R
3)
2-C (R
3)
2, C (R
3)
2-S-C (R
3)
2, C (R
3)=C (R
3)-S or C (R
3)
2-C (R
3)
2-S;
Each R
3The chemical bond condition that links to each other for core element is to have only a R independently
3And there is not R
6Or R
5Also be this chemical bond, H, alkyl, replacement alkyl, haloalkyl, alkenyl, substituted alkenyl base, halogenated alkenyl, alkynyl, substituted alkynyl, halo alkynyl ,-CN ,-NO
2, F, Br, Cl, I ,-OR
19,-C (O) N (R
10)
2,-N (R
10)
2,-SR
19,-S (O)
2R
19,-C (O) R
19,-CO
2R
19, aryl, R
7Or R
9
J, L, M and Q are N or C (R
6), condition is to have only to be a N among J, L, M or the Q, and other groups are C (R
6), and further condition is that Q is C (H) when core element connects pyridyl in the M position, and further condition is only to exist one to be connected with core element;
G and Y are C (R
6), condition is when molecule is connected to the phenyl composition at the Y place, G is CH;
R
4Alkyl, cycloalkyl, halogenated cycloalkyl, the cycloalkyl of replacement, Heterocyclylalkyl, halogenated heterocycloalkyl, substituted heterocycle alkyl, R for H, alkyl, haloalkyl, replacement
7Or R
9
Each R
5Be H, low alkyl group or low-grade alkenyl independently;
Each R
6Be independently H, F, Br, I, Cl ,-CN ,-CF
3,-OR
5,-SR
5,-N (R
5)
2, with the chemical bond condition of core element bonding be to have only a R
6And there is not R
3Or R
15Be described key;
V is selected from O, S or N (R
4);
R
7Be the assorted fragrant monocycle composition of 5-person, comprise 1-3 in the ring to be independently selected from=N-,-N (R
17)-,-O-and-heteroatoms of S-, and have 0-1 and be selected from R
18Substituting group and further have 0-3 substituting group, described substituting group is independently selected from F, Cl, Br or I, or R
7Be fused to 9-person's fused rings composition that 5-person encircles for having 6-person's ring, comprise following formula
G wherein
1Be O, S or NR
17,
Wherein G is C (R
16) or N, and each G
2And G
3Be independently selected from C (R
16)
2, C (R
16), O, S, N and N (R
18), condition is G
2And G
3Be not O simultaneously, be not S simultaneously, or be not O and S simultaneously, or
Wherein G is C (R
16) or N, and each G
2And G
3Be independently selected from C (R
16)
2, C (R
16), O, S, N and N (R
17), each 9-person's fused rings composition has 0-1 and is selected from R
18Substituting group, and further have the substituting group that 0-3 is independently selected from F, Cl, Br or I, wherein R
7During composition is connected to suc as formula I under the condition that valence link allows on defined other substituting groups on any position of arbitrary ring;
Each R
8Be alkyl, cycloalkyl, halogenated cycloalkyl, the cycloalkyl of replacement, Heterocyclylalkyl, halogenated heterocycloalkyl, substituted heterocycle alkyl, the R of H, alkyl, haloalkyl, replacement independently
7, R
9, phenyl or substituted-phenyl;
R
9Be the assorted fragrant monocycle composition of 6-person, in ring, comprise 1-3 to be selected from=heteroatoms of N-and have 0-1 and be selected from R
18Substituting group and the 0-3 substituting group that is independently selected from F, Cl, Br or I, or R
9Be 10 Yuans assorted fragrance two ring compositions, in one or two ring, comprise 1-3 to be selected from=heteroatoms of N-, include but not limited to that quinolyl or isoquinolyl, each 10-person's fused rings composition have 0-1 and be selected from R
18Substituting group and the 0-3 substituting group that is independently selected from F, Cl, Br or I, and when valence link allows, have the valence link that directly or indirectly links to each other with core element;
Each R
10Be H, alkyl, cycloalkyl, Heterocyclylalkyl independently, be selected from R by 1
13The alkyl that replaces of substituting group, be selected from R by 1
13The cycloalkyl that replaces of substituting group, be selected from R by 1
13The substituting group Heterocyclylalkyl, haloalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, phenyl or the substituted-phenyl that replace;
Each R
11Be H, alkyl, cycloalkyl, Heterocyclylalkyl, haloalkyl, halogenated cycloalkyl or halogenated heterocycloalkyl independently;
R
12For-NO
2The alkyl of ,-CN, alkyl, cycloalkyl, Heterocyclylalkyl, haloalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, replacement, the cycloalkyl of replacement, substituted heterocycle alkyl ,-OR
11,-SR
11,-NR
11R
11,-C (O) R
11,-C (O) NR
11R
11,-NR
11C (O) R
11,-S (O)
2NR
11R
11Or-NR
11S (O)
2R
11
R
13For-CN ,-CF
3,-NO
2,-OR
11,-SR
11,-NR
11R
11,-C (O) R
11,-C (O) NR
11R
11,-NR
11C (O) R
11,-S (O)
2NR
11R
11Or-NR
11S (O) R
11
Each R
14For the alkyl of H, alkyl, replacement, haloalkyl, alkenyl, substituted alkenyl base, halogenated alkenyl, alkynyl, substituted alkynyl, halo alkynyl, F, Br, Cl, I ,-CN ,-NO
2,-OR
19,-C (O) N (R
10)
2,-N (R
10)
2,-SR
19,-S (O)
2R
19,-C (O) R
19,-CO
2R
19, aryl, R
7Or R
9
Each R
15Be independently alkyl, replacement alkyl, haloalkyl, alkenyl, substituted alkenyl base, halogenated alkenyl, alkynyl, substituted alkynyl, halo alkynyl, F, Br, Cl, I ,-CN ,-NO
2,-OR
19,-C (O) N (R
10)
2,-N (R
10)
2,-SR
19,-CO
2R
19, aryl, R
7, R
9, with the valence link of core element bonding, condition is to have only a R
15And there is not R
6Or R
3Be described valence link;
Each R
16Be independently alkyl, the replacement of H, alkyl, cycloalkyl, Heterocyclylalkyl, haloalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, replacement cycloalkyl, substituted heterocycle alkyl, F, Cl, Br, I ,-NO
2,-CN ,-OR
11,-SR
11,-NR
11R
11,-C (O) R
11,-C (O) NR
11R
11,-NR
11C (O) R
11,-S (O)
2NR
11R
11,-NR
11S (O)
2R
11, the valence link that directly or indirectly links to each other with core element, condition is only to have a described valence link that links to each other with core element in 9-person's fused rings composition, other condition is that the fused rings composition has 0-1 substituting group, described substituting group be selected from alkyl, the replacement of alkyl, cycloalkyl, Heterocyclylalkyl, haloalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, replacement cycloalkyl, substituted heterocycle alkyl ,-OR
11,-SR
11,-NR
11R
11,-C (O) R
11,-NO
2,-C (O) NR
11R
11,-CN ,-NR
11C (O) R
11,-S (O)
2NR
11R
11Or-NR
11S (O) R
11, and other condition is that the fused rings composition has 0-3 substituting group that is selected from F, Cl, Br or I;
R
17For the cycloalkyl of the alkyl of H, alkyl, haloalkyl, replacement, cycloalkyl, halogenated cycloalkyl, replacement, phenyl ,-SO
2R
8Or have 1 and be selected from R
18Substituting group and further have 0-3 and be independently selected from the substituent phenyl of F, Cl, Br or I;
R
18For alkyl, cycloalkyl, Heterocyclylalkyl, haloalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl ,-OR
11,-SR
11,-NR
11R
11,-C (O) R
11,-C (O) NR
11R
11,-CN ,-NR
11C (O) R
11,-S (O)
2NR
11R
11,-NR
11S (O)
2R
11,-NO
2, be independently selected from F, Cl, Br, I or R by 1-4
13The alkyl that replaces of substituting group, be independently selected from F, Cl, Br, I or R by 1-4
13The cycloalkyl that replaces of substituting group or be independently selected from F, Cl, Br, I or R by 1-4
13The Heterocyclylalkyl that replaces of substituting group;
R
19Alkyl, haloalkyl, substituted-phenyl or substituted naphthyl for H, alkyl, cycloalkyl, replacement;
Or its pharmacologically acceptable salt, racemic mixture and pure enantiomorph.
Formula I compound can be used for treating disease or illness, wherein disease, imbalance and/or illness are following any or multiple or its combination: alzheimer's cognition and attention deficit syndrome, with disease Alzheimer's for example, the nerve retrograde affection that morning, old dementia (mild cognitive impairment) or senile dementia were associated, schizophrenia or psychosis, attention deficit or attention deficit superfunction imbalance, dysthymia disorders, anxiety disorder and common anxiety disorder imbalance and the pressure imbalance of wound back, mood and disorder of affect, amyotrophic lateral sclerosis, the borderline personality imbalance, traumatic brain injury, behavior that generality and cerebral tumor are associated and cognitive question, the AIDS chronic brain syndrome, the dementia that mongolism is associated, the dementia that Lu Yiti is associated, the Heng Yandunshi disease, Parkinson's disease, tardive dyskinesia, creutzfeldt jakob disease, the ingestion of food imbalance comprises exessive appetite and anorexia nervosa, smoking cessation and dependent drug are given up the withdrawal symptoms that is associated, lucky tired this moral Latourette Cotard, the macula lutea degenerative change relevant with the age, glaucoma, the syndrome that nerve retrograde affection that glaucoma is associated or pain are associated.
Embodiment of the present invention comprise following one or more or its combination:
Formula I compound, wherein X is O.
Formula I compound, wherein X is S.
Formula I compound, wherein Azabicyclo is one or more I, II, III, IV, V or VI.
Formula I compound, wherein W is one or more (a) and (b) or (c).
Formula I compound, wherein W is one or more following radicals:
Thieno-[2,3-b] pyridine-2-base, thieno-[2,3-b] pyridine-5-base, thieno-[2,3-b] pyridine-6-base, thieno-[3,2-b] pyridine-2-base, thieno-[3,2-b] pyridine-5-base, thieno-[3,2-b] pyridine-6-base, thieno-[2,3-c] pyridine-2-base, thieno-[2,3-c] pyridine-5-base, thieno-[3,2-c] pyridine-2-base, thieno-[3,2-c] pyridine-6-base, furo [3,2-c] pyridine-2-base, furo [3,2-c] pyridine-6-base, furo [2,3-b] pyridine-2-base, furo [2,3-c] pyridine-2-base, furo [2,3-c] pyridine-5-base, 2, the 3-dihydrofuran is [2,3-c] pyridine-5-base or 1H-pyrrolo-[2,3-c] pyridine-5-base also, thieno-[3,4-c] pyridine-6-base, thionaphthene also [3,2-c] pyridin-3-yl, thionaphthene is [2,3-c] pyridin-3-yl also, cumarone is [3,2-c] pyridin-3-yl also, or cumarone also [2,3-c] pyridin-3-yl
Arbitrary group randomly under the valence link permission situation on 4 different carbon atoms at the most by F, Br in the W definition, Cl, I ,-CN ,-NO
2,-CF
3,-OR
5,-OR
19,-SR
5,-SR
19,-N (R
5)
2,-N (R
10)
2,-C (O) R
19,-CO
2R
19,-C (O) N (R
10)
2,-S (O)
2R
19, alkyl, the alkyl of replacement, haloalkyl, alkenyl, substituted alkenyl base, halogenated alkenyl, alkynyl, substituted alkynyl, halo alkynyl, aryl, R
7, R
9Replace,
And arbitrary further group is chosen wantonly on nitrogen by alkyl, haloalkyl, the alkyl of replacement, cycloalkyl, halogenated cycloalkyl, the cycloalkyl of replacement, Heterocyclylalkyl, halogenated heterocycloalkyl, substituted heterocycle alkyl, R in the W definition
7Or R
9Replace,
Condition is to use a carbon atom that W is bonded on the core element.The composition that common ground, this area technician allows by the composition relatively mentioned and W will be recognized and replace the implication that allows.
Formula I compound, wherein (a) and (b) or (c) optional by in the W definition at the most 4 substituting groups replace, substituting group be F, Br, Cl, I ,-CN ,-CF
3,-OR
5,-SR
5,-N (R
5)
2,-C (O) R
5,-CO
2R
5,-C (O) N (R
10)
2,-S (O)
2R
5, low alkyl group, replacement low alkyl group or low-grade alkynyl replace,
Each R
10Be H, alkyl, cycloalkyl, Heterocyclylalkyl independently, be selected from R by 1
13The alkyl that replaces of substituting group, be selected from R by 1
13The cycloalkyl that replaces of substituting group, be selected from R by 1
13The substituting group Heterocyclylalkyl, haloalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, phenyl or the substituted-phenyl that replace;
R wherein
10Be H, low-grade halogenated alkyl or low alkyl group, randomly by-CN ,-CF
3,-NO
2,-OR
11,-SR
11,-NR
11R
11,-C (O) R
11,-C (O) NR
11R
11,-NR
11C (O) R
11,-S (O)
2NR
11R
11Or-NR
11S (O) R
11Replace, wherein R
11Be H, low alkyl group or low-grade halogenated alkyl or rudimentary substituted alkyl.Those of ordinary skills will recognize wherein-OR
19,-SR
19,-C (O) R
19Or-CO
2R
19Be the group that is allowed to ,-OR
5,-SR
5,-C (O) R
5Or-CO
2R
5Also be the group that is allowed to, because R
5Group in the scope is R
19The subclass of middle group.In addition, this area those skilled in the art can identify the substituting group in can defining with the W of carbon or nitrogen bonding.
Low-grade alkynyl is for having 2～4 carbon atoms and having at least one carbon carbon triple-linked straight chain and branched-chain component.
Other formula I compound comprises wherein R
1Compound for H, alkyl and cycloalkyl.
Another group formula I compound comprises that wherein Azabicyclo is II, V or VI and each k wherein
2, k
5And k
6Be 0 or 1 compound independently.
Another group formula I compound comprises wherein R
2Be the alkyl of alkyl, haloalkyl, replacement, or existence condition not k
2, k
5Or k
6It is 0 compound.
Another group formula I compound comprises wherein R
1Be H or low alkyl group, and R wherein
2For low alkyl group or not existence condition be k
2, k
5Or k
6It is 0 compound.
Another group formula I compound comprises that wherein Azabicyclo is I and R wherein
2Be the alkyl of alkyl, haloalkyl or replacement, or wherein Azabicyclo is III or IV and R wherein
2-3Compound for the alkyl of H, alkyl or replacement.
Formula I compound, wherein compound is the combination of any or multiple following free alkali or pharmacologically acceptable salt, described free alkali or pharmacologically acceptable salt are pure enantiomorph or its racemic mixture:
(S)-N-(1-azabicyclic [2.2.1] heptan-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides outward-4;
(R)-N-(1-azabicyclic [2.2.1] heptan-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides outward-4;
Outward-N-(1-azabicyclic [2.2.1] heptan-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
In (+)-N-[-and 1-azabicyclic [2.2.1] heptan-3-yl] furo [2,3-c] pyridine-5-carboxylic acid amides;
In (-)-N-[-and 1-azabicyclic [2.2.1] heptan-3-yl] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-[(is outer)-azabicyclic [2.2.1] heptan-3-yl] furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(1-azabicyclic [2.2.1]-heptan-3-yl)-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-7-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-7-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-7-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-3,3-dimethyl-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-3,3-dimethyl-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3,3-dimethyl-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-2-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-2-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
(S)-N-(1-azabicyclic [2.2.1] heptan-3-yl)-3-methyl furan [2,3-c] pyridine-5-carboxylic acid amides also outward-4;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-3-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
(outward)-N-[1-azabicyclic [3.2.1] oct-3-yl]-3-methyl furan [2,3-c] pyridine-5-carboxylic acid amides also;
(3R, 5R)-N-[1-azabicyclic [3.2.1] oct-3-yl]-3-methyl furan [2,3-c] pyridine-5-carboxylic acid amides also;
(S)-N-(1-azabicyclic [2.2.1] heptan-3-yl)-3-ethyl furan [2,3-c] pyridine-5-carboxylic acid amides also outward-4;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-3-ethyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-ethyl furan is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-furo [2,3-b] pyridine-2-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-furo [2,3-b] pyridine-2-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-furo [2,3-b] pyridine-2-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-furo [2,3-b] pyridine-2-carboxylic acid amides;
(S)-N-(1-azabicyclic [2.2.1] heptan-3-yl)-3-sec.-propyl furo [2,3-c] pyridine-5-carboxylic acid amides outward-4;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-3-sec.-propyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-sec.-propyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-7-(methylthio group) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-7-(methylthio group) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-7-(methylthio group) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-b] pyridine-2-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-b] pyridine-2-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[2,3-b] pyridine-2-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[2,3-b] pyridine-2-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-b] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-b] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) thieno-[2,3-b] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[2,3-b] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-c] pyridine-2-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-c] pyridine-2-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[2,3-c] pyridine-2-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[2,3-c] pyridine-2-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-b1 pyridine-2-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-b] pyridine-2-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[3,2-b] pyridine-2-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[3,2-b] pyridine-2-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-c] pyridine-2-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-c] pyridine-2-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[3,2-c] pyridine-2-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[3,2-c] pyridine-2-carboxylic acid amides;
Outward-4-N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides; N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
(S)-N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides outward-4;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-1H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides; N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-1H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-1H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-1H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-1-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-1-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-1-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides;
N-(outer-(4S)-1-azabicyclic [2.2.1] heptan-3-yl)-3-bromine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-3-bromine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-bromine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-[is outer-(4S)-and 1-azabicyclic [2.2.1] heptan-3-yl]-3-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-3-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides; Or
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides.
For the compound of all signs, the title of specific enantiomeric not delimit the scope of the invention, and only is used to illustrate.The title of specific enantiomeric comprises the racemic mixture of this compound.For example, outer-4 (S)-N-(1-azabicyclic [2.2.1] heptan-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides comprises outer-(racemization)-N-in the scope of the invention (1-azabicyclic [2.2.1] heptan-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides.When pure enantiomorph was discussed, this compound was racemic mixture or its pure enantiomorph.When Azabicyclo was II, pure enantiomorph comprised outer-4 (S) 1-azabicyclic [2.2.1] heptan-3-base.When Azabicyclo was V, pure enantiomorph comprised outer-3 (R), 5 (R) 1-azabicyclic [2.2.1] oct-3-yl.
Formula I compound, wherein compound is the combination of any or multiple following free alkali or pharmacologically acceptable salt, described free alkali or pharmacologically acceptable salt are pure enantiomorph or its racemic mixture:
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-vinyl furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-ethynyl furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-third-1-alkynyl furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(3-hydroxyl third-1-alkynyl) furo [3,2-c] pyridine-6-carboxylic acid amides;
3-(outer-4 (the S)-1-azabicyclics [2.2.1] of 6-{[heptan-the 3-base is amino] carbonyl } furo [3,2-c] pyridine-2-yl) third-2-acetylenic acid methyl esters;
2-(3-amino-3-oxo third-1-alkynyl)-N-[is outer-(4S)-1-azabicyclic [2.2.1] heptan-3-yl] furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-cyano group furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-chlorine furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-fluorine furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-iodofuran [3,2-c] pyridine-6-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-trifluoromethyl furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(methylthio group) furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(methylamino) furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(formyl radical amino) furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-[formyl radical (methyl) amino] furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-the 2-[(trifluoroacetyl group) amino] furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-6-[heptan-3-yl] furo [3,2-c] pyridine-2, the 6-dicarboxamide;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-formylfuran [3,2-c] pyridine-6-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(trifluoroacetyl group) furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(methyl sulphonyl) furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of 6-{[heptan-the 3-base is amino] carbonyl } furo [3,2-c] pyridine-2-carboxylic acids methyl esters;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-vinyl thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-thiophene acetylene [3,2-c] pyridine-6-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-third-1-alkynyl thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(3-hydroxyl third-1-alkynyl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
3-(outer-4 (the S)-1-azabicyclics [2.2.1] of 6-{[heptan-the 3-base is amino] carbonyl } thieno-[3,2-c] pyridine-2-yl) third-2-acetylenic acid methyl esters
Outer-4 (the S)-1-azabicyclics [2.2.1] of 2-(3-amino-3-oxo third-1-alkynyl)-N-[heptan-3-yl] thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-cyano thiophene [3,2-c] pyridine-6-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-chlorothiophene [3,2-c] pyridine-6-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-fluorine thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-iodothiophen [3,2-c] pyridine-6-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-trifluoromethyl thiophene [3,2-c] pyridine-6-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(methylthio group) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(methylamino) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(formyl radical amino) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-[formyl radical (methyl) amino] thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-the 2-[(trifluoroacetyl group) amino] thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(cyclopropyl amino) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-the 2-[dimethylamino] thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-6-[heptan-3-yl] thieno-[3,2-c] pyridine-2, the 6-dicarboxamide;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-formyl radical thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of 2-ethanoyl-N-[heptan-3-yl] thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(trifluoroacetyl group) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(methyl sulphonyl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of 6-{[heptan-the 3-base is amino] carbonyl } thieno-[3,2-c] pyridine-2-carboxylic acids methyl esters;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-vinyl furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-ethynyl furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-third-1-alkynyl furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(3-hydroxyl third-1-alkynyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
3-(outer-4 (the S)-1-azabicyclics [2.2.1] of 5-{[heptan-the 3-base is amino] carbonyl } furo [2,3-c] pyridin-3-yl) third-2-acetylenic acid methyl esters;
Outer-4 (the S)-1-azabicyclics [2.2.1] of 3-(3-amino-3-oxo third-1-alkynyl)-N-[heptan-3-yl] furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-cyano group furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-fluorine furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-iodofuran [2,3-c] pyridine-5-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-trifluoromethyl furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(methylthio group) furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(methylamino) furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(formyl radical amino) furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-[formyl radical (methyl) amino] furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-the 3-[(trifluoroacetyl group) amino] furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(cyclopropyl amino) furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-the 3-[dimethylamino] furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-5-[heptan-3-yl] furo [2,3-c] pyridine-3, the 5-dicarboxamide;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-formylfuran [2,3-c] pyridine-5-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(trifluoroacetyl group) furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(methyl sulphonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of 5-{[heptan-the 3-base is amino] carbonyl } furo [2,3-c] pyridine-3-carboxylic acid methyl esters;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-vinyl thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-thiophene acetylene [2,3-c] pyridine-5-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-third-1-alkynyl thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(3-hydroxyl third-1-alkynyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
3-(outer-4 (the S)-1-azabicyclics [2.2.1] of 5-{[heptan-the 3-base is amino] carbonyl } thieno-[2,3-c] pyridin-3-yl) third-2-acetylenic acid methyl esters;
Outer-4 (the S)-1-azabicyclics [2.2.1] of 3-(3-amino-3-oxo third-1-alkynyl)-N-[heptan-3-yl] thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-cyano thiophene [2,3-c] pyridine-5-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-chlorothiophene [2,3-c] pyridine-5-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-fluorine thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-iodothiophen [2,3-c] pyridine-5-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-trifluoromethyl thiophene [2,3-c] pyridine-5-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(methylthio group) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(methylamino) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(formyl radical amino) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-[formyl radical (methyl) amino] thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-the 3-[(trifluoroacetyl group) amino] thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(cyclopropyl amino) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-the 3-[dimethylamino] thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-5-[heptan-3-yl] thieno-[2,3-c] pyridine-3, the 5-dicarboxamide;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-formyl radical thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(trifluoroacetyl group) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(methyl sulphonyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of 5-{[heptan-the 3-base is amino] carbonyl } thieno-[2,3-c] pyridine-3-carboxylic acid methyl esters;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(phenylacetylene base) furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(3,3,3-trifluoropropyl-1-alkynyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(3,3-difluoro third-1-alkynyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(phenylacetylene base) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(3,3,3-trifluoropropyl-1-alkynyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(3,3-difluoro third-1-alkynyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(phenylacetylene base) thieno-[3,2-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(3,3,3-trifluoropropyl-1-alkynyl) thieno-[3,2-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(3,3-difluoro third-1-alkynyl) thieno-[3,2-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-methyl-furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-methyl-furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-ethyl-furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-ethyl-furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-4-methyl-furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-4-methylthio group-furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-4-methoxyl group-furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-4-chloro-furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-vinyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-ethynyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-third-1-alkynyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-cyano group furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-ethynyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-third-1-alkynyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-cyano group furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-fluorine furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-chlorine furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-bromine furo [3,2-c] pyridine-6-carboxylic acid amides;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-iodofuran is [3,2-c] pyridine-6-carboxylic acid amides also for N-;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-trifluoromethyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-trifluoromethyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-sulfydryl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(methylthio group) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(methylamino) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(formyl radical amino) furo [3,2-c] pyridine-6-carboxylic acid amides;
2-(acetylamino)-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
2-(ethanoyl (methyl) amino)-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 2-[(trifluoroacetyl group) amino] furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(benzoyl-amido) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(diethylamino) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(diisopropylaminoethyl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(tetramethyleneimine-1-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(piperidines-1-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(morpholine-4-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(thiomorpholine-4-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(piperazine-1-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(4-methylpiperazine-1-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(cyclopropyl amino) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 2-[dimethylamino] furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(tetramethyleneimine-1-base carbonyl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(piperidines-1-base carbonyl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(piperazine-1-base carbonyl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-[(4-methylpiperazine-1-yl) carbonyl] furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(morpholine-4-base carbonyl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(thiomorpholine-4-base carbonyl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(azetidin-1-base carbonyl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(azetidin-1-base carbonyl) furo [3,2-c] pyridine-6-carboxylic acid amides;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-formylfuran is [3,2-c] pyridine-6-carboxylic acid amides also for N-;
2-ethanoyl-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(trifluoroacetyl group) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 2-[(phenyl) alkylsulfonyl] furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(methyl sulphonyl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-4-methyl-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-4-methylthio group-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-4-methoxyl group-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-4-chloro-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-vinyl thieno-[3,2-c] pyridine-6-carboxylic acid amides;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-thiophene acetylene is [3,2-c] pyridine-6-carboxylic acid amides also for N-;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-third-1-alkynyl thieno-[3,2-c] pyridine-6-carboxylic acid amides;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-cyano thiophene is [3,2-c] pyridine-6-carboxylic acid amides also for N-;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-fluorine thieno-[3,2-c] pyridine-6-carboxylic acid amides;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-chlorothiophene is [3,2-c] pyridine-6-carboxylic acid amides also for N-;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-bromothiophene is [3,2-c] pyridine-6-carboxylic acid amides also for N-;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-iodothiophen is [3,2-c] pyridine-6-carboxylic acid amides also for N-;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-trifluoromethyl thiophene is [3,2-c] pyridine-6-carboxylic acid amides also for N-;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-mercapto-thiophene is [3,2-c] pyridine-6-carboxylic acid amides also for N-;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(methylthio group) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(methylamino) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(formyl radical amino) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
2-(acetylamino)-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
2-(ethanoyl (methyl) amino)-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 2-[(trifluoroacetyl group) amino] thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(benzoyl-amido) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(diethylamino) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(diisopropylaminoethyl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(tetramethyleneimine-1-yl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(piperidines-1-yl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(morpholine-4-yl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(thiomorpholine-4-yl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(piperazine-1-yl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(4-methylpiperazine-1-yl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(cyclopropyl amino) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 2-[dimethylamino] thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(tetramethyleneimine-1-base carbonyl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(piperidines-1-base carbonyl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(piperazine-1-base carbonyl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-[(4-methylpiperazine-1-yl) carbonyl] thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(morpholine-4-base carbonyl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(thiomorpholine-4-base carbonyl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(azetidin-1-base carbonyl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(azetidin-1-base carbonyl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-formyl radical thieno-[3,2-c] pyridine-6-carboxylic acid amides;
2-ethanoyl-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(trifluoroacetyl group) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 2-[(phenyl) alkylsulfonyl] thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(methyl sulphonyl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-vinyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-7-methyl-furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-7-methoxyl group-furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-ethynyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-third-1-alkynyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-cyano group furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-fluorine furo [2,3-c] pyridine-5-carboxylic acid amides;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-iodofuran is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-trifluoromethyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-sulfydryl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(methylthio group) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(methylamino) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(formyl radical amino) furo [2,3-c] pyridine-5-carboxylic acid amides;
3-(acetylamino)-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
3-(ethanoyl (methyl) amino)-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 3-[(trifluoroacetyl group) amino] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(benzoyl-amido) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(diethylamino) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(diisopropylaminoethyl) furo [2,3-c] pyridine-5-carboxylic acid amides
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(tetramethyleneimine-1-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(piperidines-1-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(morpholine-4-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(thiomorpholine-4-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(piperazine-1-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(4-methylpiperazine-1-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(cyclopropyl amino) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 3-[dimethylamino] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(tetramethyleneimine-1-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(piperidines-1-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(piperazine-1-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-[(4-methylpiperazine-1-yl) carbonyl] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(morpholine-4-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(thiomorpholine-4-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(azetidin-1-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(azetidin-1-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-formylfuran is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
3-ethanoyl-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(trifluoroacetyl group) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 3-[(phenyl) alkylsulfonyl] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(methyl sulphonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-ethyl-furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-ethynyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-third-1-alkynyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-cyano group furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-fluorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-bromine furo [2,3-c] pyridine-5-carboxylic acid amides;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-iodofuran is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-trifluoromethyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-sulfydryl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(methylthio group) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(methylamino) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(formyl radical amino) furo [2,3-c] pyridine-5-carboxylic acid amides;
2-(acetylamino)-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
2-(ethanoyl (methyl) amino)-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 2-[(trifluoroacetyl group) amino] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(benzoyl-amido) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(diethylamino) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(diisopropylaminoethyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(tetramethyleneimine-1-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(piperidines-1-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(morpholine-4-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(thiomorpholine-4-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(piperazine-1-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(4-methylpiperazine-1-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(cyclopropyl amino) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 2-[dimethylamino] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(tetramethyleneimine-1-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(piperidines-1-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(piperazine-1-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-[(4-methylpiperazine-1-yl) carbonyl] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(morpholine-4-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(thiomorpholine-4-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(azetidin-1-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(azetidin-1-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-formylfuran is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
2-ethanoyl-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(trifluoroacetyl group) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 2-[(phenyl) alkylsulfonyl] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(methyl sulphonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-7-methyl-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-7-methylthio group-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-7-methoxyl group-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-7-chloro-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-vinyl thieno-[2,3-c] pyridine-5-carboxylic acid amides;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-thiophene acetylene is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-third-1-alkynyl thieno-[2,3-c] pyridine-5-carboxylic acid amides;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-cyano thiophene is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-fluorine thieno-[2,3-c] pyridine-5-carboxylic acid amides;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-chlorothiophene is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3 bromo thiophene is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-iodothiophen is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-trifluoromethyl thiophene is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
((3R, 5R)-1-azabicyclic [3.2-1] oct-3-yl)-3-mercapto-thiophene is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(methylthio group) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(methylamino) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(formyl radical amino) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
3-(acetylamino)-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
3-(ethanoyl (methyl) amino)-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 3-[(trifluoroacetyl group) amino] thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(benzoyl-amido) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(diethylamino) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(diisopropylaminoethyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(tetramethyleneimine-1-yl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(piperidines-1-yl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(morpholine-4-yl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(thiomorpholine-4-yl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(piperazine-1-yl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(4-methylpiperazine-1-yl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(cyclopropyl amino) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 3-[dimethylamino] thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(tetramethyleneimine-1-base carbonyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(piperidines-1-base carbonyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(piperazine-1-base carbonyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-[(4-methylpiperazine-1-yl) carbonyl] thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(morpholine-4-base carbonyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(thiomorpholine-4-base carbonyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(azetidin-1-base carbonyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(azetidin-1-base carbonyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-formyl radical thieno-[2,3-c] pyridine-5-carboxylic acid amides;
3-ethanoyl-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2-1] oct-3-yl)-3-(trifluoroacetyl group) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 3-[(phenyl) alkylsulfonyl] thieno-[2,3-c] pyridine-5-carboxylic acid amides; Or
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(methyl sulphonyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides.
Formula I compound, wherein compound is the combination of any or multiple following free alkali or pharmacologically acceptable salt, described free alkali or pharmacologically acceptable salt are pure enantiomorph or its racemic mixture:
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-7-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-7-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-7-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-3,3-dimethyl-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3,3-dimethyl-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3,3-dimethyl-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-2-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-3-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-3-ethyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-ethyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-ethyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-furo [2,3-b] pyridine-2-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-furo [2,3-b] pyridine-2-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-furo [2,3-b] pyridine-2-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-3-sec.-propyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-sec.-propyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-sec.-propyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-7-(methylthio group) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-7-(methylthio group) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-7-(methylthio group) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[2,3-b] pyridine-2-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[2,3-b] pyridine-2-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[2,3-b] pyridine-2-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[2,3-b] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[2,3-b] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[2,3-b] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[2,3-c] pyridine-2-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[2,3-c] pyridine-2-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[2,3-c] pyridine-2-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[3,2-b] pyridine-2-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[3,2-b] pyridine-2-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[3,2-b] pyridine-2-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[3,2-c] pyridine-2-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[3,2-c] pyridine-2-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[3,2-c] pyridine-2-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-1H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-1H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-1H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-1-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-1-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-1-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-3-bromine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-bromine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-bromine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-3-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides; Or
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides.
Formula I compound, wherein compound is the combination of any or multiple following free alkali or pharmacologically acceptable salt, described free alkali or pharmacologically acceptable salt are pure enantiomorph or its racemic mixture:
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-2-ethynyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-2-third-1-alkynyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-2-cyano group furo [3,2-c] pyridine-6-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-2-fluorine furo [3,2-c] pyridine-6-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-2-chlorine furo [3,2-c] pyridine-6-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-2-bromine furo [3,2-c] pyridine-6-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-2-iodofuran [3,2-c] pyridine-6-carboxylic acid amides also;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-2-trifluoromethyl furo [3,2-c] pyridine-6-carboxylic acid amides;
2-(acetylamino)-N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl] furo [3,2-c] pyridine-6-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-2-(tetramethyleneimine-1-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-the 2-[dimethylamino] furo [3,2-c] pyridine-6-carboxylic acid amides;
N-6-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl] furo [3,2-c] pyridine-2, the 6-dicarboxamide;
2-ethanoyl-N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl] furo [3,2-c] pyridine-6-carboxylic acid amides;
6-{[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl amino] carbonyl } furo [3,2-c] pyridine-2-carboxylic acids methyl esters;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-3-vinyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-3-ethynyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-3-third-1-alkynyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-3-cyano group furo [2,3-c] pyridine-5-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-3-fluorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-3-iodofuran [2,3-c] pyridine-5-carboxylic acid amides also;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-3-trifluoromethyl furo [2,3-c] pyridine-5-carboxylic acid amides;
3-(acetylamino)-N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-3-(tetramethyleneimine-1-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-the 3-[dimethylamino] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-5-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl] furo [2,3-c] pyridine-3, the 5-dicarboxamide;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-3-formylfuran [2,3-c] pyridine-5-carboxylic acid amides also;
3-ethanoyl-N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl] furo [2,3-c] pyridine-5-carboxylic acid amides;
5-{[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl amino] carbonyl } furo [2,3-c] pyridine-3-carboxylic acid methyl esters;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2-ethynyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2-third-1-alkynyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2-cyano group furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2-fluorine furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2-chlorine furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2-bromine furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2-iodofuran is [3,2-c] pyridine-6-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2-trifluoromethyl furo [3,2-c] pyridine-6-carboxylic acid amides;
2-(acetylamino)-N-(2-azabicyclic [2.2.1] heptan-5-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2-(tetramethyleneimine-1-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2-[dimethylamino] furo [3,2-c] pyridine-6-carboxylic acid amides;
N-6-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl] furo [3,2-c] pyridine-2, the 6-dicarboxamide;
2-ethanoyl-N-(2-azabicyclic [2.2.1] heptan-5-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
6-[(2-azabicyclic [2.2.1] heptan-5-base is amino) carbonyl] furo [3,2-c] pyridine-2-carboxylic acids methyl esters;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-vinyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-ethynyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-third-1-alkynyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-cyano group furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-fluorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-iodofuran is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-trifluoromethyl furo [2,3-c] pyridine-5-carboxylic acid amides;
3-(acetylamino)-N-(2-azabicyclic [2.2.1] heptan-5-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-(tetramethyleneimine-1-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-[dimethylamino] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-5-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl] furo [2,3-c] pyridine-3, the 5-dicarboxamide;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-formylfuran is [2,3-c] pyridine-5-carboxylic acid amides also;
3-ethanoyl-N-(2-azabicyclic [2.2.1] heptan-5-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
5-[(2-azabicyclic [2.2.1] heptan-5-base is amino) carbonyl] furo [2,3-c] pyridine-3-carboxylic acid methyl esters;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2-ethynyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2-third-1-alkynyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2-cyano group furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2-fluorine furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2-chlorine furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2-bromine furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2-iodofuran is [3,2-c] pyridine-6-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2-trifluoromethyl furo [3,2-c] pyridine-6-carboxylic acid amides;
2-(acetylamino)-N-(2-azabicyclic [2.2.1] heptan-6-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2-(tetramethyleneimine-1-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2-[dimethylamino] furo [3,2-c] pyridine-6-carboxylic acid amides;
N-6-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl] furo [3,2-c] pyridine-2, the 6-dicarboxamide;
2-ethanoyl-N-(2-azabicyclic [2.2.1] heptan-6-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
6-[2-azabicyclic [2.2.1] heptan-6-base is amino) carbonyl] furo [3,2-c] pyridine-2-carboxylic acids methyl esters;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-vinyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-ethynyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-third-1-alkynyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-cyano group furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-fluorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-iodofuran is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-trifluoromethyl furo [2,3-c] pyridine-5-carboxylic acid amides;
3-(acetylamino)-N-(2-azabicyclic [2.2.1] heptan-6-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-(tetramethyleneimine-1-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-[dimethylamino] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-5-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl] furo [2,3-c] pyridine-3, the 5-dicarboxamide;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-formylfuran is [2,3-c] pyridine-5-carboxylic acid amides also;
3-ethanoyl-N-(2-azabicyclic [2.2.1] heptan-6-yl) furo [2,3-c] pyridine-5-carboxylic acid amides; Or
5-[2-azabicyclic [2.2.1] heptan-6-base is amino) carbonyl] furo [2,3-c] pyridine-3-carboxylic acid methyl esters.
Formula I compound, wherein compound is the combination of any or multiple following free alkali or pharmacologically acceptable salt, described free alkali or pharmacologically acceptable salt are pure enantiomorph or its racemic mixture:
N-(1-azabicyclic [2.2.1] heptan-3-yl) thieno-[3,4-c] pyridine-6-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl) thieno-[3,4-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) thieno-[3,4-c] pyridine-6-carboxylic acid amides; Or
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl) thieno-[3,4-c] pyridine-6-carboxylic acid amides.
Formula I compound, wherein compound is the combination of any or multiple following free alkali or pharmacologically acceptable salt, described free alkali or pharmacologically acceptable salt are pure enantiomorph or its racemic mixture:
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl) thieno-[3,4-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl) thieno-[3,4-c] pyridine-6-carboxylic acid amides; Or
N-(2-azabicyclic [2.2.1] heptan-6-yl) thieno-[3,4-c] pyridine-6-carboxylic acid amides.
Formula I compound, wherein compound is the combination of any or multiple following free alkali or pharmacologically acceptable salt, described free alkali or pharmacologically acceptable salt are pure enantiomorph or its racemic mixture:
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thionaphthene is [3,2-c] pyridine-3-carboxylic acid amides also;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thionaphthene is [3,2-c] pyridine-3-carboxylic acid amides also;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thionaphthene is [3,2-c] pyridine-3-carboxylic acid amides also for N-;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thionaphthene is [3,2-c] pyridine-3-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl] [1] cumarone [2,3-c] pyridine-3-carboxylic acid amides also; Or
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl] [1] thionaphthene [2,3-c] pyridine-3-carboxylic acid amides also.
Formula I compound, wherein compound is the combination of any or multiple following free alkali or pharmacologically acceptable salt, described free alkali or pharmacologically acceptable salt are pure enantiomorph or its racemic mixture:
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thionaphthene is [3,2-c] pyridine-3-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thionaphthene is [3,2-c] pyridine-3-carboxylic acid amides also; Or
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thionaphthene is [3,2-c] pyridine-3-carboxylic acid amides also.
Other embodiments of the present invention comprise The compounds of this invention, be included as free alkali or be the pharmaceutical composition of the active compound of pharmacologically acceptable salt and pharmaceutically acceptable carrier, and the method for disease is specified in treatment.
On the other hand, the present invention includes treatment and suffer from schizophrenia or psychotic mammiferous method, by using formula I compound and antipsychotics.The compounds of this invention and antipsychotics can be side by side or are carried out administration with the timed interval of separating.In the time of the while administration, The compounds of this invention and antipsychotics can join in the single pharmaceutical composition.Perhaps, two kinds of compositions that separate, that is, a kind of composition comprises The compounds of this invention, and another kind comprises antipsychotics, two kinds of composition administrations simultaneously.
Another embodiment of the present invention provides a kind of method, and described method comprises to the The compounds of this invention of administration treatment significant quantity or comprises the pharmaceutical composition of described compound.
The present invention also comprises a kind of pharmaceutical composition, and described composition comprises formula I compound or pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipient.But pharmaceutical composition per rectum, part, oral, hypogloeeis or administered parenterally keep the effective timed interval of treatment.Pharmaceutical composition carries out administration with the dosage of carrying the described weight of mammal of about 0.001～100mg/kg every day.Pharmaceutical composition also can the described weight of mammal of about 0.1～50mg/kg every day dosage carry The compounds of this invention to carry out administration.
A kind of pharmaceutical composition comprises formula I compound or pharmaceutically acceptable salt thereof of the present invention, antipsychotics and pharmaceutically acceptable excipient.Pharmaceutical composition is carried described compound and described medicine independently, and per rectum, part, oral, hypogloeeis or parenteral carry out administration, to keep the effective timed interval of treatment.The pharmaceutical composition of using also can be carried the The compounds of this invention of the described weight of mammal dosage of about 0.001～100mg/kg every day.The pharmaceutical composition of using also can be carried the The compounds of this invention of the described weight of mammal dosage of about 0.1～50mg/kg every day.
The present invention also comprises according to the compound or pharmaceutically acceptable salt thereof of formula I and is used for the treatment of purposes in the medicine of disease or illness in preparation, and wherein said Mammals is received treatment, and symptom will alleviate behind the alpha 7 nicotinic acetyl choline receptor agonists of significant quantity.
The present invention also comprises according to the compound or pharmaceutically acceptable salt thereof of formula I and is used for the treatment of purposes in the medicine of disease or illness in preparation, wherein said Mammals is received treatment, and symptom will alleviate behind the alpha 7 nicotinic acetyl choline receptor agonists of significant quantity, wherein disease, imbalance and/or illness are following any or multiple or its combination: alzheimer's cognition and attention deficit syndrome, with disease Alzheimer's for example, the nerve retrograde affection that morning, old dementia (mild cognitive impairment) or senile dementia were associated, schizophrenia or psychosis, attention deficit or attention deficit superfunction imbalance, dysthymia disorders, anxiety disorder and common anxiety disorder imbalance and the pressure imbalance of wound back, mood and disorder of affect, amyotrophic lateral sclerosis, the borderline personality imbalance, traumatic brain injury, behavior that generality and cerebral tumor are associated and cognitive question, the AIDS chronic brain syndrome, the dementia that mongolism is associated, the dementia that Lu Yiti is associated, the Heng Yandunshi disease, Parkinson's disease, tardive dyskinesia, creutzfeldt jakob disease, the ingestion of food imbalance comprises exessive appetite and anorexia nervosa, smoking cessation and dependent drug are given up the withdrawal symptoms that is associated, lucky tired this moral Latourette Cotard, the macula lutea degenerative change relevant with the age, glaucoma, the syndrome that nerve retrograde affection that glaucoma is associated or pain are associated.
The present invention also comprises the method for disease in a kind of Mammals for the treatment of needs treatments or illness, wherein said Mammals is received treatment, and symptom will alleviate behind the alpha 7 nicotinic acetyl choline receptor agonists of significant quantity, comprise the formula I compound or pharmaceutically acceptable salt thereof to administration treatment significant quantity.
The present invention also comprises the method for disease in a kind of Mammals for the treatment of needs treatments or illness, wherein said Mammals is received treatment, and symptom will alleviate behind the alpha 7 nicotinic acetyl choline receptor agonists of significant quantity, comprise formula I compound or pharmaceutically acceptable salt thereof, wherein disease to administration treatment significant quantity, imbalance and/or illness are following any or multiple or its combination: alzheimer's cognition and attention deficit syndrome, with disease Alzheimer's for example, the nerve retrograde affection that morning, old dementia (mild cognitive impairment) or senile dementia were associated, schizophrenia or psychosis, attention deficit or attention deficit superfunction imbalance, dysthymia disorders, anxiety disorder and common anxiety disorder imbalance and the pressure imbalance of wound back, mood and disorder of affect, amyotrophic lateral sclerosis, the borderline personality imbalance, traumatic brain injury, behavior that generality and cerebral tumor are associated and cognitive question, the AIDS chronic brain syndrome, the dementia that mongolism is associated, the dementia that Lu Yiti is associated, the Heng Yandunshi disease, Parkinson's disease, tardive dyskinesia, creutzfeldt jakob disease, the ingestion of food imbalance comprises exessive appetite and anorexia nervosa, smoking cessation and dependent drug are given up the withdrawal symptoms that is associated, Ji tires out this. moral Latourette Cotard, the macula lutea degenerative change relevant with the age, glaucoma, the syndrome that nerve retrograde affection that glaucoma is associated or pain are associated.
Formula I compound (Azabicyclo is I) has the optical activity center on rubane.The compounds of this invention comprises the quinine of 3R configuration and also comprises racemic mixture, the mixture of isomer that separates and stereochemistry purity in various degree.Such as but not limited to, formula I compound comprises having following stereochemical compound
Formula I compound (Azabicyclo is II) has the optical activity center in the C3 and the C4 position of [2.2.1] azabicyclic.The scope of the invention comprises the racemic mixture of purity in various degree, the isomer that separates and the mixture of stereochemistry purity in various degree, and formula I is interior-4S, interior-4R, outer-4S, outer-4R:
Endo isomer is that the non-hydrogen substituting group of the wherein C3 position of [2.2.1] assorted bicyclic compound is invested the big person in 2 residue bridges.Exo isomer is that the non-hydrogen substituting group of the wherein C3 position of [2.2.1] assorted bicyclic compound is invested the little person in 2 residue bridges.Therefore, four kinds of steric isomers can be arranged: outer-4 (R), outer-4 (S), interior-4 (R) and interior-4 (S).
Formula I compound (Azabicyclo is III) has the optical activity center in C1, C4 and the C5 position of [2.2.1] azabicyclic.The scope of the invention comprises the racemic mixture of stereochemistry purity in various degree, the isomer that separates and the mixture of stereochemistry purity in various degree, formula I be (1R, 4R, 5S), (1R, 4R, 5R), (1S, 4S, 5R), (1S, 45,5S):
Endo isomer is that the non-hydrogen substituting group of the wherein C5 position of [2.2.1] assorted bicyclic compound is invested the big person in 2 residue bridges.Exo isomer is that the non-hydrogen substituting group of the wherein C5 position of [2.2.1] assorted bicyclic compound is invested the little person in 2 residue bridges.Therefore, 4 kinds of isomer that separate are arranged: outer-(1R, 4R, 5S), outer-(1S, 4S, 5R), interior-(1S, 4S, 5S), interior-(1R, 4R, 5R).
Formula I compound (Azabicyclo is IV) has the optical activity center in C1, C4 and the C6 position of [2.2.1] azabicyclic.The scope of the invention comprises the mixture of the racemic mixture of the stereochemistry purity of different purity, the steric isomer that separates and different stereochemistry purity, formula I be outer-(1S, 4R, 6S), outer-(1R, 4S, 6R), interior-(1S, 4R, 6R) and interior-(1R, 4S, 6S):
Internal (position) isomer is an isomer of wherein investing big person in 2 residue bridges at the non-hydrogen substituting group of the C6 position of [2.2.1] Azabicyclic compound.Outer isomer be wherein the non-hydrogen substituting group of the C6 position of [2.2.1] Azabicyclic compound invest 2 medium and small persons of residue bridge isomer.Therefore, four kinds of isomer that separate can be arranged: outer-(1S, 4R, 6S), outer-(1R, 4S, 6R), interior-(1S, 4R, 6R) and interior-(1R, 4S, 6S).
Formula I compound (Azabicyclo is V) has the optical activity center in the C3 and the C5 position of [3.2.1] azabicyclic.The mixture of the stereochemistry purity of the racemic mixture of the stereochemistry purity of scope of the invention different purity, the steric isomer that separates and multiple degree, formula I compound are interior-3S, 5R, interior-3R, and 5S, outer-3R, 5R, outer-3S, 5S:
Work as R
2In the time of disappearance, formula I compound (Azabicyclo is VI) has the optical activity center on [3.2.2] azabicyclic, a center is arranged on C3.The scope of the invention comprises that formula I is the racemic mixture of the different stereochemistry purity of 3 (S) and 3 (R), and the mixture of different stereochemistry purity:
The compounds of this invention with particular stereoisomer has different activity levels, and may be better than another isomer for the substituting group of a certain group of set-point on a kind of isomer.Although wish that stereochemistry purity is high as much as possible, does not need absolute purity.The present invention relates to the mixture of racemic mixture and multiple stereochemistry purity, when Azabicyclo is only replaced by acid amides/thioamides or the substituting group replacement of quilt except that acid amides/thioamides, for example R
2Be alkyl.When referring to racemic mixture and mixture, be meant the mixture of racemic mixture and different stereochemistry purity.It is synthetic and/or reaction product carried out suitable purification step to produce the material of enantiomer-pure basically preferably to carry out stereoselectivity.The suitable stereoselectivity step that produces the material of enantiomer-pure is well known in the art, and is used for becoming the method for level part of enantiomer-pure the same the racemic mixture purifying.
Stereoselectivity is synthetic and/or reaction product is carried out suitable purification step produce the material of enantiomer-pure basically.The suitable stereoselectivity step that produces the material of enantiomer-pure is well known in the art, and is used for becoming the step of level part of enantiomer-pure the same the racemic mixture purifying.
The another embodiment of formula I compound comprises one or more combinations of compound of following configuration:
Wherein (i) compound is a racemic mixture, or
(ii) compound has R stereochemistry discussed here and does not indicate in the stereochemistry of C-6 at C-3.
The another embodiment of formula I compound comprises one or more combinations of compound of following configuration:
(i) k wherein
2Be 0 (R
2Disappearance);
(ii) R
2Alkyl, cycloalkyl or aryl for alkyl, haloalkyl, replacement;
(iii) R
2Alkyl, cycloalkyl or aryl for alkyl, haloalkyl, replacement; Or
(iv) the 2.2.1 composition has outer as discussed here-4 (S) stereochemistry.
The another embodiment of formula I compound comprises one or more combinations of compound of following configuration:
(i) R wherein
2-3Be H;
(ii) R
2-3Alkyl, cycloalkyl or aryl for F, Cl, Br, I, alkyl, haloalkyl, replacement; Or
(iii) R
2-3Alkyl, cycloalkyl or aryl for alkyl, haloalkyl, replacement.
The another embodiment of formula I compound comprises one or more combinations of compound of following configuration:
(i) R wherein
2-3Be H;
(ii) R
2-3Alkyl, cycloalkyl or aryl for F, Cl, Br, I, alkyl, haloalkyl, replacement; Or
(iii) R
2-3Alkyl, cycloalkyl or aryl for alkyl, haloalkyl, replacement.
The another embodiment of formula I compound comprises one or more combinations of compound of following configuration:
(i) k wherein
5Be 0 (R
2Disappearance);
(ii) R
2The disappearance and wherein Azabicyclo have 3R, the stereochemistry of 5R;
(iii) k
5Be 2, R wherein
2-aBe alkyl, cycloalkyl or the aryl of alkyl, haloalkyl, replacement, and R wherein
2-bAlkyl, cycloalkyl or aryl for F, Cl, Br, I, alkyl, haloalkyl, replacement;
(iv) k
5Be 1, R wherein
2Alkyl, cycloalkyl or aryl for alkyl, haloalkyl, replacement; Or
(v) k
5Be 1, R wherein
2Alkyl, cycloalkyl or aryl for F, Cl, Br, I, alkyl, haloalkyl, replacement.
The another embodiment of formula I compound comprises one or more combinations of compound of following configuration:
(i) k wherein
6Be 0 (R
2Disappearance);
(ii) k
6Be 2, each R wherein
2-aBe alkyl, cycloalkyl or the aryl of alkyl, haloalkyl, replacement and each R wherein
2-bAlkyl, cycloalkyl or aryl for F, Cl, Br, I, alkyl, haloalkyl, replacement;
(iii) k
6Be 1, R wherein
2Alkyl, cycloalkyl or aryl for alkyl, haloalkyl, replacement; Or
(iv) k
6Be 1, R wherein
2Be F, Cl, Br, I, alkyl, haloalkyl, substituted alkyl, cycloalkyl or aryl.
Based on following detailed description and embodiment and additional claim, other aspects of the present invention and embodiment are clearly for this area those skilled in the art.Although the present invention is subject to the influence of the embodiment of various ways, described below is specific embodiments of the present invention, and it is illustrative being construed as the disclosure, is not described herein for the present invention is defined as
Specific embodiment.
Detailed Description Of The Invention
Surprisingly, our discoverable type I compound:
Formula I
Wherein Azabicyclo is
W is
Condition is-C (=X)-chemical bond between group and the W group can connect as at R
3, R
6And R
15Any in the W group that provides becomes on the key carbon atom;
X is O or S;
R
0Be H, low alkyl group, replacement low alkyl group or junior alkyl halides;
Low alkyl group is the side chain of 1-4 carbon atom or the composition of straight chain;
Junior alkyl halides is a low alkyl group, has 1～(2n+1) individual substituting group, be independently selected from F, Cl, Br or I wherein n be the maximum number of carbon atom in the composition;
Replace low alkyl group for having 0-3 substituting group low alkyl group, be independently selected from F, Cl, Br or I and further have 1 substituting group, be selected from-CN ,-NO
2,-OR
10,-SR
10,-NR
10R
10,-C (O) R
10,-C (O) OR
10,-C (S) R
10,-C (O) N (R
10)
2,-NR
10C (O) N (R
10)
2,-NR
10C (O) R
10,-S (O) R
10,-S (O)
2R
10,-OS (O)
2R
10,-S (O)
2NR
10R
10,-NR
10S (O)
2R
10, phenyl or have 1 and be selected from R
18Substituent phenyl, and further have the substituting group that 0-3 is independently selected from F, Cl, Br or I;
Each R
1Be H, alkyl, cycloalkyl, haloalkyl, substituted-phenyl or substituted naphthyl;
Alkyl is the straight or branched composition of 1-6 carbon atom;
Haloalkyl is to have the alkyl composition of 1-6 carbon atom and have 1～(2n+1) individual substituting group, and substituting group is independently selected from F, Cl, Br or I, and wherein n is the maximum value of carbonatoms in the composition;
Cycloalkyl is the cycloalkyl composition of 3-6 carbon atom;
Substituted-phenyl is a phenyl, perhaps has 1-4 substituting group that is independently selected from F, Cl, Br or I, perhaps has 1 and is selected from R
12Substituting group and the 0-3 substituting group that is independently selected from F, Cl, Br or I;
Substituted naphthyl is the naphthalene composition, perhaps has 1-4 and is independently selected from F, Cl, Br or I substituting group, perhaps has 1 and is selected from R
12Substituting group and the 0-3 substituting group that is independently selected from F, Cl, Br or I, wherein replace and can carry out on two rings on the ring at described naphthalene composition independently;
Each R
2Be alkyl, cycloalkyl, aryl, F, Cl, Br, the I of alkyl, haloalkyl, replacement, or R
2Do not exist, condition is k
2, k
5Or k
6Be 0;
R
2-3Be H, alkyl, substituted alkyl, haloalkyl, F, Cl, Br or I;
The alkyl that replaces is to have the alkyl composition of 1-6 carbon atom and have 0-3 substituting group that is independently selected from F, Cl, Br or I, and further has 1 substituting group, is selected from R
7, R
9,-CN ,-NO
2,-OR
10,-SR
10,-NR
10R
10,-C (O) R
10,-C (O) OR
10,-C (S) R
10,-C (O) N (R
10)
2,-NR
10C (O) N (R
10)
2,-NR
10C (O) R
10,-S (O) R
10,-S (O)
2R
10,-OS (O)
2R
10,-S (O)
2NR
10R
10,-NR
10S (O)
2R
10, phenyl or substituted-phenyl, have 1 and be selected from R
18Substituting group and further have the substituting group that 0-3 is independently selected from F, Cl, Br or I;
k
2Be 0 or 1;
k
5And k
6Independently 0,1 or 2;
A---A '---A " is N (R
4)-C (R
3)=C (R
3), N=C (R
3)-C (R
15)
2, C (R
3)=C (R
3)-N (R
4), C (R
3)
2-N (R
4)-C (R
3)
2, C (R
15)
2-C (R
3)=N, N (R
4)-C (R
3)
2-C (R
3)
2, C (R
3)
2-C (R
3)
2-N (R
4), O-C (R
3)=C (R
3), O-C (R
3)
2-C (R
3)
2, C (R
3)
2-O-C (R
3)
2, C (R
3)=C (R
3)-O, C (R
3)
2-C (R
3)
2-O, S-C (R
3)=C (R
3), S-C (R
3)
2-C (R
3)
2, C (R
3)
2-S-C (R
3)
2, C (R
3)=C (R
3)-S or C (R
3)
2-C (R
3)
2-S;
Each R
3The chemical bond condition that links to each other for core element is to have only a R independently
3And there is not R
6Or R
5Also be this chemical bond, H, alkyl, replacement alkyl, haloalkyl, alkenyl, substituted alkenyl base, halogenated alkenyl, alkynyl, substituted alkynyl, halo alkynyl ,-CN ,-NO
2, F, Br, Cl, I ,-OR
19,-C (O) N (R
10)
2,-N (R
10)
2,-SR
19,-S (O)
2R
19,-C (O) R
19,-CO
2R
19, aryl, R
7Or R
9
Aryl is phenyl, substituted-phenyl, naphthyl or substituted naphthyl;
Alkenyl is the side chain and the straight chain composition of 2～6 carbon atoms and has at least one carbon-carbon double bond;
Halogenated alkenyl is undersaturated alkene composition, has 2～6 carbon atoms and has 1～(2n-1) the individual substituting group that independently is selected from F, Cl, Br or I, and wherein n is the maximum value of carbonatoms in the composition;
The alkenyl that replaces refers to undersaturated alkene composition, has 2～6 carbon atoms and has 0～3 substituting group that independently is selected from F or Cl, and further have 1 and be selected from R
7, R
9,-CN ,-NO
2,-OR
10,-SR
10,-NR
10R
10,-C (O) R
10,-C (O) OR
10,-C (S) R
10,-C (O) N (R
10)
2,-NR
10C (O) N (R
10)
2,-NR
10C (O) R
10,-S (O) R
10,-S (O)
2R
10,-OS (O)
2R
10,-S (O)
2NR
10R
10,-NR
10S (O)
2R
10, phenyl or substituted-phenyl, have 1 and be selected from R
18Substituting group and further have the substituting group that 0-3 is independently selected from F, Cl, Br or I;
Alkynyl is the side chain and the straight chain composition of 2～6 carbon atoms and has at least one carbon carbon triple bond;
The halo alkynyl is undersaturated alkynyl composition, has 3～6 carbon atoms and has 1～(2n-3) the individual substituting group that independently is selected from F, Cl, Br or I, and wherein n is the maximum value of carbonatoms in the composition;
The alkynyl that replaces refers to undersaturated alkynyl composition, has 3～6 carbon atoms and has 0～3 substituting group that independently is selected from F or Cl, and further have 1 and be selected from R
7, R
9,-CN ,-NO
2,-OR
10,-SR
10,-NR
10R
10,-C (O) R
10,-C (O) OR
10,-C (S) R
10,-C (O) N (R
10)
2,-NR
10C (O) N (R
10)
2,-NR
10C (O) R
10,-S (O) R
10,-S (O)
2R
10,-OS (O)
2R
10,-S (O)
2NR
10R
10,-NR
10S (O)
2R
10, phenyl or substituted-phenyl, have 1 and be selected from R
18Substituting group and further have the substituting group that 0-3 is independently selected from F, Cl, Br or I;
Halogenated cycloalkyl is the cycloalkyl composition, has 3～6 carbon atoms and has 1～4 substituting group that independently is selected from F or Cl;
The cycloalkyl finger ring alkyl composition that replaces has 3～6 carbon atoms and has 0～3 substituting group that independently is selected from F or Cl, and further has 1 and be selected from R
7, R
9,-CN ,-NO
2,-OR
10,-SR
10,-NR
10R
10,-C (O) R
10,-C (O) OR
10,-C (S) R
10,-C (O) N (R
10)
2,-NR
10C (O) N (R
10)
2,-NR
10C (O) R
10,-S (O) R
10,-S (O)
2R
10,-OS (O)
2R
10,-S (O)
2NR
10R
10,-NR
10S (O)
2R
10, phenyl or substituted-phenyl, have 1 and be selected from R
18Substituting group and further have the substituting group that 0-3 is independently selected from F, Cl, Br or I;
Heterocyclylalkyl is the cyclic group composition, has 4～7 atoms, 1～2 atom in the ring is-S-,-N (R
17)-or-O-;
Halogenated heterocycloalkyl is the cyclic group composition, has 4～7 atoms, 1～2 atom in the ring is-S-,-N (R
17)-or-O-, and have 1～4 substituting group that independently is selected from F or Cl;
Substituted heterocyclic radical is the cyclic group composition, has 4～7 atoms, 1～2 atom in the ring is-S-,-N (R
17)-or-O-, and have 0～3 substituting group that independently is selected from F or Cl, and further have 1 and be selected from R
7, R
9,-CN ,-NO
2,-OR
10,-SR
10,-NR
10R
10,-C (O) R
10,-C (O) OR
10,-C (S) R
10,-C (O) N (R
10)
2,-NR
10C (O) N (R
10)
2,-NR
10C (O) R
10,-S (O) R
10,-S (O)
2R
10,-OS (O)
2R
10,-S (O)
2NR
10R
10,-NR
10S (O)
2R
10, phenyl or substituted-phenyl, have 1 and be selected from R
18Substituting group and further have the substituting group that 0-3 is independently selected from F, Cl, Br or I;
J, L, M and Q are N or C (R
6), condition is to have only to be a N among J, L, M or the Q, and other groups are C (R
6), and further condition is that Q is C (H) when core element connects pyridyl in the M position, and further condition is only to exist one to be connected with core element;
G and Y are C (R
6), condition is when molecule is connected to the phenyl composition at the Y place, G is CH;
R
4Alkyl, cycloalkyl, halogenated cycloalkyl, the cycloalkyl of replacement, Heterocyclylalkyl, halogenated heterocycloalkyl, substituted heterocycle alkyl, R for H, alkyl, haloalkyl, replacement
7Or R
9
Each R
5Be H, low alkyl group or low-grade alkenyl independently;
Low-grade alkenyl is the side chain and the straight chain composition of 2～4 carbon atoms and has at least one carbon-carbon double bond;
Each R
6Be independently H, F, Br, I, Cl ,-CN ,-CF
3,-OR
5,-SR
5,-N (R
5)
2, with the chemical bond condition of core element bonding be to have only a R
6And there is not R
3Or R
15Be described key;
V is selected from O, S or N (R
4);
R
7Be the assorted fragrant monocycle composition of 5-person, comprise 1-3 in the ring to be independently selected from=N-,-N (R
17)-,-O-and-heteroatoms of S-, and have 0-1 and be selected from R
18Substituting group and further have 0-3 substituting group, described substituting group is independently selected from F, Cl, Br or I, or R
7Be fused to 9-person's fused rings composition that 5-person encircles for having 6-person's ring, comprise following formula
G wherein
1Be O, S or NR
17,
Wherein G is C (R
16) or N, and each G
2And G
3Be independently selected from C (R
16)
2, C (R
16), O, S, N and N (R
18), condition is G
2And G
3Be not O simultaneously, be not S simultaneously, or be not O and S simultaneously, or
Wherein G is C (R
16) or N, and each G
2And G
3Be independently selected from C (R
16)
2, C (R
16), O, S, N and N (R
17), each 9-person's fused rings composition has 0-1 and is selected from R
18Substituting group, and further have the substituting group that 0-3 is independently selected from F, Cl, Br or I, wherein R
7During composition is connected to suc as formula I under the condition that valence link allows on defined other substituting groups on any position of arbitrary ring;
Each R
8Be alkyl, cycloalkyl, halogenated cycloalkyl, the cycloalkyl of replacement, Heterocyclylalkyl, halogenated heterocycloalkyl, substituted heterocycle alkyl, the R of H, alkyl, haloalkyl, replacement independently
7, R
9, phenyl or substituted-phenyl;
R
9Be the assorted fragrant monocycle composition of 6-person, in ring, comprise 1-3 to be selected from=heteroatoms of N-and have 0-1 and be selected from R
18Substituting group and the 0-3 substituting group that is independently selected from F, Cl, Br or I, or R
9Be 10 Yuans assorted fragrance two ring compositions, in one or two ring, comprise 1-3 to be selected from=heteroatoms of N-, include but not limited to that quinolyl or isoquinolyl, each 10-person's fused rings composition have 0-1 and be selected from R
18Substituting group and the 0-3 substituting group that is independently selected from F, Cl, Br or I, and when valence link allows, have the valence link that directly or indirectly links to each other with core element;
Each R
10Be H, alkyl, cycloalkyl, Heterocyclylalkyl independently, be selected from R by 1
13The alkyl that replaces of substituting group, be selected from R by 1
13The cycloalkyl that replaces of substituting group, be selected from R by 1
13The substituting group Heterocyclylalkyl, haloalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, phenyl or the substituted-phenyl that replace;
Each R
11Be H, alkyl, cycloalkyl, Heterocyclylalkyl, haloalkyl, halogenated cycloalkyl or halogenated heterocycloalkyl independently;
R
12For-NO
2The alkyl of ,-CN, alkyl, cycloalkyl, Heterocyclylalkyl, haloalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, replacement, the cycloalkyl of replacement, substituted heterocycle alkyl ,-OR
11,-SR
11,-NR
11R
11,-C (O) R
11,-C (O) NR
11R
11,-NR
11C (O) R
11,-S (O)
2NR
11R
11Or-NR
11S (O)
2R
11
R
13For-CN ,-CF
3,-NO
2,-OR
11,-SR
11,-NR
11R
11,-C (O) R
11,-C (O) NR
11R
11,-NR
11C (O) R
11,-S (O)
2NR
11R
11Or-NR
11S (O) R
11
Each R
14For the alkyl of H, alkyl, replacement, haloalkyl, alkenyl, substituted alkenyl base, halogenated alkenyl, alkynyl, substituted alkynyl, halo alkynyl, F, Br, Cl, I ,-CN ,-NO
2,-OR
19,-C (O) N (R
10)
2,-N (R
10)
2,-SR
19,-S (O)
2R
19,-C (O) R
19,-CO
2R
19, aryl, R
7Or R
9
Each R
15Be independently alkyl, replacement alkyl, haloalkyl, alkenyl, substituted alkenyl base, halogenated alkenyl, alkynyl, substituted alkynyl, halo alkynyl, F, Br, Cl, I ,-CN ,-NO
2,-OR
19,-C (O) N (R
10)
2,-N (R
10)
2,-SR
19,-CO
2R
19, aryl, R
7, R
9, with the valence link of core element bonding, condition is to have only a R
15And there is not R
6Or R
3Be described valence link;
Each R
16Be independently alkyl, the replacement of H, alkyl, cycloalkyl, Heterocyclylalkyl, haloalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, replacement cycloalkyl, substituted heterocycle alkyl, F, Cl, Br, I ,-NO
2,-CN ,-OR
11,-SR
11,-NR
11R
11,-C (O) R
11,-C (O) NR
11R
11,-NR
11C (O) R
11,-S (O)
2NR
11R
11,-NR
11S (O)
2R
11, the valence link that directly or indirectly links to each other with core element, condition is only to have a described valence link that links to each other with core element in 9-person's fused rings composition, other condition is that the fused rings composition has 0-1 substituting group, described substituting group be selected from alkyl, the replacement of alkyl, cycloalkyl, Heterocyclylalkyl, haloalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, replacement cycloalkyl, substituted heterocycle alkyl ,-OR
11,-SR
11,-NR
11R
11,-C (O) R
11,-NO
2,-C (O) NR
11R
11,-CN ,-NR
11C (O) R
11,-S (O)
2NR
11R
11Or-NR
11S (O) R
11, and other condition is that the fused rings composition has 0-3 substituting group that is selected from F, Cl, Br or I;
R
17For the cycloalkyl of the alkyl of H, alkyl, haloalkyl, replacement, cycloalkyl, halogenated cycloalkyl, replacement, phenyl ,-SO
2R
8Or have 1 and be selected from R
18Substituting group and further have 0-3 and be independently selected from the substituent phenyl of F, Cl, Br or I;
R
18For alkyl, cycloalkyl, Heterocyclylalkyl, haloalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl ,-OR
11,-SR
11,-NR
11R
11,-C (O) R
11,-C (O) NR
11R
11,-CN ,-NR
11C (O) R
11,-S (O)
2NR
11R
11,-NR
11S (O)
2R
11,-NO
2, be independently selected from F, Cl, Br, I or R by 1-4
13The alkyl that replaces of substituting group, be independently selected from F, Cl, Br, I or R by 1-4
13The cycloalkyl that replaces of substituting group or be independently selected from F, Cl, Br, I or R by 1-4
13The Heterocyclylalkyl that replaces of substituting group;
R
19Alkyl, haloalkyl, substituted-phenyl or substituted naphthyl for H, alkyl, cycloalkyl, replacement;
Or its pharmacologically acceptable salt, racemic mixture and pure enantiomorph can be used for treating any or its combination in the following disease: alzheimer's cognition and attention deficit syndrome, with disease Alzheimer's for example, the nerve retrograde affection that morning, old dementia (mild cognitive impairment) or senile dementia were associated, schizophrenia or psychosis, attention deficit or attention deficit superfunction imbalance, dysthymia disorders, anxiety disorder and common anxiety disorder imbalance and the pressure imbalance of wound back, mood and disorder of affect, amyotrophic lateral sclerosis, the borderline personality imbalance, traumatic brain injury, behavior that generality and cerebral tumor are associated and cognitive question, the AIDS chronic brain syndrome, the dementia that mongolism is associated, the dementia that Lu Yiti is associated, the Heng Yandunshi disease, Parkinson's disease, tardive dyskinesia, creutzfeldt jakob disease, the ingestion of food imbalance comprises exessive appetite and anorexia nervosa, smoking cessation and dependent drug are given up the withdrawal symptoms that is associated, lucky tired this moral Latourette Cotard, the macula lutea degenerative change relevant with the age, glaucoma, the syndrome that nerve retrograde affection that glaucoma is associated or pain are associated.
On the other hand, the present invention includes treatment and suffer from schizophrenia or psychotic mammiferous method, by using formula I compound and antipsychotics.The compounds of this invention and antipsychotics can be side by side or are carried out administration with the timed interval of separating.In the time of the while administration, The compounds of this invention and antipsychotics can join in the single pharmaceutical composition.Perhaps, two kinds of compositions that separate, that is, a kind of composition comprises The compounds of this invention, and another kind comprises antipsychotics, two kinds of composition administrations simultaneously.
The present invention also comprises The compounds of this invention, comprises the pharmaceutical composition of active compound and the method that disease is specified in treatment.
May use abbreviation known to a person of ordinary skill in the art (for example, " Ph " expression phenyl, " Me " expression methyl, " Et " expression ethyl, " h " expression hour, " min " expression minute and " rt " expression room temperature).
All temperature all are centigradetemperature.
Room temperature refers to the temperature in 15～25 ℃ of scopes.
ACHR represents acetylcholine receptor.
Presenile dementia also refers to the mild cognitive damage.
NACHR represents nAChR.
5HT
3R refers to 5-hydroxytryptamine receptor 3 types.
α-btx refers to the ABTX element.
FLIPR refers to a kind of by Molecular Devices, the Inc commercial device, and design is in order accurately to measure the fluorescence (Schroeder et al.J.Biomolecular Screening, 1 (2), p 75-78,1996) of cell in full cell high throughput analysis.
TLC refers to thin-layer chromatography.
HPLC refers to high-pressure liquid phase.
MeOH nail alcohol.
EtOH refers to ethanol.
IPA refers to Virahol.
THF refers to tetrahydrofuran (THF).
DMSO refers to methyl-sulphoxide.
DMF refers to dimethyl formamide.
EtOAc refers to ethyl acetate.
Na
2SO
4Refer to sodium sulfate.
K
2CO
3Refer to salt of wormwood.
MgSO
4Sal epsom.
Work as Na
2SO
4, K
2CO
3, MgSO
4In the time of as siccative, refer to for anhydrous.
TMS is a tetramethylsilane.
TEA is a triethylamine.
DIEA is N, the N-diisopropylethylamine.
MLA nail base lycoctonine (methyllycaconitine)
Ether refers to ether.
HATU refers to O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate.
DBU refers to 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene.
DPPA refers to diphenyl phosphoryl azide.
50% 1: 1 saturated sodium-chlor/sodium bicarbonate refers to that the solution that falls 1: 1 saturated sodium-chlor/sodium bicarbonate adds the solution that isopyknic water is mixed with.
CH
3SO
2Cl nail SULPHURYL CHLORIDE.
Halogen is F, Cl, Br or I.
At R
7And R
9The example of non-the comprising property heteroaryl compound in the definition includes but not limited to, thienyl, thionaphthene x base, pyridyl, thiazolyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furyl, benzofuryl, benzothiazolyl, isothiazolyl, the benzisothiazole base, benzisoxa azoles base, benzimidazolyl-, indyl, the benzoxazol base, pyrazolyl, triazolyl, tetrazyl, different azoles base, azoles base, pyrryl, isoquinolyl, the cinnolinyl base, indazolyl, indolyl, 2, the 3-phthalazinyl, pyridazinyl, triazinyl, pseudoindoyl, purine radicals, the di azoly, the furazan base, benzo furazan base, benzothienyl, benzothiazolyl, quinazolyl, quinoline quinoline base, the naphthyridine base, the furo pyridyl, pyrrolopyridinyl, the thienopyridine base.The form of all isomer of mentioning composition of these non-comprising property all comprises, for example, cumarone comprises 1-cumarone-2-base, 1-cumarone-3-base, 1-cumarone-4-base, 1-cumarone-5-base, 1-cumarone-6-base, 1-cumarone-7-base, 2-cumarone-1-base, 2-cumarone-2-base, 2-cumarone-3-base, 2-cumarone-4-base, 2-cumarone-5-base.Under the condition that valence link allows, R
7And R
9Non-comprising property example discriminably by as R
7And R
9Be substituted like that in the definition.This area those skilled in the art are by more non-comprising property example and R
7And R
9Each is self-defined, just can determine the replacement of permission.
Non-the comprising property example of Heterocyclylalkyl includes but not limited to tetrahydrofuran base, THP trtrahydropyranyl, morpholinyl, pyrrolidyl, piperidino-(1-position only), piperazine, azelidinyl, azetidinono, oxyindole base (oxindolo), glyoxalidine base (dihydroimidazolo), pyrryl or different azoles quinoline base.
The carbonatoms of multiple hydrocarbonaceous composition represents by the prefix of indicating maximum in the composition and minimum, that is, and and prefix C
I-jRepresent that this composition comprises carbonatoms between " i " and " j ".Therefore, for example, C
1-6Alkyl refers to the alkyl of 1～6 carbon atom.
Core element is Azabicyclo-N (R
1)-C (=X):
Amine described herein need use amine-blocking group need to guarantee the functionalized of nitrogen.Persons of ordinary skill in the art will recognize that the place of in synthetic schemes, using described blocking group.Amido protecting includes but not limited to carbobenzoxy-(Cbz) (CBz), tertbutyloxycarbonyl (BOC) etc.The example of the amino protecting group that other are suitable is known to a person of ordinary skill in the art and is found in, and " Protective Groups inOrganic synthesis, " 3rd Edition, author are Theodora Greene and Peter Wuts.
Mammals is represented people and other Mammals.
Salt solution refers to saturated sodium chloride aqueous solution.
Equ refers to that mole equates.
IR refers to infrared spectra.
Lv refers to the leavings group in the molecule, comprises Cl, OMe, OEt or mixed acid anhydride.
Parr refers to the Business Name of sell pressure retort.
PSI refers to pound/square inch.
NMR refers to that nuclear (proton) nuclear magnetic resonance spectroscopy, chemical shift are with ppm (δ) report with respect to low of TMS.
MS refers to mass spectrum, is expressed as m/e or mass unit.HRMS refers to high resolution mass spectrum, is expressed as m/e or mass unit.M+H
+Refer to that parent molecule adds the positively charged ion of hydrogen atom.M-H
-Refer to that parent molecule deducts the negatively charged ion of hydrogen atom.M+Na
+Refer to that parent molecule adds the positively charged ion of sodium atom.M+K+ refers to that parent molecule adds the positively charged ion of potassium atom.EI refers to electron-bombardment.ESI refers to electro-spray ionization.CI refers to chemi-ionization.FAB refers to fast atom bombardment(FAB).
The compounds of this invention can be the form of pharmacologically acceptable salt.Term " pharmacologically acceptable salt " refers to comprise mineral alkali and organic bases from the salt that pharmaceutically acceptable nontoxic alkali prepares, and the salt for preparing from mineral acid and organic acid.Salt derived from mineral alkali comprises aluminium salt, ammonium salt, calcium salt, molysite, lithium salts, magnesium salts, sylvite, sodium salt, zinc salt etc.Salt derived from pharmaceutically useful organic nontoxic alkali comprises one-level, secondary and tertiary amine, replace amine and comprise naturally occurring replacement amine, cyclic amine, arginine for example, trimethyl-glycine, caffeine, choline, N, the N dibenzyl-ethylenediamin, diethylamide, the 2-DEAE diethylaminoethanol, the 2-dimethylaminoethanol, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histamine, hydrabamine, isopropylamine, Methionin, methyl glucoside amine, morpholine, piperazine, piperidines, the polyamines resin, PROCAINE HCL, PHARMA GRADE, fast quinoline, Theobromine, triethylamine, Trimethylamine, tripropylamine etc.Salt derived from mineral acid comprises hydrochloride, hydrobromate, hydriodate, vitriol, phosphoric acid salt, phosphite etc.Salt derived from pharmaceutically useful organic nontoxicity acid comprises-C
1-6Alkyl carboxylate, two-carboxylate salt and tricarboxylate, for example acetate, propionic acid, fumaric acid, succsinic acid, tartrate, toxilic acid, hexanodioic acid and citric acid, and aryl and alkylsulphonic acid toluenesulphonic acids etc. for example.
" significant quantity " of the compound that provides here refer to the nontoxic of compound but capacity so that the effect of needs to be provided.As hereinafter pointed, the accurate amount that needs is different because of object, depends on the particular compound, administering mode of the severity of generalized case, treatment disease of kind, age and treatment target and use etc.Therefore, can not specify one accurate " significant quantity ".But the significant quantity that is fit to can use conventional test method(s) to determine by this area those skilled in the art.
The compounds for treating significant quantity of using and depend on multiple factor with the dosage of the compound and/or the present composition, comprise the physical appearance of age, body weight, sex and administration object, severity, route of administration and frequency the particular compound of disease, therefore can in the scope of broad, change to use.Composition comprises known carrier and excipient, and the formula I compound of treatment significant quantity.For the adult, the scope that pharmaceutical composition can comprise activeconstituents is about 0.001-100mg/kg/ days, is preferably about 0.1-50mg/kg/ days.For the adult, total per daily dose of about 1-1000mg activeconstituents is suitable.Per daily dose can every day 1～4 dose carry out administration.
Except formula I compound, the composition that is used for the treatment of purposes can comprise also that one or more are nontoxic, pharmaceutically acceptable carrier material or excipient.Term " carrier " material or " excipient " refer to it itself is not any material of therapeutical agent here, as carrier and/or thinner and/or adjuvant, or therapeutical agent flowed to patient's solvent or join pharmaceutical composition and increase operation or storage properties or permission or help composition and form capsule or the tablet that discrete goods for example are suitable for oral administration with unitary dose.Excipient can comprise, illustrative and nonrestrictive, material, seasonings, dyestuff, the perfume compound of offending taste or smell is covered or is resisted in thinner, disintegrating agent, tackiness agent, binding agent, wetting agent, polymkeric substance, lubricant, glidant, adding, and adds the material that improves the composition outward appearance.Acceptable material comprises lactose, sucrose, starch, Mierocrystalline cellulose alkanoic acid ester, Mierocrystalline cellulose alkyl ester, talcum powder, stearic acid, Magnesium Stearate, magnesium dioxide, phosphoric acid and vitriolic sodium salt and calcium salt, gelatin, Sudan Gum-arabic, sodiun alginate, polyvinylpyrrolidone and/or polyvinyl alcohol, and then in flakes or seal to make things convenient for administration.These capsules or tablet can comprise controlled release preparation, as form that can the dispersion of active compound in HYDROXY PROPYL METHYLCELLULOSE, or other the method known of those of ordinary skills.In order to carry out oral administration, pharmaceutical composition can be for example form of tablet, capsule, suspension or liquid.The activeconstituents that can comprise if desired, other in the composition.
Except the above-mentioned oral administration of mentioning, composition of the present invention can be fit to the form of the pharmaceutical composition of these approach and carry out administration with any suitable pathways, and the effective dosage of treatment carrying out.Composition can be for example, in parenteral, for example blood vessel, intraperitoneal, subcutaneous or intramuscular carry out administration.In order to carry out administered parenterally, salt brine solution, glucose solution or water can be used as suitable carriers.The formulation of administered parenterally can be the form that the aqueous solution or non--aqueous solution etc. are opened aseptic injectable solution or suspension.These solution and suspension can obtain from sterilized powder or the granules preparation with one or more carriers that are used for oral Preparation of addressing or thinner.These compounds may be dissolved in water, polyoxyethylene glycol, propylene glycol, ethanol, Semen Maydis oil, Oleum Gossypii semen, peanut oil, sesame oil, benzylalcohol, sodium-chlor and/or the multiple damping fluid.Other adjuvants and administering mode are known widely at pharmacy field.
Serotonin type 3 receptor (5HT
3R) be the member of part-gated ion channel superfamily, it comprises muscle and neural nAChR, Padil acceptor, and γ-An Jidingsuan A receptor.The same with other members of this superfamily, 5HT
3R and α 7 nAChR demonstrate bigger sequence homology, but two kinds of ligand-gated ion channels are significantly different on the function.For example, α 7 nAChR rapid deactivations, calcium ion have the height impregnability and can be activated by vagusstoff and nicotine.On the other hand, 5HT
3The R inactivation is slow, and relatively calcium ion soaks into lowlyer, is activated by serotonin.These tests hint α 7 nAChR and 5HT3R albumen have homology to a certain degree, but function is different fully.Really, the pharmacologically active of these two kinds of passages is significantly different.For example, ondansetron, a kind of 5HT of high selectivity
3The R antagonist does not almost have activity to α 7 nAChR.Otherwise also be like this, for example, GTS-21, a kind of α 7 nAChR agonists of high selectivity are to 5HT
3R does not almost have activity.
α 7 nAChR are the calcium channel of part gate, are formed by identical α 7 subunit pentamers.Aforementioned research has confirmed that (α-btx) optionally is attached to this pentamer altogether to the ABTX element, α 7nAChR hypotype, and α 7 nAChR have the two high affinity combined sites of α-btx and methyllycaconitine (MLA).α 7 nAChR express in hippocampus, abdomen lid zone and the rising cholinergic view field from nuclear basilis to thalamus cortex zone with high level.α 7 nAChR agonists increase the release of neurotransmitter, and increase cognitive ability, awakening, attention, study and memory capability.
Confirm that from the pharmacological datum of people and animal many aspects of nicotine cholinergic nerve path control cognitive function comprise attention, study and memory (Levin, E.D., Psychopharmacology, 108:417-31,1992; Levin, E.D. and Simon B.B., Psychopharmacology, 138:217-30,1998).For example, known that nicotine increases people's cognitive ability and attention.ABT-418, a kind of compound that activates α 4 β 2 and α 7 nAChR improves understanding and attention (Potter in the clinical trial of Alzheimer (family name) disease and the not enough disease of attention, A. etc., Psychopharmacology (Berl)., 142 (4): 334-42, Mar.1999; Wilens, T.E. etc., Am.J.Psychiatry, 156 (12): 1931-7, Dec.1999).Also know very much nicotine and selectivity but weak alpha 7 nAChR agonists increases the cognition and the attention of rodent and inhuman primate.
Schizophrenia is a kind of multi-factor disease of complexity, is caused by heredity and non-genetic risk factor, produces positive and negative syndrome constellation.Positive syndrome comprises illusion and illusion, and negative syndrome comprises emotion, attention, cognition and information processing capability deficiency.In this disease, there is not single biology key element to become main paathogenic factor.In fact, possible situation is that schizophrenia is a kind of syndrome, is produced by the combination of many lower outer apparent factors.Pharmacological research confirms that dopamine-receptor antagonist can be used for the treatment of tangible schizoid psychotic features (positive syndrome), for example illusion and illusion effectively.Leoponex, a kind of " atypical " antipsychotics is because therefore positive and some negative syndromes that it can be used for the treatment of this disease effectively belong to very new a kind of medicine.To cause the risk of granulocytopenia and epileptic seizures to increase because continue use, leoponex is greatly limited as the purposes of medicine.There is not other antipsychotics can be used for the treatment of the negative syndrome of schizophrenia effectively.Recovery of this very important because cognitive function is successful clinical and schizophrenia patient's a functional outcome (Green, M.F., Am J Psychiatry, 153:32130,1996).From wider angle, clearly need better medicament to return to better state with the patient's that will have this disease the mental status to treat the imbalance of schizoid awareness.
The cognitive insufficient one side of schizophrenia can utilize the relevant sensory gating voltage (P50) of auditory events to measure.In this test, the neururgic electric encepholographic of hippocampus (EEG) record is used for the reaction (Adler, L.E. etc., Biol.Psychiatry, 46:8-18,1999) of measurement Research object to the serial sense of hearing " ticktocks ".The reaction that normal individual drips greater than the rising tone to the degree of the reaction of dripping for first.Usually, schizophrenia and patient schizotypal are to the reaction of dripping for two (Cullum, C.M. etc., Schizophr Res., 10:131-41,1993) much at one.These data reflection schizophrenia are to " filtration " or ignore the scarce capacity of inessential information.This responsive gate defective is one of the important pathological characters (Cadenhead, K.S. etc., Am.J.Psychiatry, 157:55-9,2000) of this kind disease seemingly.The multinomial nicotine that studies show that makes schizoid sensory defect recover normal (Adler, L.E. etc., Am.J.Psychiatry, 150:1856-61,1993).Pharmacological research show nicotine to the effect of sensory gating by α 7 nAChR work (Adler, L.E. etc., Schizophr.Bull., 24:189-202,1998).In fact, the α 7 nAChR acceptors in biochemical data demonstration schizophrenia patient's the hippocampus reduce 50%, so this has provided the reasonable dismissal (Freedman of the functional partial losses of α 7 nAChR, R. etc., Biol.Psychiatry, 38:22-33,1995).Interesting is, genetic data shows polymorphism and the sensory gating in the schizophrenia of the promoter region of α 7 nAChR genes be associated strongly (Freedman, R. etc., Proc.Natl Acad.Sci.USA, 94 (2): 587-92,1997; Myles-Worsley, M. etc., Am.J.Med.Genet, 88 (5): 544-50,1999).Up to the present, also do not identify the sudden change of α 7 nAChR coding regions.Therefore, the schizophreniac expresses identical α 7 nAChR with non-schizophreniac.
Selectivity α 7 nAChR agonists can be found (referring to WO00/73431A2) with functional selection on FLIPR.FLIPR is designed to and can reads fluorescent signal from 96 or 384 orifice plates, to per second 2 times, can read to be thirty minutes long soon.This analysis can be used to accurately measure α 7 nAChR and 5HT
3The functional pharmacology of R.In order to carry out this analysis, a kind of α 7 nAChR that use the expressive function form utilize α 7/5-HT3 passage as drug targets and expressive function 5HT
3The clone of R.In both cases, ligand-gated ion channel is expressed in the SH-EP1 cell.Two kinds of ionic channels all produce strong signal in FLIPR analyzes.
The compounds of this invention is α 7 nAChR agonists, can be used for treating multiple disease, for example, can be used for treating schizophrenia or psychosis.
Schizophrenia is the disease with multiple manifestation.Present existing medicine is usually all at control schizoid positive aspect, for example illusion.A kind of medicine, leoponex is conceived to the syndrome that the schizophrenia of wide spectrum is associated.This medicine has many side effects, and is therefore improper to many patients.Therefore, need a kind of medicine to be used for the treatment of cognition and the attention deficit that schizophrenia is associated.Similarly, cognition and attention deficit or the similar syndrome of visible in schizophrenia patient relatives that needs a kind of medicine to be associated to treat spiritual disorder of affect.
Psychosis is a kind of psychataxia, is characterized as the overall impairment of the true perception of patient.Patient may suffer illusion and illusion and incoherent.His behavior excitement and people on every side often can not understand.In the past, the term psychosis is often used in the numerous disease that does not satisfy above-mentioned given strict difinition.For example, psychosis also is appointed as in emotional maladjustment.
Many antipsychotics are arranged at present.Conventional antipsychotics comprises chlorpromazine, Fluphenazine, haloperidol, loxapine, mesoridazine, molindone, trilafon, pimozide, thioridazine, tiotixene and trifluoperazine.These medicines all have avidity to dopamine 2 receptor.
These conventional antipsychotics have some side effects, comprise calmness, weight increase, tremble, the prolactin level increases, cathisophobia (being on tenterhooks), dystonia and myotony.These medicines also can cause tardive dyskinesia.Unfortunately, 70% schizophrenia patient the antipsychotics reaction of only having an appointment to routine.To these patients, existing atypical antipsychotics.
Atypical antipsychotics can alleviate psychotic positive syndrome usually, also improves psychotic negative syndrome simultaneously, and the improvement degree is greater than the antipsychotics of routine.These medicines can improve the neuro-cognitive deficiency.In the time of with atypical antipsychotic, outer (motion) side effect of pyramidal tract can not take place, therefore, these atypical antipsychotics have the risk of lower generation tardive dyskinesia.At last, these atypical antipsychotics cause seldom or do not cause that the prolactin level increases.Unfortunately, these medicines are not to be free from side effects.These medicines produce different side effects separately, and side effect comprises: granulocytopenia; The increase of epileptic seizures risk, weight increase, somnolence, feel dizzy, tachycardia, ejaculation gonosome are long-pending descends, and the QTc compartment of terrain slightly prolongs.
In treatment disease for example schizoid syndromic combined therapy, formula I compound and antipsychotics can be side by side or the timed interval administration to separate.In the time of administration side by side, formula I compound and antipsychotics can join in the single medicine composition, for example, and the drug regimen therapeutic composition.Perhaps, two compositions that separate promptly, a kind ofly comprise formula I compound and another kind comprises antipsychotics, administration simultaneously.The example of antipsychotics, except above-described those, include but not limited to chlorpromazine, thioridazine, trilafon, tiotixene, trifluoperazine, Fluphenazine, fluphenazine hydrochloride, Wei Sitong, olanzapine, Seroquel, ZELDOX, Acetophenazine, carphenazine, chlorprothixene, droperidol, loxapine, mesoridazine, molindone, ondansetron, pimozide, prochlorperazine and promazine.
Medicinal combined therapy composition can comprise formula I compound for the treatment of significant quantity and the antipsychotics for the treatment of significant quantity.These compositions can be prepared with common excipient, diluent or carrier, and are pressed into tablet or are made into elixir or solution is used for conventional oral administration or carries out administration through the intramuscular approach.But these compound per rectums, part, oral, hypogloeeis or parenteral carry out administration, and can be mixed with formulation that slowly-releasing discharges etc.
In the time of separate administration, the composition that the treatment significant quantity comprises formula I compound and antipsychotics carries out administration according to different time schedules.A kind of can administration before another, as long as twice administration time satisfies the effective timed interval of treatment at interval.Treating the effective timed interval is for some time, rises to start from a kind of or (a) formula I compound, and perhaps (b) antipsychotics is to people's administration, the time between schizophrenia or psychosis (a) and the beneficial effect end of extent (EOE) of (b) treating.The medication of formula I compound and antipsychotics can change.Therefore, but a kind of medicine or two kinds of medicine per rectums, part, oral, hypogloeeis or administered parenterally.
As discussed, compound of the present invention is α 7 nAChR agonists.Therefore, as another aspect of the present invention, The compounds of this invention can be used to treat cognition and attention deficit syndrome that multiple disease comprises that Alzheimer (family name) is sick, for example Alzheimer (family name) is sick for disease, presenile dementia (also being mild cognitive impairment), and the nerve retrograde affection that is associated of senile dementia.
Alzheimer (family name) disease has a lot of manifestation, comprises cognition and attention deficit.At present, these defectives are treated with anticholinesterase.These inhibitor slow down the degraded of vagusstoff and therefore provide a kind of cholinergic nerve system active common non-specific increase.Because medicine is nonspecific, they have many side effects.Therefore, need a kind of medicine irritation part cholinergic path and therefore provide Alzheimer (family name) cognition that disease is associated and the improvement of attention deficit, and do not have the side effect that is brought of the nonspecific stimulation of cholinergic path.
Nerve retrograde affection is for example FAQs that is associated of Alzheimer (family name) disease of a kind of and disease.Although the syndrome of this disease of pharmacological agent is arranged at present, they also represent the basic pathology of control disease.Therefore, need provide a kind of medicine to slow down the sick process of Alzheimer (family name).
Presenile dementia (mild cognitive impairment) relates to memory impairment rather than attention deficit problem and other not damage of cognitive function.The significantly different mild cognitive impairments that are with senile dementia of mild cognitive impairment relate to more lasting and thorny memory loss problem to elderly patients.Do not have clear and definite medicine to can be used to treat mild cognitive impairment at present, part is because the disease of this disease for identifying recently.Therefore, the memory problems that needs a kind of pharmacological agent mild cognitive impairment to be associated.
Senile dementia is not single morbid state.But the disease that is categorized under this title generally includes cognition and attention deficit.Usually, this defective can't be treated.Therefore, cognition and the improvement of attention deficit ground that needs a kind of medicine to be associated so that senile dementia to be provided.
As discussed herein, The compounds of this invention is α 7 nAChR agonists.Therefore, the other diseases of available The compounds of this invention treatment comprises cognition and the attention deficit and the nerve retrograde affection of treatment one or more or following combination disease-related connection: attention deficit or attention deficit superfunction imbalance, dysthymia disorders, anxiety disorder and common anxiety disorder imbalance and the pressure imbalance of wound back, mood and disorder of affect, amyotrophic lateral sclerosis, the borderline personality imbalance, traumatic brain injury, behavior that generality and cerebral tumor are associated and cognitive question, the AIDS chronic brain syndrome, the dementia that mongolism is associated, the dementia that Lu Yiti is associated, the Heng Yandunshi disease, Parkinson's disease, tardive dyskinesia, creutzfeldt jakob disease, the ingestion of food imbalance comprises exessive appetite and anorexia nervosa, smoking cessation and dependent drug are given up the withdrawal symptoms that is associated, lucky tired this moral Latourette Cotard, the macula lutea degenerative change relevant with the age, glaucoma, the syndrome that nerve retrograde affection that glaucoma is associated or pain are associated.
Attention deficit imbalance is usually with the Methylphenidylacetate treatment, a kind of molecule of amphetamine-class, but the possibility of abuse is arranged.Therefore, need a kind ofly treat the attention deficit imbalance and have the medicine littler simultaneously than the drug side effect of present use.
Attention deficit superfunction imbalance is also referred to as ADHD, is a kind of neurobehavioral imbalance, influences the U.S. children of 3-5%.ADHD only singly relate to cognition or relate to cognition and behavior the two, disturb the people to do the sustainability and the suitable controllability of age of a job.The ADHD that has a few types: mainly do not note hypotype, the hyperfunction impulsion hypotype of primary activity, and the combination hypotype.Treatment can comprise medicine for example Methylphenidylacetate, Dextroamphetamine or pemoline, and it act as and reduces impulsion and superfunction and increase attention.Do not exist at present and cure the ADHD method.Children with this disease seldom can break away from it; Therefore, need a kind of suitable medicine.
Dysthymia disorders is a kind of emotional maladjustment, and time of usually changing several months～surpass 2 years, the mood of variation relates to sadness, despair and discouraged.The heterocyclic thymoleptic (HCA ' s) is the thymoleptic of maximum kind at present, but oxidase inhibitor (MAOI ' s) in specific dysthymia disorders type, use.The common side effect of HCA ' s is calmness and weight increase.In the elderly patients that the brain organ disease is arranged, the side effect of HCA ' s also comprises epileptic seizures and behavior syndrome.Use of the interaction of the main syndrome of MAOI ' s from diet and medicine.Therefore, having the medicine of less side effect will be of great use.
Anxiety disorder (having the disease that outstanding anxiety disorder or fear are dodged) has been represented a field that is not resolved in the psychiatric treatment medical need.The disease form of multiple anxiety disorder is referring to Diagnostic ﹠amp; Statistical Manual of Mental Disorders, IV (1994), pp 393-394.
When for example family, health or the work of people's worry thing, worry when having no reason but when must worry, general anxiety disease imbalance (GAD) will take place.About 3～4% American had GAD in 1 year.GAD usually occurs in the middle of children or the young adult, but also can begin in the Adulthood.It more is common in the women.At present, treatment relates to cognitive behavioral therapy, loosens technology, and biofeedback is to control muscular tone and medicine for example diazepam, imipramine and buspirone.These medicines effectively but side effect is all arranged.Therefore, need medicine, have less side effect simultaneously to solve above-mentioned syndrome.
Pressure was lacked of proper care (PTSD) after anxiety disorder also comprised wound, and it is a kind of anxiety disorder of the memory initiation of traumatic event, this incident that described incident has directly influenced patient or patient's witness.This imbalance influences the survivor of traumatic event usually, and incident comprises that sexual assault, physical aggression, war, torment, natural disaster, motor-vehicle accident, aircraft fall, the hostage meets with or dead campsite.Aircraft fall or scale shooting in, this misery also can influence the rescue personnel, some witnesses the tragedy incident the people or lost the people's who is liked people unexpectedly.The treatment of PTSD comprises for example for example fluoxetine, Sertraline, Paroxetine, citalopram and Fluvoxamine of clonazepam, lorazepam and selectivity serotonin-reuptake inhibitor of treatment of cognitive behavioral therapy, group mind and medicine.These medicines help to control anxiety disorder and dysthymia disorders.The treatment (for example the whole body desensitization and the imagination are spread unchecked) that exposes to the open air of various ways has been used for patient PTSD.PTSD exposes the reproduction that treatment relates under certain conditions wound repeatedly to the open air, and purpose is in order to promote the processing of wound.Therefore, need a kind of better medicament to lack of proper care with pressure after treating wound.
Mood and disorder of affect comprise a big class disease, comprise one pole dysthymia disorders and bipolar emotional maladjustment.These diseases can be with the main compounds for treating of three classes.First group is heterocyclic thymoleptic (HCA ' s).This group comprises the tricyclics that is widely known by the people.The second group of compound that is used for treating emotional maladjustment is the oxidase inhibitor that is used for the disease specific type (MAOI ' s).The third medicine is the lithium agent.The common adverse effect of HCA ' s is calmness and weight increase.In the elderly patients that the cerebral tissue disease is arranged, the side effect of HCA ' s also comprises epilepsy and behavior syndrome.The major side effects of using MAOI ' s is from diet and drug interaction.The optimum side effect of lithium agent includes but not limited to, weight increase, feel sick, diarrhoea, diuresis, polydipsia and tremble.The toxic side effects of lithium agent comprises lasting headache, confusion and epilepsy and arrhythmia may take place.Therefore, have less side effect or with food or the other drug less medicine that interacts will be very useful.
The borderline personality imbalance although there is not bipolar imbalance to be widely known by the people, is a kind of more common disease.People with borderline personality imbalance easily suffers from emotion and regulates imbalance.Can make the concrete syndrome that heals with medicine, for example dysthymia disorders or thought distortion.
Acquired immune deficiency syndrome (AIDS) (AIDS) is infected by human immunodeficiency virus (HIV) and causes.The function of the cell that this virus attack is selected and infringement immunity, nerve and other system.HIV infect can cause other problem such as but not limited to the thinking difficulty, and other be known as the AIDS dementia.Therefore, need a kind of medicine to descend with confusion and the intelligence that alleviates patient AIDS.
Amyotrophic lateral sclerosis (spinal cord) lateral sclerosis also is a Lou Gehrig ' s disease, belongs to the illness that a class is known as motor neurone disease, and the concrete neurocyte in its midbrain and the notochord degenerates to gradually can not control active movement.Although patient can accept some syndromic treatments and the verified survival that can prolong patient of Riluzole, amyotrophic lateral sclerosis (spinal cord) lateral sclerosis does not at present have methods of treatment.Therefore, need a kind of medicine for the treatment of this disease.
Be subjected to unexpected physical property right overhead and attack brain, traumatic brain injury will take place.Traumatic brain injury syndrome comprises confusion of thinking and other cognitive question.Therefore, need a kind of medicine that solves chaotic syndrome and other cognitive questions.
Cerebral tumor is the misgrowth that sees the tissue in the skull.Cerebral tumor syndrome comprises behavior and cognitive question.Surgical operation, irradiation and chemotherapy are used for treating tumour, but need other medicine to solve the syndrome that is associated.Therefore, need solution behavior and cognitive question syndrome.
Suffer from mongolism the people whole cells or have No. 21 extra chromosomal key components in the part cell at least.The known adult who suffers from mongolism has the risk of suffering from Alzheimer type dementia.At present, do not treat the method for mongolism.Therefore, there is the dull-witted demand that mongolism is associated that solves.
The procedural degeneration of the heredity of some regional neurocyte causes the Heng Yandunshi disease in the brain.The early stage syndrome of Heng Yandunshi disease comprises and takes the fling or learn new thing or memory incident difficulty.Most medicines of treatment Heng Yandunshi disease syndrome have for example tired, the unpeaceful or superexcitation of side effect.At present, there is not to end or reverse the methods of treatment of Heng Yandunshi disease process.Therefore, need a kind of medicine, have less side effect simultaneously to solve this syndrome.
Lu Yi body dementia is a kind of neurological sexual maladjustment, and the visible unusual structure in some zone that relates in brain is called Lu Yiti.Lu Yi body chronic brain syndrome includes but not limited to have sporadic insane fluctuation cognitive impairment.At present, treatment relate to solve Parkinson (family name) sick and spirituality syndrome.But control is trembled or in fact the medicine of muscular movement forfeiture may increase the weight of Lu Yi body dementia.Therefore, need a kind of medicine with treatment Lu Yi body dementia.
Parkinson (family name) disease is the imbalance of a kind of nervosa, feature show as tremble, hypokinesia and myotony.At present, do not end the treatment of this disease process.Therefore, need a kind of medicine to treat Parkinson (family name) disease.
Tardive dyskinesia is a kind of disease that is associated with the conventional antipsychotics of use.The feature of this disease is involuntary motion, and modal manifestation is that lip and tongue wrinkle and/or arm or leg seethe.The sickness rate of tardive dyskinesia is about routine and takes 5% of antipsychotics every year.Suffer among the patient of this disease about 2%, tardive dyskinesia seriously is out of shape.At present, there is not general tardive dyskinesia methods of treatment.And, because the potential problem abandons causing always not a kind of usually selection of medicine of disease.Therefore, need a kind of medicine to solve tardive dyskinesia syndrome.
Gram (family name) pathogeny is from the slow progressive degeneration of social skill and change individual character, produces the syndrome of intelligence, memory and language damage.Common syndrome comprises concentrated difficulty of memory loss, spontaneous disappearance, thinking or attention and language confusion.At present, do not have a treatment sick specificity method of gram (family name), but some syndromes can be handled with the thymoleptic of cholinergic and serotonin-increase.And, but antipsychotics ameliorate body error checking is felt or patient's FTD syndrome of illusion.Therefore, need a kind ofly have the medicine of less side effect to treat progressive degeneration of social skill and personality change and to solve syndrome.
Ingestion of food imbalance with eating the disease-related connection comprises exessive appetite and anorexia nervosa, relates to the nervous physiology path.Anorexia nervosa is difficult to treatment, because patient does not participate in or remains in project.At present, the patient who suffers from serious anorexia nervosa there is not effective methods of treatment.Cognitive behavioral therapy can help to suffer from bulimiac patient; But responsiveness only has an appointment 50%, and the certainly emotion adjusting of family sufficiently of present methods of treatment.Therefore, need a kind of medicine to solve ingestion of food imbalance potential nervous physiology problem.
Smoking is used as main public safety problem for a long time.But, although public consciousness to its danger to health, smoking habit is still lasting singularly and be very difficult to stop.Many methods of treatment are arranged at present, but people continue smoking.Transdermal administration nicotine, or to use nicotine in chewing gum be common methods of treatment.But nicotine has a lot of effects to human body, therefore has many side effects.Clearly, long-term also a kind of convenience of demand and relative simpler method are to help smoker's minimizing or to abandon cigarette consumption.To give up in smoking will be very useful to a kind of medicine that can the selective stimulating nAChR in the works.
Plan is given up in smoking can relate to the oral administration of selecting medicine.Medicine can tablet form.But, preferably use dosage every day, by the serial cumulative dosed administration during a day at recovery time.Preferred medication is slow dissolved lozenge, tablet or chewing gum, and therein, medicine is disperseed.The habit-forming medicine of another kind of treatment nicotine is a Zyban.This is not the nicotine replacement therapy, and it is chewing gum and sheet.And, other zones of its action scope brain, its validity helps to want that the people that give up smoking control nicotine and thirst for or missing cigarette.Zyban is not very effective, needs effective medicine to end smoking to help the smoker.These medicines can carry out transdermal administration by using pieces of skin.In some cases, medicine can be through the subcutaneous injection administration, when particularly using sustained release preparation.
The use of medicine and dependency are complex phenomena, can not get across in a definition.Different medicines has different effects, and dissimilar dependencys.Drug dependence has 2 basic reasons, i.e. tolerance and physical dependence.When the user need take much more gradually dosage when producing the initial effect that obtains with low dose, just there is tolerance.When the user develops into the physiological status that a kind of medicine is adapted to, just there is physical dependence, and when no longer taking medicine, just has drug withdrawal syndrome.When medicine is ended or work as antagonist medicine under its binding site displacement at cell receptor and when resisting its effect, drug withdrawal syndrome is just taken place.Drug dependence does not always need physical dependence.
In addition, drug dependence usually relates to psychologic dependence,, when taking medicine, just feels happy or satisfied that is.Thisly feel to cause the user to repeat medicine to experience or avoid occurring being deprived the unhappy of medicine.Can produce the medicine of strong physical dependence, for example nicotine, heroine and alcohol are abused usually, and the dependence pattern is difficult to destroyed.On CNS, produce dependent and reduce the medicine of anxiety disorder and pressure usually; Produce tingle, joyous sense or other happy emotional change; The spirit and the physical ability of increase are provided for the user; Or in some happy modes, change sensory feel.Usually the medicine of abuse is ethanol, opium, anxiolytic, soporific, hemp (marijuana), Cocaine, Amphetamine and fantasy.The people's of drug habit treatment is usually directed to the combination of behavior therapy and medicine; for example methadone or LAAM (left-handed-α-ethanoyl-Dimepheptanol); can be used to suppress the medicine that withdrawal symptoms and narcotics addiction be associated effectively and thirst for, thereby reduce the use of illegal medicine and improve still in the individual chance of treatment.The auxiliary withdrawal method of the main medical science of narcotics addiction is to allow patient take the comparable medicine that produces light withdrawal symptoms, and reduces alternative medicine then gradually.Normally used medicine is a methadone, and is once a day oral.Patient is begun by the minimum dosage of the more serious withdrawal symptoms of prevention, and then dosage is reduced gradually.Substitute can also be used for from the tranquilizer withdrawal.Patient is convertible into and takes long-acting tranquilizer, and for example diazepam or phenylethyl barbituric acid reduce then gradually.
Lucky tired this moral Latourette (family name) syndrome is a kind of heredity nervosa imbalance.This imbalance feature is that uncontrollable sounding becomes tic and involuntary motion.This syndrome generally displays in less than 18 years old individuality.Ataxia can begin to twitch from simple, develops into the tic of multiple complexity gradually, comprises and breathing and sound.Sound is twitched to rise and is started from snore or loud noise and be evolved into involuntary speaking.Coprolalia (involuntary foul language) takes place in about 50% patient.Serious tic and coprolalia can cause health and social maimed.Tic is more complicated than muscle spasm, but does not have choreic movement smooth like that, they can be distinguished from this point.Patient can control several seconds or several minutes on one's own initiative.Simple at present the tic handled with Benzodiazepine usually.For simple and complicated tic, can use clonidine catapresan.The life-time service clonidine catapresan can not cause tardive dyskinesia; Its restricted side effect is a ypotension.Under more serious situation, need to use antipsychotics, haloperidol for example, but side effect is as having the fidgets, tremble (property) paralysis and cathisophobia and tardive dyskinesia has limited the use of antipsychotics.Therefore, need a kind of safe and efficient method to be used for the treatment of this syndrome.
The macula lutea degenerative change (AMD) relevant with the age is a kind of common disease of eye, and very little regional spottiness on retina, retina help to produce and comprise reading and drive " directly movable forward " needed clear, central vision.The patient who suffers from AMD has lost clear, central vision.AMD presents two kinds of forms: wet type and dry type.In doing AMD, in the slow collapse of speckle regions generation photosensitive cell.At present dryness AMD there is not methods of treatment.In wet type AMD, blood vessel that growth makes new advances below spot, frangible when dried AMD worsens, and these blood vessels usually spill the quick damage of blood and liquid spot, forfeiture with causing central vision apace.Laser therapy can be treated some wet type AMD cases.Therefore, the medicine that needs treatment AMD.
Glaucoma works to start from pathologic that the intraocular pressure increase causes CD and change and negatively influence visual zone in one group of disease.Treating glaucomatous medicine or minimizing enters the amount of liquid of eyes or increases output from the liquid of eyes to reduce intraocular pressure.But present medicine defectiveness for example can not play a role for a long time or cause that the such Eye Care professional of side effect must leave other drug or revise the prescription that uses medicine.Need a kind of safety and effective means to be used to handle the problem that glaucoma demonstrates.
The amino acid whose release of glaucomatous local asphyxia exitotoxicity also stimulates the nitric oxide synthase (iNOS) of induction type to cause nerve retrograde affection.The alpha 7 nicotinic agonist can stimulate for example release of GABA of inhibitory aminoacid, and it is with the high excitability of humidity.The alpha 7 nicotinic agonist also has direct neuroprotective to neurocyte.Therefore, the alpha 7 nicotinic agonist has the potentiality of neuroprotective to glaucoma.
The people who is tormented by pain usually has the pain that is subjected to be referred to as usually " fearful three levy ", causes insomnia and sad, and all these are very difficult to the individuality and the individual family thereof of getting involved.Pain can appear as various ways, includes but not limited to, serious headache, back pain, neuropathic pain and the pain that is derived from other diseases is sacroiliitis and cancer for example, is derived from the position of its existence or is derived from treatment institute to cause.Pain can be chronic (lasting pain, experience several months～several years) or acute (time is very short, pain is handled to inform possible damage and to need immediately).The people who stands pain is different to difference treatment reflection, and successful degree is also different.Need a kind of safety and effective means to treat pain.
Finally, The compounds of this invention can be used in combination with typical and atypical anti-psychotropic (being also referred to as neuroleptics).Compound of the present invention can be used for and can make up with pharmaceutical compositions mutually.These combined therapies have reduced the effective dose of antipsychotics and have therefore reduced the side effect of antipsychotics.Can be used for typical antipsychotics more of the invention process and comprise haloperidol.Some atypical antipsychotics comprise Ziprasidone, olanzapine, Resperidone and Quetiapine.
Formula I compound can be prepared by the method described in the route 1.Prepare committed step in this compounds and be with azabicyclic composition and necessary sour muriate (Lv=Cl), mixed acid anhydride (as, Lv=diphenylphosphine acyl group, two (2-oxo-3- oxazolidinyl) phosphinyl or general formula O-C (O)-R
LvIn acyloxy, R wherein
LvComprise the phenyl or the tertiary butyl) or carboxylic acid (Lv=OH) in the presence of activator, carry out coupling.Suitable activator be known in the art those, for example referring to Kiso, Y., Yajima, H. " Peptides " pp.39-91, San Diego, CA, Academic Press, (1995), and include but not limited to that reagent is carbodiimide class, phosphorus and urea salt (for example HATU) for example.
Route 1
Usually, acid is activated with HATU or change into acyl azide with DPPA.Suitable azabicyclic-amine is joined obtain the final compound that needs in the solution of suitable activatory acid or trinitride.Perhaps, acid is changed into mixed acid anhydride, use CH by being used under the TEA existence
2Cl
2Or CHCl
3Handle with two (2-oxo-3- oxazolidinyl) inferior phosphoryl chlorides as solvent.The pure suitable amine aldehyde solution that obtains is direct and that add reacts or uses the DMF or the DMF aqueous solution as solvent.In some cases, ester (Lv is OMe or OEt) can directly obtain formula I compound with amine reaction in reflux ground methyl alcohol or ethanol.
Several methods is arranged, can obtain the amine precursor of azabicyclic I.Some 6-replacement-[2.2.2]-3-amine is what known in the art.The preparation of azabicyclic I compound is described at Acta Pol.Pharm.179-85 (1981).Perhaps, the preparation of 6-replacement-[2.2.2]-3-amine can utilize present technique field those of ordinary skill known method to reduce (referring to J.Labelled Compds.Radiopharm. by oxime or the imines with corresponding 6-replacement-3-quininone, 53-60 (1995), J.Med.Chem.988-995, (1998), Synth.Commun.1895-1911 (1992), Synth.Commun.2009-2015 (1996)).Perhaps, 6-replace [2.2.2]-3-amine and can replace from 6--3-hydroxyl quinine carries out the Mitsunobu reaction, carries out deprotection then and be prepared, as described in the Synth.Commun.18951911 (1995).Perhaps, 6-replacement-[2.2.2]-3-amine can replace 6--3-hydroxyl quinine changes into corresponding methanesulfonates or tosylate, replaces then with sodium azide that reduction is prepared then, as described in J.Med Chem.587-593 (1975).
The preparation of oxime can be by handling with the oxyamine hydrochloride 3-quininone under the existence condition of alkali.The preparation of imines can be reacted with primary amine the 3-quininone under dehydration conditions.3-hydroxyl quinine can prepare the reduction of 3-quininone.6-replacement-3-quininone can prepare (referring to J.Gen.Chem.Russia 3791-3795, (1963), J.Chem.Soc.Perkin Trans.1409-420 (1991), J.Org Chem.3982-3996 (2000)) with known step.
Those of ordinary skills will realize that (Azabicyclo is not wherein R of II at replacing 3-amino-1-azabicyclic [2.2.1] heptane
2The reaction method of description disappearance) also can be used for substitution compound (R with being equal to
2Existence is not H).R wherein
2The compound that is not hydrogen can obtain from suitable replacement nitroalcohol, and is shown in Tetrahedron (1997) below utilizing, and 53, the method for describing in p.11121.The method of synthesizing nitryl alcohol be methods known in the art (referring to J.Am.Chem.Soc. (1947), 69, p2608).Following proposal is described in detail, to show any these amine precursors that obtains here for synthesizing the modification method of outer-3-amino-1-azabicyclic [2.2.1] heptane two (tosilate).The salt available standards step that needs prepares.
For Azabicyclo is wherein R of II
2Be not outer-2-[2.2.1 of H]-3 amine compound also can be prepared by the improvement of intermediate, described herein outer-3-amino-1 azabicyclic [2.2.1] heptane two (tosilate), the synthetic of its here is described in detail.For example, Int 6 oxidable one-tenth aldehyde are also handled with organometallic reagent Int 20 are provided, and utilize Tetrahedron (1999), and 55, the step of describing among the p13899.Int 20 can change into amine, utilizes and synthesizes the step of describing in outer-3-amino-1-azabicyclic [2.2.1] heptane two (tosilate).In case obtain amine, the available standards step obtains needed salt.
Used scheme is used for preparing outer-3-amino-1-azabicyclic [2.2.1] heptane.But the improvement of discussion also is applicable to the preparation endo isomer.
N-(2-azabicyclic [2.2.1] heptan)-5-amine and 6-amine
Wherein Lv is-CH
2Ph, CH (Me) Ph ,-OH ,-OMe or-OCH
2Ph.
For Azabicyclo is that III and Azabicyclo are that the amine precursor separately of IV can be prepared from the oxime of corresponding N-2-azabicyclic [2.2.1]-heptanone or method that imines is familiar with those of ordinary skills and obtains (referring to J.Labelled Compds.Radiopharm., 53-60 (1995), J.Med.Chem.988-995, (1998), Synth.Commun.1895-1911 (1992), Synth.Commun.2009-2015 (1996)).The preparation of oxime can be by handling with the oxyamine hydrochloride N-2-azabicyclic [2.2.1] heptanone in the presence of alkali.The preparation of imines can be handled with primary amine N-2-azabicyclic [2.2.1]-heptanone under dehydration conditions.N-2-azabicyclic [2.2.1] heptanone can be prepared with known method (referring to Tet.Lett.1419-1422 (1999), J.Med.Chem.2184-2191 (1992), J.Med.Chem.706-720 (2000), J.Org.Chem., 4602-4616 (1995)).
Those of ordinary skills will realize at do not replace 1-azabicyclic [3.2.1] suffering-3-amine or 1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-amine (R
2The reaction method of description disappearance) equally also is applicable to substitution compound (R
2Be not H) (Azabicyclo is respectively V and VI).R
2The method that substituting group can utilize those of ordinary skills to be familiar with is introduced by the alkylation chemistry of standard.1-azabicyclic [3.2.1] suffering-3-ketone or 1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-ketone and hindered base for example LDA (diisopropylamide base lithium) solvent for example THF or ether 0 ℃～-78 ℃ reactions, add alkylating reagent (R2Lv then, wherein Lv=Cl, Br, I, OTs etc.) be warmed to 0 ℃～rt then, carry out aftertreatment then, be provided as the required compound of isomer mixture.Chromatogram splits the alkane ketone that (HPLC or chirality HPLC fast) will provide the purifying that needs.Therefrom, the formation of oxime and reduction subsequently will provide the steric isomer that needs.
Thioamides can prepare by carrying out the direct substitution of thioesters with the amino nitrogen Heterobicyclic compounds from requisite monothioester.Monothioester can be according to JOrganometallicChem., and the method for describing among the 95-98 (1987) is prepared.Those of ordinary skill in the art will recognize soon that described compound also can directly directly prepare from the acid amides of giving an example here, directly for example handle Lawesson ' s reagent (referring to Lawesson etc. with reagent, Bull.Soc.Chim.Belg., 229 (1978)) or P
4S
10(referring to Chem.Rev., 45 (1961)).Perhaps, dithiocarboxylic esters and corresponding amino-Azabicyclic compound reaction can be formed same thioamides.
The preparation of amine:
Outward-(hydropara-toluenesulfonate) synthetic of 3-amino-1-azabicyclic [2.2.1] heptane two (right-tosylate):
The preparation of steps A .2-(benzoyl oxygen base)-1-nitroethane (Int 1)
(14.9mL, (9.2mL is in dry benzene 128mmol) (120mL) solution 128mmol) to join the nitroethyl alcohol of stirring with Benzoyl chloride.Solution refluxed 24 hours and vacuum concentration then.With raw product through the flash chromatography on silica gel purifying.Obtain Int 1 with hexane-ethyl acetate (80: 20) wash-out, be white solid (productive rate 68%):
1HNMR (CDCl
3) δ 8.0,7.6,7.4,4.9,4.8.
The preparation of step B.E-4-(benzylamino)-2-butylene acetoacetic ester (Int 2)
(16mL is in methylene dichloride 146mmol) (200mL) solution under the room temperature E-4-bromo-2-butylene acetoacetic ester (10mL, 56mmol, technical grade) to be joined the benzyl amine of stirring.Reaction mixture was stirred 15 minutes, and dilute with ether (1L).With saturated sodium bicarbonate aqueous solution (3 *) and water washing, dried over sodium sulfate is filtered and vacuum concentration with mixture.With residue through the flash chromatography on silica gel purifying.Obtain Int 2 with hexane-ethyl acetate (70: 30) wash-out, be transparent oily matter (productive rate 62%):
1HNMR (CDCl
3) δ 7.4-7.2,7.0,6.0,4.2,3.8,3.4,2.1-1.8,1.3.
Step C. is anti--preparation of 4-nitro-1-(phenyl methyl)-3-pyrrolidine acetic acid ethyl ester (Int 3)
(6.81g is 34.9mmol) with Int 2 (7.65g, ethanol 34.9mmol) (70mL) solution stirring at room 15 hours, vacuum concentration then with Int 1.Residue is diluted with ether (100mL), and wash with saturated sodium bicarbonate aqueous solution (100mL).Organic layer is separated, and used dried over sodium sulfate, filter and vacuum concentration.With raw product through the flash chromatography on silica gel purifying.Use hexane: ethyl acetate (85: 15) wash-out obtains Int 3, is transparent oily matter (productive rate 76%):
1HNMR (CDCl
3) δ 7.4-7.3,4.8-4.7,4.1,3.8-3.6,3.3-3.0,2.7-2.6,2.4-2.3,1.2.
Step D. is anti--preparation of 4-amino-1-(phenyl methyl)-3-pyrrolidine acetic acid ethyl ester (Int 4)
With Int 3 (3.28g, 11.2mmol) and the mixture of RaNi (1.5g) in ethanol (100mL) is placed in the Parr bottle and (46psi) room temperature hydrogenation 4 hours under nitrogen atmosphere.With mixture filtration over celite pad, and the solvent vacuum removed obtain Int 4, be transparent oily matter (productive rate 100%):
1HNMR (300MHz, CDCl
3) δ 7.37.2,4.1,3.6,3.2,3.0-2.9,2.8,2.8-2.6,2.6-2.4,2.30-2.2,1.2.
Step e. the preparation of trans-4-(1,1-dimethyl ethoxy carbonyl amide group)-(phenyl methyl)-3-pyrrolidine acetic acid ethyl ester (Int 5)
Under ice bath cooling, (3.67g, (2.94g is in methylene dichloride 11.2mmol) (30mL) solution 16.8mmol) to join the Int4 of stirring with two-tertiary butyl pyrocarbonate.Reaction is warmed to room temperature and stirs spend the night.With the mixture vacuum concentration.With raw product through the flash chromatography on silica gel purifying.Obtain Int 5 with hexane-ethyl acetate (80: 20) wash-out, be white solid (productive rate 77%):
1HNMR (300MHz, CDCl
3) δ 7.4-7.2,5.1-4.9,4.1,4.0-3.8,3.6,3.2-3.0,2.8-2.6,2.5-2.4,2.3-2.1,1.4,1.3.
Step F. the preparation of trans (t-butoxycarbonyl amino)-4-(2-hydroxyethyl)-1-(N-phenyl methyl) tetramethyleneimine (Int 6)
Under-5 ℃ of cryostats, with LiAlH
4(627mg, (3.0g is in anhydrous tetrahydro furan 8.3mmol) (125mL) solution 16.5mmol) to join the Int 5 of stirring with short run for powder.Mixture was stirred 20 minutes under-5 ℃ of cryostats, add entry (0.6mL), 15% (w/v) aqueous sodium hydroxide solution (0.6mL) and water (1.8mL) termination reaction then successively.Add excessive Anhydrous potassium carbonate, and mixture was stirred 1 hour, filter then.With the filtrate vacuum concentration.With residue through the flash chromatography on silica gel purifying.Provide Int 6 with eluent ethyl acetate, be white solid (productive rate 94%):
1HNMR (CDCl
3) δ 7.4-7.3,5.3-5.2,4.1-4.0,3.9-3.7,3.3-3.2,2.8-2.7,2.3-2.1,1.7,1.5.
Int 6 is a racemic mixture, can utilize Diacel chiral pack AD post to split by chromatogram.From two enantiomorphs that obtain, utilize the method that provides not have substantial change here, with (+)-enantiomorph, [α]
25 D+ 35 (c1.0, methyl alcohol) obtain the whole compound of outer-4-S of corresponding enantiomer-pure, and (-)-enantiomorph, [α]
25 D34 (c0.98, methyl alcohol) obtain the whole compound of outer-4-R of enantiomer-pure.
The preparation of the outer 3-(t-butoxycarbonyl amino) of step G.-1-azabicyclic [2.2.1] heptane (Int 7)
(8.0g, (2.5g in methylene dichloride 7.8mmol) (50mL) solution, and will be reflected in ice-water-bath and cool off 78.9mml) to join the Int 6 of stirring with TEA.Drip CH then
3SO
2(5.5g 47.8mmol), and stirred mixture 10 minutes Cl on ice-water bath.With the yellow mixture that obtains with saturated sodium bicarbonate aqueous solution dilution, with dichloromethane extraction for several times up to the product that detects with TLC in the water layer noresidue.Organic layer is merged, use the salt water washing, dried over sodium sulfate, and vacuum concentration.Residue is dissolved in the ethanol (85mL) and reflux 16 hours.With the reaction mixture cool to room temperature, transfer in the Parr bottle and also handle with 10% Pd/C catalyzer (1.25g).This bottle was placed on nitrogen atmosphere (53psi) following 16 hours.With the mixture filtration over celite, and add fresh catalyzer (10% Pd/C, 1.25g).Continuing hydrogenolysis spends the night.This process is repeated to finish up to hydrogenolysis more than 3 times.With whole mixture filtration over celite, and vacuum concentration.With residue through the flash chromatography on silica gel purifying.Provide Int 7 with chloroform-methanol-ammonium hydroxide (90: 9.5: 0.5) wash-out, be white solid (46% productive rate):
1HNMR (CDCl
3) δ 5.6-5.5,3.8-3.7,3.3-3.2,2.8-2.7,2.0-1.8,1.7-1.5,1.5.
Step H. is outer-preparation of 3-amino-1-azabicyclic [2.2.1] heptane two (right-tosylate)
(1.46g, (770mg is in ethanol 3.63mmol) (50mL) solution 7.68mmol) to join the Int 7 of stirring with right-toluenesulphonic acids monohydrate.With reaction mixture reflux 10 hours, cool to room temperature then.The vacuum filtration collecting precipitation, and obtain outer-[2.2.1]-3-amine (for racemic mixture) with cold washing with alcohol, be white solid (84% productive rate):
1HNMR (CD
3OD) δ 7.7,7.3,3.9-3.7,3.7-3.3,3.2,2.4,2.3-2.2,1.9-1.8.
That corresponding amine can utilize the Int 6 of fractionation to obtain is outer-(4R)-and [2.2.1]-3-amine and outer-(4S)-[2.2.1]-3-amine.
Synthesizing of interior-3-amino-1-azabicyclic [2.2.1] heptane two (right-tosylate):
Step is hydroxyl-6-oxo-1,2,3 I.5-, the preparation of 6-tetrahydropyridine-4-carboxylic acid, ethyl ester (Int 10)
(92.0mL, (33.2g is 395mmol) in the suspension of dry toluene (0.470L) 1.58mol) to join churned mechanically potassium ethylate with dehydrated alcohol.When mixture reached homogeneous, (33.6g 395mmol), and added oxalic acid diethyl ester (53.1mL, toluene 390mmol) (98mL) solution by dropping funnel then to add 2-Pyrrolidone.After adding is finished, add toluene (118mL) and ethanol (78mL) successively.Mixture heating up was refluxed 18 hours.Mixture is cooled to room temperature, and adds the HCl aqueous solution (the 6.0M solution of 150mL).And with mixture mechanical stirring 15 minutes.With the water layer dichloromethane extraction, and the organic layer that merges is dry on sal epsom, and filtration and vacuum concentration are to yellow residue.Residue is obtained Int 10 from re-crystallizing in ethyl acetate, is yellow solid (38% productive rate):
1HNMR (CDCl
3) δ 11.4,7.4,4.3,3.4,2.6,1.3.
Step J. is suitable-preparation of 3-hydroxyl-2-oxo-piperidine-4-carboxylic acid, ethyl ester (Int 11)
With Int 10 (15g, 81mmol) and the mixture of 5% rhodium-carbon (2.0g) in glacial acetic acid be placed under the nitrogen atmosphere (52psi).With mixture vibration 72 hours.With the mixture filtration over celite, and the filtrate vacuum concentration obtained Int 11 (98% productive rate) into white solid:
1HNMR (CDCl
3) δ 6.3,4.2,4.0-3.8,3.4,3.3-3.2,2.2,1.3.
Step K. the preparation of suitable-4-(hydroxymethyl) piperidines-3-alcohol (Int 12)
Under the ice-water bath condition, (3.7g 19.9mmol) joins the LiAlH of stirring with short run with the Int 11 of solid form
4Tetrahydrofuran solution (the 1.0M solution of 80mL) in.Mixture is warmed to room temperature, and will reacts reflux then 48 hours.Mixture is cooled off on ice-water bath, drip then water (3.0mL, 170mmol), add successively then sodium hydroxide (15% (w/v) solution of 3.0mL) and water (9.0mL, 500mmol).Add excessive salt of wormwood, and with mixture vigorous stirring 15 minutes.Mixture is filtered, and the filtrate vacuum concentration is obtained Int 12, be yellow powder (70% productive rate):
1HNMR (DMSO-d
6) δ 4.3,4.1,3.7,3.5-3.2,2.9-2.7,2.5-2.3,1.5,1.3.
Step L. is suitable-preparation of 3-hydroxyl-4-(hydroxymethyl) piperidines-1-benzyl carboxylate (Int 13)
(3.04g, (1.6g is in the saturated sodium bicarbonate aqueous solution (15mL) 12.2mmol) 12.2mmol) to join the Int 12 of stirring with N-(benzyloxycarbonyloxy base) succinimide under the room temperature.With mixture stirring at room 18 hours.Separating obtains organic and aqueous layer.With water layer with ether extraction (3 *).With the organic layer Anhydrous potassium carbonate drying that merges, filtration and vacuum concentration obtain the Int 13 (99% productive rate) of yellow oily:
1HNMR (CDCl
3) δ 7.4-7.3,5.2,4.3,4.1,3.8-3.7,3.0-2.8,2.1,1.91.7,1.4.
Step M. is suitable-3-hydroxyl-4-[(4-aminomethyl phenyl) and the preparation of alkylsulfonyl oxygen ylmethyl piperidines-1-benzyl carboxylate (Int14)
Under-15 ℃ of cryostats, (1.0g, (3.6g is in pyridine 5.3mmol) (10mL) solution 5.3mmol) to join the Int13 of stirring with p-toluenesulfonyl chloride.Mixture was stirred 4 hours, add HCl (the 6.0M solution of 4.5mL) then.Add methylene dichloride (5mL).Separate organic and aqueous layer.With the water layer dichloromethane extraction.With the organic layer salt water washing that merges, dried over mgso, filtration and vacuum concentration obtain the Int 14 (productive rate 78%) of colorless oil:
1HNMR (CDCl
3) δ 7.8,7.4-7.2,5.1,4.3-4.2,4.1,3.9-3.8,2.9-2.7,2.4,1.9,1.6-1.3.
Step N. is outer-preparation of 1-azabicyclic [2.2.1] heptan-3-alcohol (Int 15)
(3.6g 8.6mmol) is placed under the nitrogen atmosphere with the mixture of 10% Pd/C catalyzer (500mg) in ethanol (50mL) with Int 14.With mixture vibration 16 hours.With the mixture filtration over celite.(1.1g 13mmol) joins in the filtrate, and mixture was heated 5 hours at 50 ℃ in oil bath with solid sodium bicarbonate.Solvent removed in vacuo.Residue is dissolved in the saturated wet chemical.Water layer carries out continuous extraction (18 hours) with liquid-liquid extraction equipment, and is then that organic layer is dry on Anhydrous potassium carbonate, and vacuum is removed the Int 15 (productive rate 91%) that solvent obtains white solid:
1HNMR δ 3.8,3.0-2.8,2.6-2.5,2.4-2.3,1.7,1.1.
In the step O.-[preparation of 2.2.1 heptane (Int 16) of 3-azido--1-azabicyclic
Under ice-water bath, to Int 15 (1.0g, 8.9mmol) and triphenylphosphine (3.0g, 11.5mmol) toluene-tetrahydrofuran (THF) (50mL, 3: 2) add toluene solution (about 2M solution of 15mL) and azepine diethyl dicarboxylate (1.8mL, toluene solution 11.5mmol) (20mL) of hydrazoic acid in the mixture successively.Mixture is warmed to room temperature and stirred 18 hours.With mixture 1.0M HCl aqueous solution extraction.The water layer ethyl acetate extraction, and the organic layer that merges discarded.With 50% aqueous sodium hydroxide solution with water layer pH regulator to 9.Water layer dichloromethane extraction (3 *), and with the organic layer salt water washing that merges, dried over sodium sulfate is filtered and vacuum concentration.With raw product through the flash chromatography on silica gel purifying.With chloroform-methanol-NH
4OH (92: 7: 1) wash-out obtains Int 16, is colourless oily matter (productive rate 41%):
1HNMR (CDCl
3) δ 4.1,3.2,2.8,2.7-2.5,2.2,1.9,1.5.
In the step P.-preparation of 3-amino-1-azabicyclic [2.2.1] heptane two (right-tosylate)
With Int 16 (250mg, 1.8mmol) and the mixture of 10% Pd/C catalyzer (12mg) in ethanol (10mL) be placed under the nitrogen atmosphere (15psi).With mixture stirring at room 1 hour.And with the mixture filtration over celite, and with the filtrate vacuum concentration.Residue is dissolved in the ethanol (10mL), and adding tosic acid monohydrate (690mg, 3.7mmol).Mixture was stirred 30 minutes, and filtering-depositing.To precipitate successively with cold ethanol and ether washing.Precipitation vacuum-drying is obtained interior-[2.2.1]-3-amine (85% productive rate) of white solid:
1HNMR (CD
3OD) δ 7.7,7.3,4.2,3.9,3.6-3.4,3.3-3.2,2.4,2.3,2.1.
3.2.1-the preparation of amine:
Outward-and interior-1-azabicyclic [3.2.1] suffering-3-amine from 1 azabicyclic [3.2.1] suffering-3-ketone (Thill, B.P., Aaron, H.S., J Org Chem., 4376-4380 (1968)) according to Lewin, A.H., et al., the general method of discussing among the J.Med.Chem., 988-995 (1998) is prepared.
Outward-1-azabicyclic [3.2.1] suffering-3-amine dihydrochloride (outer-[3.2.1]-amine):
With 1-azabicyclic [3.2.1] suffering-3-ketone hydrochloride (2.80g, 17.3mmol), (1.56g, (7.07g 51.2mmol) handles mixture 22.4mmol) with sodium acetate trihydrate for ethanol (25mL) and oxyamine hydrochloride.Mixture was stirred 3 hours and vacuum-evaporation.Residue is diluted with methylene dichloride, handle, filter and evaporation with charcoal.The substance dissolves that obtains in 1-propyl alcohol (45mL), and is heated in 100 ℃ of oil baths.Solution is handled with sodium Metal 99.5 (6.4g in batches).Continued heating 3 hours and mixture is cooled to room temperature.Add entry carefully and extract organic layer, dry (sal epsom), filtration, usefulness methyl alcohol/HCl (g) acidifying, and evaporation.Adding 2-propyl alcohol also will obtain solid filtering and vacuum-drying and obtain outer-[3.2.1]-amine, productive rate 49%.C
7H
14N
2(HCl)
2MS (ESI) (M+H)
+M/z=127.
In-1-azabicyclic [3.2.1] suffering-3-amine dihydrochloride (interior-[3.2.1]-amine):
With 1-azabicyclic [3.2.1] suffering-3-ketone hydrochloride (2.80g, 17.3mmol), (1.56g, (7.07g 51.2mmol) handles mixture 22.4mmol) with sodium acetate trihydrate for ethanol (25mL) and oxyamine hydrochloride.Mixture was stirred 3 hours and vacuum-evaporation.Residue is diluted with methylene dichloride, handle, filter and evaporation with charcoal.The oxime (3.1mmol) that obtains handled with acetate (30mL) and at PtO
2(50mg) went up under 50psi hydrogenation 12 hours.Then mixture is filtered and evaporation.Residue is dissolved in the minimum water (6mL), and with solid sodium hydroxide with pH regulator to＞12.Then with mixture with ethyl acetate extraction (4 * 25mL), dried over mgso, filtration, handle with the ethereal solution of HCl, and evaporation obtain in-[3.2.1]-amine.
1-azabicyclic [3.2.1] suffering-3-amine:
3R, 5R-[3.2.1]-preparation of amine:
This amine also can be prepared according to following method:
(3S)-1-[(S)-the 1-styroyl]-5-oxo-3-tetramethyleneimine-carboxylic acid:
According to literature method (J.Med.Chem 1990 such as Nielsen, 70-77), with the methylene radical butyric acid (123.17g, 946.7mmol) and (S)-(-)-(122.0mL, mixture 946.4mmol) heated 4 hours in 160 ℃ of oil baths α-Jia Jibianji amine.After the cooling, adding methyl alcohol (～200mL), and filter and collect the solid that obtains.With the (～700mL) processing and warm until residue～450mL solvent of solid ethanol with vapor bath.After being cooled to room temperature, obtain 83.2g crystalline solid after collection solid and the drying: [α]
25 D=-80 (c 0.97, DMSO).
1HNMR(400MHz，DMSO-d6)δ12.66，7.20-7.40，5.23，3.40-3.55，3.10-3.25，2.40-2.65，1.45；MS(EI)m/z?233(M
+)。
(3S)-the 1-[-1-styroyl]-3-(hydroxymethyl) tetramethyleneimine:
With (3S)-1-[(S)-1-styroyl]-(82.30g, 352.8mmol) suspension in ether (200mL) joins LiAlH with short run to 5-oxo-3-tetramethyleneimine-carboxylic acid
4(17.41g is 458.6mmol) in the slurry in ether (700mL).Mixture begins to reflux in adition process.The addition funnel that will comprise suspension is with ether (2 * 50mL) washings, and with mixture reheat 2 hours in 50 ℃ of oil baths, and at first be cooled to room temperature and further cool off with ice bath then.With mixture water (62mL) processing carefully.With the sedimentation and filtration that generates, wash and discard with ether.Filtrate concentrating obtained yellow oil.When joining ethyl acetate in the oil, begin to form solid.Add hexane then, and obtain 43.3g with the mixture filtration and with solid drying.[α]
25 D=-71 (c0.94, chloroforms);
1HNMR (400MHz, CDCl
3) δ 7.20-7.45,3.60-3.70,3.40-3.60,3.19,3.05-3.15,2.35-2.55,2.252.35,1.95-2.10,1.75-1.90,1.42; C
13H
19The HRMS of NO (FAB) (MH
+) calculated value 206.1545, measured value 206.1532.
(3R)-1-[(S)-the 1-styroyl]-3-(cyano methyl) tetramethyleneimine:
With (3S)-1-[(5)-1-styroyl]-(42.75g, the solution in chloroform 208.23mmol) (350mL) is at N for 3-(hydroxymethyl) tetramethyleneimine
2Following reflux.(41.8mL, chloroform 573mmol) (40mL) solution was handled with 45 minutes thionyl chloride with solution.With mixture restir 30 minutes, cooling also concentrated.(200mL) dilution adds 1N sodium hydroxide until pH～8 (pH test paper) with the residue water.The saturated sodium bicarbonate of adding short run (～50mL), and with alkaline mixt ethyl acetate extraction (3 * 400mL), use the salt water washing, dried over mgso, filtration and concentrating under reduced pressure obtain (3S)-1-[(S)-1-styroyl of 46.51g]-3-(chloromethyl) tetramethyleneimine: MS (ESI+) m/z 224.2 (MH
+).(46.35g 208.0mmol) is transferred in the flask, adds DMSO (200mL), and (17.84g 363.9mmol) handles with NaCN with solution with muriate.With mixture at N
2Heated overnight is cooled off then in 100 ℃ of oil baths.With the mixture impouring of brown to water (300mL), and with ethyl acetate (1000mL, extraction in batches).With the organic layer water that merges (6 *～50mL), salt solution (～100mL) washing, dry (sal epsom) filter and concentrating under reduced pressure obtains the oily matter of 40.61g:
1HNMR(400MHz，CDCl
3)δ7.20-7.40，3.26，2.70-2.85，2.40-2.60，2.27，2.10-2.20，1.50-1.70，1.41；MS(ESI+)：m/z?215.2(M+H
+)。
(3R)-methyl isophthalic acid-[(S)-and the 1-styroyl] tetramethyleneimine-3-acetic ester:
(270mL 3.8mol) joins in the flask that comprises ice-cold (0 ℃) methyl alcohol (1100mL) carefully with Acetyl Chloride 98Min..After adding is finished, acidic solution is stirred 45 minutes (0 ℃), and adds (3R)-1-[(S)-1-styroyl then]-3 (cyano methyl) tetramethyleneimine (40.50g, methyl alcohol 189.0mmol) (200mL) solution.Remove ice bath, and with mixture stirring at room 100 hours.The suspension that obtains is concentrated.Add entry (～600mL), and mixture stirred 45 minutes, and then by the saturated sodium bicarbonate aqueous solution of addings～700mL with pH regulator to alkaline.With mixture ethyl acetate extraction (3 * 300mL).With the organic layer salt water washing that merges, dry (sal epsom), filtration over celite and concentrating under reduced pressure obtain 36.86g oily matter:
1HNMR (400MHz, CDCl
3) δ 7.20-7.40,3.69,3.30-3.40,2.85-2.95,2.40-2.70,2.00-2.20,1.10-1.65; MS (ESI+) m/z248.2 (M+H
+).
(5R)-1-azabicyclic [3.2.1] suffering-3-ketone hydrochloride:
Under nitrogen, with (3R)-methyl 1-[(S)-the 1-phenylethyl] (25.72g, tetrahydrofuran (THF) 104.0mmol) (265mL) solution is at CO for tetramethyleneimine-3-acetic ester
2Cool off on/the acetone bath.Then, add ICH
2Cl (22.7mL, 312.0mmol), and with mixture stirring 30 minutes.With slowly added in 30 minutes 2.0M LDA solution (heptane/tetrahydrofuran/ethylbenzene, 156mL, 312mmol).In adition process, interior temperature maximum reaches-40 ℃.After 1 hour, add saturated NH
4Cl (100mL), and mixture is warmed to room temperature separates organic layer, and dry (sal epsom) filters also and concentrates.The foam that obtains is carried out chromatography, and (300g SiO2, chloroform-methanol-ammonium hydroxide (89: 10: 1) are used chloroform-methanol (3: 1) wash-out then.Collect product level part, and concentrate obtain (5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-nitrogen two ring [3.2.1] octane muriates (10.12g), be foam (MS (ESI+) m/z230.1 (M+H+).(10.1g 38mmol) is dissolved in the methyl alcohol (500mL), adds 10% Pd (C) (3.0g), and mixture hydrogenation (45psi) is spent the night with this foam.Mixture is filtered, and reduce (9.1g, 10% Pd/C, 50psi).After 5 hours, TLC shows (5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-nitrogen two ring [3.2.1] octane muriates are exhausted.Filtering mixt concentrates and grinds (minimum Virahol) and obtains 3.73g, two parts, is solid: [α]
25 D=33 (c0.97, DMSO); C
7H
11The HRMS of NO (FAB) calculated value (M+H
+) 126.0919, observed value 126.0937.
(3R, 5R)-1-azabicyclic [3.2.1] suffering-3-amine dihydrochloride:
To comprise (5R)-1-azabicyclic [3.2.1] suffering-3-ketone hydrochloride (3.64g, 22.6mmol), the oxyamine hydrochloride (2.04g, 29.4mmol) and in the flask of ethanol (130mL), add sodium acetate trihydrate (9.23g, 67.8mmol).Mixture was stirred 3 hours and filtered and concentrates.The white solid that obtains is dissolved in the n-propyl alcohol (100mL), divide add for 20-25 time sodium (13.6g, 618mmol).Reaction spontaneously begins to reflux, and will be reflected at heating in the oil bath (100 ℃), be added in-20 minutes and finish, and mixture was at～40 minutes after fixing.Remove oil bath, and add n-propyl alcohol (2 * 25mL) dissolving metal remained sodium.Mixture is stopped by dripping water (100mL) carefully.Add saturated sodium chloride aqueous solution (20mL), and layering.Methyl alcohol/HCl of organic layer drying (sal epsom), filtration, usefulness prepared fresh is handled, and concentrate.The solid that obtains is ground, filters also vacuum-drying with 30mL ethanol obtain the 3.51g white solid: [α]
25 D=-3 (c 0.94, DMSO);
1HNMR (400MHz, DMSO-d
6) δ 3.60-3.80,2.95-3.10,2.65-2.75,1.90-2.15,1.70-1.90; C
7H
14N
2HRMS (FAB) calculated value (M+H
+) 127.1235, measured value 127.1235.
The preparation of two (tosylate) ([the 3.2.2]-amine) of 1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-amine
The preparation of 4-(2-oxo propylidene) piperidines-1-carboxylic acid tert-butyl ester (Int 101):
(60% oil suspensions, 2.01g is 50.2mmol) with pentane washing (3 *) and be suspended in the dry tetrahydrofuran (40mL) with sodium hydride.Solution is cooled to 0 ℃, drip then diethyl (2-oxopropyl) phosphonic acid ester (9.75g, 50.2mmol).Add finish after, solution be warmed to room temperature and stirred 30 minutes.Added 4-oxo-1-piperidine carboxylic acid tert-butyl ester with 10 minutes (5.0g, 25.1mmol), stirring at room is 2 hours then in batches.Add saturated aqueous ammonium chloride solution, dilute with ether then.The organic layer water is extracted.With the organic layer anhydrous magnesium sulfate drying, filter and the concentrated yellow oil that obtains.With raw product through the flash chromatography on silica gel purifying.Obtain the Int 101 of 4.5g (75%) with hexane-ether (60: 40) wash-out, be white solid:
1HNMR (CDCl
3) δ 6.2,3.5,3.4,2.9,2.3,2.2,1.5.
The preparation of 4-(2-oxopropyl) piperidines-1-carboxylic acid tert-butyl ester (Int 102):
With Int 101 (4.5g, 19mmol) and the mixture of 10% palladium gac (450mg) in ethanol (150mL) be placed in the Parr bottle, and 50psi hydrogenation 5 hours.With the mixture filtration over celite, and the filtrate vacuum concentration obtained the Int 102 of 4.3g (94%), is transparent oily matter:
1HNMR (CDCl
3) δ 4.1,2.8,2.4,2.2,2.0,1.7,1.5,1.1.
The preparation of 4-(3-bromo-2-oxopropyl) piperidines-1-carboxylic acid tert-butyl ester (Int 103):
Under-78 ℃ of cryostats, to the tetrahydrofuran (THF) of the hexamethyl dimethyl silyl acid amides lithium that stirs (20.0mL, 1.0M) in the solution, drip the chlorine trimethyl silane (11.0mL, 86.4mmol).Mixture was stirred 20 minutes at-78 ℃, be added dropwise to Int 102 (3.21g, tetrahydrofuran (THF) 13.3mmol) (50mL) solution then.After adding finishes, mixture was stirred 30 minutes at-78 ℃.Mixture is warmed to 0 ℃ in ice-water bath, and adding phenyltrimethyammonium tribromide (5.25g, 14.0mmol).Mixture was stirred in ice-water bath 30 minutes, add entry and ether then.Water layer is washed with ether, and the organic layer that merges is washed with saturated sodium thiosulfate solution.With the organic layer anhydrous magnesium sulfate drying, filtering also, vacuum concentration obtains xanchromatic oily matter.With rough product purification by flash chromatography on silica gel.Obtain the Int 103 of 2.2g (52%) with hexane-ether (60: 40) wash-out, be xanchromatic oily matter:
1HNMR (CDCl
3) δ 4.2-4.1,3.9,2.8,2.7,2.6,2.1-2.0,1.7,1.5,1.2-1.1.2.
The preparation of 1-bromo-3-piperidin-4-yl acetone trifluoroacetate (Int 104):
Under the ice-water bath condition, to the Int 103 that stirs (2.2g, in methylene dichloride 6.9mmol) (30mL) solution, add trifluoroacetic acid (10mL, 130mmol).Mixture was stirred 30 minutes at 0 ℃.The Int 104 that volatile component obtains 2.0g (87%) is removed in decompression, is xanchromatic residue: C
8H
15The MS of BrNO (ESI): [M+H] m/e 220.
The preparation of 1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-ketone (Int 105):
Under reflux temperature, in acetonitrile (680mL) solution of the DIEA (13mL) that stirs, added Int 104 (2.0g, acetonitrile 6.0mmol) (125mL) solution by syringe pump with 4 hours.Mixture is kept spending the night at reflux temperature.Distribute between saturated wet chemical and chloroform-methanol (90: 10) with the mixture vacuum concentration and with remaining residue.Water layer is extracted with chloroform-methanol (90: 10), and the organic layer that merges is dry on sal epsom, and filtration and vacuum concentration obtain brown oil.With raw product through the flash chromatography on silica gel purifying.Obtain the Int 105 of 600mg (72%) with chloroform methanol-ammonium hydroxide (95: 4.5: 0.5) wash-out, be transparent solid:
1HNMR (CDCl
3) δ 3.7,3.3-3.2,3.1-3.0,2.7,2.3,2.0-1.8.
To the Int 105 that stirs (330mg, 2.4mmol) and sodium acetate trihydrate (670mg, 4.8mmol) add in the mixture in ethanol (6.0mL) the oxyamine hydrochloride (200mg, 2.8mmol).With mixture stirring at room 10 hours.Obtain the xanchromatic solid with the mixture filtration and with the filtrate vacuum concentration.Under reflux temperature, to solid (350mg, 2.3mmol) in the solution of n-propyl alcohol (30mL), with 30 minutes branch short runs add sodium Metal 99.5 (2.0g, 87mmol).Reflux 2 hours.Solution is cooled to room temperature and adds salt solution.Mixture is extracted with n-propyl alcohol, and with the organic layer vacuum concentration that merges.Residue is dissolved in the chloroform, and with residual solid filtering.Filtrate is used anhydrous magnesium sulfate drying, and filtering also, vacuum concentration obtains transparent solid.To the solid that stirs (320mg, 2.3mmol) in the solution of ethanol (4mL), add right-toluenesulphonic acids monohydrate (875mg, 4.6mmol).Water-bath to 45 ℃ warm 30 minutes, concentrated solvent obtained [3.2.2]-amine of 710mg (62%) then, is white solid with solution:
1HNMR (CD
3OD) δ 7.7,7.3,4.1-3.9,3.6-3.4,2.6-2.5,2.4,2.2-2.1,2.1-2.0,1.9.
The fractionation of steric isomer:
But described amine coupling forms suitable racemic mixture acid amides or thioamides.The technology that this racemic mixture can utilize chiral column or chirality HPLC, present technique field to be widely known by the people splits, so that described acid amides or the thioamides enantiomorph 3 (R) and 3 (S) of the fractionation that needs to be provided.
Following embodiment is provided as example and does not mean that embodiment that provides and the compound of mentioning are provided scope of the present invention.Equally, the salt for preparing among the embodiment is also just as exemplifying the illustrative the present invention that is not used for limiting.Can prepare any pharmacologically acceptable salt by arbitrary those of ordinary skill of this area.And the name of concrete steric isomer is explanation for example just, and the disappearance of concrete steric isomer name is for simplicity, and any naming method is not in order to limit the scope of the invention by any way.Present invention resides in the pure stereoisomers form at all optical activity centers and the following example of racemic mixture.
And the embodiment that is provided carries out with concrete amine, as shown in the embodiment.But, do not carry out any important change and can use any disclosed amine, but from suitable amine-initiated.Therefore, the stereospecificity of compound is not drawn and not narration.But scope of the present invention comprises different steric isomer as described herein and racemic mixture.
Amine and necessary sour coupling:
Embodiment 1 (i): outer-4 (S)-N-(1-azabicyclic [2.2.1] heptan-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides fumarate:
With 2-chloro-3-pyridine alcohol (20.0g, 0.154mole), sodium bicarbonate (19.5g, 0.232mole, 1.5equ) and the water of 150mL be placed in the flask.With flask in being placed on 90 ℃ oil bath, after 5 minutes, the aqueous solution (40.5mL with 37% formaldehyde, 0.541mole, 3.5equ) according to following order with six not equal portions add: 12mL, 3 * 8mL is 2.2mL then, with 90-minute at interval, and add last 2.3mL after stirring 15 hours being reflected at 90 ℃ then.To be reflected at 90 ℃ of restir 4 hours, and flask be placed on the ice bath again cooled off then.PH with reaction is adjusted to 1 with 6N HCl then.To react restir 1.5 hours on the ice bath so that unwanted solid forms.Remove by filter unwanted solid, and filtrate is used ethyl acetate extraction 7 times.With the organic extract vacuum concentration that merges, and toluene joined in the flask, and the vacuum azeotropic removes water, adds methylene dichloride and vacuum then and removes and obtain 2-chloro-6-(hydroxymethyl)-3-pyridine alcohol (Cl), for faint yellow solid (81% productive rate), be used for afterreaction enough pure.MS(EI)：C6H6ClNO2，m/z：159(M)
+.
With C1 (11.6g, 72.7mmol) and sodium bicarbonate (18.3g 218mmol) joins in the water of 200mL.Mixture is stirred until forming homogeneous phase, flask is placed in the ice bath, (19.4g 76.3mmol), and will react stirring at room and spend weekend to add iodine.The pH of mixture is adjusted to 3 with the sodium pyrosulfate of 2N, and with mixture with 4 * 50mL ethyl acetate extraction.The organic layer that merges is dry on sal epsom, filter and the filtrate vacuum concentration is obtained the xanchromatic solid.Rough solid is washed so that 2-chloro-6-(hydroxymethyl)-4-iodo-3-pyridine alcohol (C2) to be provided with ethyl acetate, be linen solid (62% productive rate), and filtrate concentrated obtain small volume and on 250g silica gel (230-400 order), carry out chromatography, with 2.5: 4.5: 4: 0.1 ethyl acetate/dichloromethane/hexane/acetate wash-out obtained other pure C2 (12% productive rate).C
6H
5ClINO
2MS (EI), m/z:285 (M)
+
Under nitrogen, with C2 (13.9g, 48.6mmol) with the silica-based acetylene of trimethylammonium first (9.6mL, 68mmol), two (triphenylphosphine) palladium dichloride (1.02g, 1.46mmol) and cuprous iodide (139mg 0.73mmol) mixes in 80mL chloroform/40mL tetrahydrofuran (THF).(21mL 151mmol), and will react stirring at room 3 hours and use the chloroform of 200mL to dilute to add TEA.With mixture with 2 * 150mL, 5% HCl washing and with the water layer that merges chloroform extraction with 2 * 50mL.The organic layer that merges is washed with 100mL 50% saturated sodium-chlor, dry on sal epsom, and vacuum concentration obtains amber oily matter.Thick material is carried out chromatography on 350g silica gel (230-400 order), it is silica-based to obtain 2-chloro-6-(hydroxymethyl)-4-[(trimethylammonium first with 35% ethyl acetate/hexane wash-out) ethynyl]-3-pyridine alcohol C3, be flavous solid (92% productive rate).C
11H
14ClNO
2The MS of Si (EI), m/z:255 (M)
+
With C3 (7.9g, 31.2mmol) and cuprous iodide (297mg, 1.6mmol) suspension at 60mL ethanol/60mL TEA is added in the flask.Placed 3.5 hours being reflected in 70 ℃ the oil bath, and be cooled to room temperature and vacuum concentration.Residue (is distributed between 4 * 50mL) at 100mL 5% HCl and methylene dichloride.Organic layer drying, filtration and the vacuum concentration on sal epsom that merges obtained the rough amber solid of 6.5g.Thick material is carried out chromatography on 300g silica gel (230-400 order), with 30-40% ethyl acetate/hexane wash-out.Two groups of level parts of 2 different required compounds are proved conclusively with TLC/UV.2 kinds of compounds of difference wash-out.The level that elutes in early days part merged and concentrate obtain [7-chloro-2 (the trimethylammonium first is silica-based) furo [2,3-c] pyridine-5-yl] methyl alcohol (C5), be white solid (46% productive rate).The level of wash-out after a while part is merged and concentrate, be white solid (27% productive rate) so that (7-chlorine furo [2,3-c] pyridine-5-yl) methyl alcohol (C4) to be provided.The C of C4
8H
6ClNO
2MS (EI), m/Z:183 (M)
+C to C5
11H
14ClNO
2The HRMS of Si (FAB) calculated value m/z:255.0482, measured value 255.0481.
(1.05g 4.1mmol) is placed in the 20mL absolute ethanol with 10% Pd/C catalyzer (1.05g) with C5.(4mL 40.1mmol), and will react backflow 2.5 hours, and filtration over celite then to add tetrahydrobenzene.Filter cake is washed with 1: 1 ethanol/dichloromethane, and filtrate concentrating obtained faint yellow solid.Residue is distributed in the saturated sodium bicarbonate of 40mL, and with dichloromethane extraction (4 * 20mL).With the organic layer that merges with dried over mgso, filtration and then vacuum concentration obtain white oily matter (1.04g).The oily matter of white is carried out chromatography at 50g silica gel (230-400 order), with 50-70% ethyl acetate/hexane wash-out obtain 5-hydroxymethyl-2-trimethylammonium first silica-based-furo [2,3-c] pyridines (C14) are white solid (90% productive rate).The MS of C11H15NO2Si (EI), m/z:221 (M)
+
(770mg 3.48mmol) is dissolved in the methyl alcohol of 10mL with C14.(3mL 6mmol), and will react stirring at room 1.5 hours to add 2N sodium hydroxide.Solution for vacuum concentration is obtained residue.(20mL) joins in the residue with water, and with 4 * 10mL dichloromethane extraction.The organic layer that merges is obtained furo [2,3-c] pyridine-5-base methyl alcohol (C16) with Anhydrous potassium carbonate drying, filtration and vacuum concentration, be white solid (90% productive rate).C
8H
7NO
2Theoretical value: C, 64.42; H, 4.73; N, 9.39.Actual value: C, 64.60; H, 4.56; N, 9.44.
In dry flask, (685 μ L 7.8mmol) are dissolved in the 30mL methylene dichloride with oxalyl chloride under nitrogen.To be placed in the flask in the dry ice/acetone batch, dropping DMSO (1.11mL, 5mL dichloromethane solution 15.6mmol), and with mixture stirring 20 minutes.Adding C16 (1.0g, 10mL dichloromethane solution 6.7mmol), and will be reflected at-78 ℃ of stirrings 30 minutes.(4.7mL 33.5mmol), is warmed to room temperature with reaction, stirs 1 hour, and washs with the saturated sodium bicarbonate of 25mL to add TEA.The useless aqueous carbonate potassium of organic layer drying, filtration and vacuum concentration are obtained orange solid.Thick material is carried out chromatography at 50g silica gel (230-400 order), so that furo [2,3-c] pyridine-5-carboxylic aldehyde (C17) to be provided, be white solid (86% productive rate) with 33% ethyl acetate/hexane wash-out.C
8H
5NO
2MS (EI), m/z:147 (M)
+
(850mg 5.8mmol) is dissolved among the 10mL DMSO with C17.(221mg, 3mL aqueous solution 1.6mmol) adds NaClO then to add potassium primary phosphate
2(920mg, 7mL aqueous solution 8.2mmol), and will react stirring at room 3 hours.To react with the dilution of 25mL water, pH will be adjusted to 10 with 2N sodium hydroxide, and mixture will be extracted (3 * 20mL) with ether.Blended ether layer is discarded.With the pH regulator to 3.5 of the 10%HCl aqueous solution, and extract with 13 * 10Ml, 10% ethanol/methylene with water layer.The ethanol/methylene organic layer is obtained the oily matter of white with anhydrous sodium sulfate drying, filtration and vacuum concentration.Under the room temperature nitrogen gas stream, residual DMSO is removed so that the mashed prod of white to be provided.Be dissolved in mashed prod in the methyl alcohol and be concentrated into dried.The solid of white is obtained rough furo [2,3-c] pyridine-5-carboxylic acid (C18) (94% productive rate) with ether washing and drying.C
8H
5NO
3MS (ESI), 162.8 (MH)
-
The preparation of step 1a. carboxylic acid amides:
(294mg is 1.80mmol) at dry tetrahydrofuran-DMF (12mL to furo [2, the 3-c] pyridine-5-carboxylic acid (C18) that stirs, 5: 1) solution in, add DIEA (956gel, 5.49mmol), outside adding then-(4S)-[2.2.1]-3-amine (747mg, 1.64mmol).Solution is cooled off with ice bath, add then HATU (684mg, 1.80mmol).Solution is warmed to room temperature and stirred 16 hours.Vacuum is removed solvent, and with residue at saturated wet chemical and chloroform-methanol between distribute at 9: 1.Water layer is extracted with 9: 1 chloroform-methanols, and with the organic layer salt water washing that merges, dried over mgso, filtration and vacuum concentration obtain the carboxylic acid amides of needs, are jonquilleous solid (420mg, 100%): C
14H
16N
3O
2MS (ESI) m/z 258 (M+H).
The preparation of step 1b. fumarate
(200mg in acetone 0.78mmol) (5mL) solution, adds fumaric acid (90mg, IPA 0.78mmol) (2mL) hot solution to the step 1a product that stirs.With mixture 50 ℃ of stirred in water bath 30 minutes.Vacuum is removed solvent, and residue is dissolved in the acetone (5mL).With the mixture stirred overnight at room temperature.The solid collected by filtration precipitation, and use washing with acetone.Embodiment 1 (i) with solid vacuum-drying is spent the night and obtained 156mg (54%) is white solid:
1HNMR (CD
3OD) δ 8.9,8.5, and 8.1,7.1,6.7,4.3,3.7,3.6,3.4,3.3,3.2,3.1,2.2,1.9.
Embodiment 1 (i-b): outer-4 (R)-N-(1-azabicyclic [2.2.1] heptan-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides, use outer-(4R)-[2.2.1]-3-amine:
1HNMR (400MHz, methyl alcohol-d
4) δ 8.9,8.5,8.1,7.1,6.7,4.3,3.7,3.6,3.4,3.3,3.2,3.1,2.2,1.9.
Embodiment 1 (i-c):
Outward-and (racemic)-N-(1-azabicyclic [2.2.1] heptan-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides, use outer-[2.2.1]-3-amine.
Embodiment 1 (i-d):
In (+)-N-[-1-azabicyclic [2.2.1] heptan-3-yl] furo [2,3-c] pyridine-5-carboxylic acid amides and
Embodiment 1 (i-e):
In (-)-N-[-and 1-azabicyclic [2.2.1] heptan-3-yl] furo [2,3-c] pyridine-5-carboxylic acid amides:
To furo [2, the 3-c] pyridine-5-carboxylic acid that stirs (400mg, 0.877mmol) in the solution of dry DMF (10mL), add DIEA (626uL, 3.59mmol) and interior [2.2.1]-3-amine (175mg, 0.877mmol).Mixture is cooled to 0 ℃ in ice bath, and a add HATU (333mg, 0.877mmol).Reaction mixture is warmed to room temperature and stirs spend the night.Vacuum is removed solvent, and residue is distributed between saturated wet chemical and chloroform.Water layer is extracted with chloroform (2 *).With the organic layer salt water washing that merges, use dried over sodium sulfate, filtering also, vacuum concentration obtains the 230mg solid.Use Chiralcel OJ post to utilize chromatogram to split racemic mixture.Acid amides is changed into the form of its fumarate, as shown in step 1b.(+)-enantiomorph ([α]
25 D31 (c0.28, methyl alcohol)) obtain embodiment 1-d, and (-)-enantiomorph ([α]
25 D-31 (c0.30, methyl alcohol)) obtain embodiment 1-e.For embodiment 1-d:
1HNMR (400MHz, CD
3OD) δ 8.94,8.46,8.14,7.13,6.71,4.75-4.70,3.86-3.79,3.48-3.42,3.28-3.21,2.21-2.03.
Embodiment 1 (i-f)
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides:
This embodiment is prepared according to coupling method discussed here.
Embodiment 1 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides:
This embodiment is prepared according to coupling method discussed here.
Embodiment 1 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl) furo [2,3-c] pyridine-5-carboxylic acid amides:
This embodiment is prepared according to coupling method discussed here.
Embodiment 1 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl) furo [2,3-c] pyridine-5-carboxylic acid amides:
This embodiment is prepared according to coupling method discussed here.
Embodiment 1 (v):
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides:
The coupling productive rate is 70%.C
15H
17N
3O
2HRMS (FAB) calculated value (MH+) 272.1399, observed value 272.1413.
Embodiment 1 (vi):
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides fumarate:
The embodiment 1 that obtains (vi) be white solid:
1HNMR (CD
3OD) δ 8.9,8.4,8.1,7.1,6.7,4.8-4.7,3.8,3.7-3.6,3.5-3.3,2.4,2.2-2.0.
Embodiment 2 (i):
N-[(is outer-1-azabicyclic [2.2.1] heptan-3-yl] and furo [3,2-c] pyridine-6-carboxylic acid amides:
(8.99mL 100.0mmol) is dissolved among the DMF (8.5mL), is cooled to 0 ℃, with dripping POCl with 3-bromine furans
3(9.79mL 105.0mmol) handles, stirring at room 1 hour and then 80 ℃ of heating 2 hours.Mixture is cooled to RT, is poured on the ice (1kg), and be neutralized to pH9 with solid carbonic acid potassium.Mixture was stirred 1 hour, and (3 * 500mL), the salt of wormwood drying also concentrates the oily matter that obtains brownish black with extracted with diethyl ether.Thick material on piling up silica gel, the 600g pulpous state is carried out chromatography, with 6% ethyl acetate/hexane (4L), 8% ethyl acetate/hexane (2L), 10% ethyl acetate/hexane (1L) and finally use 20% ethyl acetate/hexane wash-out.Suitable level part merged and vacuum concentration obtains the 3-bromo-2-furfural of 14.22g (81%), be xanchromatic oily matter.MS(EI)m/z：174(M
+)。
With 3-bromo-2-furfural (14.22g, 81.3mmol) with ethylene glycol (6.55mL, 117.4mmol) and the tosic acid monohydrate (772mg 4.06mmol) mixes in benzene (200mL), and use Dean-Stark trap reflux 5 hours.Add again ethylene glycol (1.64mL, 29.41mmol) and benzene (150mL), and with solution reheat 2 hours.Mixture is cooled to RT, handles and stirred 0.5 hour with saturated sodium bicarbonate.Layering is also dry and concentrate and obtain brown oil (18.8g) on sodium sulfate with organism.The silica gel that thick material is filled at the 700g pulpous state carries out chromatography, with 15% ethyl acetate/hexane wash-out.Suitable level part merged and vacuum concentration obtains the 2-(3-bromo-2-furyl)-1 of 16.45g (92%), 3-two penta ring is orange-yellow oily matter.MS(EI)m/z：218(M+)。
In nitrogen, in dry flask, with 2-(3-bromo-2-furyl)-1,3-two penta ring (438mg 2.0mmol) is dissolved in the ether (5mL), is cooled to-78 ℃, drip tert-butyl lithium (2.59mL, 4.4mmol) and stirred 1 hour.Drip DMF (178, uL, ether 2.3mmol) (2mL) solution, and mixture stirred 4 hours at-78 ℃, (504mg 4.0mmol) handles, and adds entry (2mL) then to use oxalic acid dihydrate then.Remove cryostat, and mixture was warmed to room temperature 1 hour.With the dilution of mixture water (20mL) and ethyl acetate (20mL), layering and with water layer with ethyl acetate extraction (1 * 20mL).With organism dry and concentrated xanchromatic oily matter that obtains on sodium sulfate.Thick material is carried out chromatography on the silica gel that the 12g pulpous state is filled, with 15% ethyl acetate/hexane wash-out.Merge 2-(1,3-dioxolane-2-yl)-3-furfural that suitable level part and vacuum concentration obtain 228mg (68%), be lurid oily matter.MS(EI)m/z：168(M
+)。
With 2-(1,3-dioxolane-2-yl)-3-furfural (2.91g, 17.31mmol) with formic acid (17mL, 451mmol) and water (4.25mL) mixing, and stirring at room 18 hours.Mixture is slowly transferred to sodium bicarbonate, and (45g in water 541mmol) (600mL) solution, stirred 0.5 hour then.Add ethyl acetate (200mL), layering, and with water layer ethyl acetate extraction (2 * 200mL).With the organic layer dry and concentrated xanchromatic oily matter (3.28g) that obtains on sodium sulfate that merges.The silica gel that thick material is filled at the 90g pulpous state carries out chromatography, with 20% ethyl acetate/hexane wash-out.Merge suitable level part, and concentrate the furans-2 that obtains 2.45g, 3-dicarboxyl aldehyde comprises a spot of glycol diformate, is xanchromatic oily matter.
1HNMR(CDCl
3)：δ7.00(d，J＝2Hz，1H)，7.67(d，J＝2Hz，1H)，10.07(s，1H)，10.49(s，1H)ppm。
With methyl (acetylamino) (dimethoxy phosphoryl) acetic ester (2.34g; 9.8mmol) be dissolved in the chloroform (40mL); with DBU (1.46mL; 9.8mmol) handle; stirred 5 minutes; drop to 0 ℃ furans-2 then, (1.65g is in chloroform 8.9mmol) (80mL) solution for 3-dicarboxyl aldehyde.Mixture was stirred 2.5 hours, and after cooling stopped, stirring at room also stirred 24 hours at 50 ℃ in 5.5 hours at last then.The mixture vacuum concentration is obtained xanchromatic oily solid (6.66g).Thick material is carried out chromatography at the silica gel of the filling of the 100g of standard pulpous state, with 65% ethyl acetate/hexane wash-out.Merge furo [3,2-c] pyridine-6-carboxylic acid methyl ester that suitable level part and vacuum concentration obtain 1.30g (82%), be the xanchromatic solid.MS(EI)m/z：177(M+)。
(1.55g 8.74mmol) is dissolved in methyl alcohol (30mL) and the water (15mL), handles and stirring at room 7 hours with 3N sodium hydroxide (6.4mL) with furo [3,2-c] pyridine-6-carboxylic acid methyl ester.Mixture is concentrated into dried, is dissolved in the water (10mL) and and is acidified to pH 2 with concentrating hydrochloric acid.Solution concentration to doing, is suspended in the water (7mL) of small volume, and collects the solid (lot A) that generates by filtering.Filtrate is concentrated, and water (3mL) grinds, and filters and collect the solid (lot B) that generates.Concentrate filtrate, do not carry out further purifying and make it to become acid/salt mixture (lot C) from lot B.With lot A and B 50 ℃ of dryings 18 hours in vacuum drier, obtain the lot A of 690mg (48%) and the lot B of 591mg (42%), be furo [3, the 2-c] pyridine-6-carboxylic acid of yellow solid.MS(CI)m/z：164(M+H
+)。
Embodiment 2 (i), 2 (i-a), 2 are (ii), 2 (iii), 2 (iv) and 2 (vi) can utilize method described herein to be prepared, not carry out any material alterations.
Embodiment 2 (i-a):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl) furo [3,2-c] pyridine-6-carboxylic acid amides
Embodiment 2 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl) furo [3,2-c] pyridine-6-carboxylic acid amides
Embodiment 2 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl) furo [3,2-c] pyridine-6-carboxylic acid amides
Embodiment 2 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl) furo [3,2-c] pyridine-6-carboxylic acid amides
Embodiment 2 (v)
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [3,2-c] pyridine-6-carboxylic acid amides:
The coupling productive rate is 94%.
1HNMR(400MHz，CD
3OD)δ9.30，8.75-8.80，8.35-8.45，7.35-7.45，4.65-4.80，3.25-3.80，2.85-2.95，2.30-2.45，2.10-2.25，1.95-2.10。
Embodiment 2 (vi):
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl) furo [3,2-c] pyridine-6-carboxylic acid amides
Embodiment 3 (i):
N-(1-azabicyclic [2.2.1]-heptan-3-yl)-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also:
Under nitrogen, in dry flask, (3.1mL 35mmol) is dissolved in the 200mL methylene dichloride with oxalyl chloride.Flask is placed in-78 ℃ the dry ice/acetone batch, drips DMSO (4.95mL, 10mL dichloromethane solution 70mmol), and mixture stirred 20 minutes.Adding (7-chlorine furo [2,3-c] pyridine-5-yl) methyl alcohol (C4) (5.5g, 10mL dichloromethane solution 30mmol), and will be reflected at-78 ℃ of stirrings 30 minutes.Add then TEA (21.3mL, 153mmol).To be reflected in the dry ice/acetone batch and stir 30 minutes, replace dry ice/acetone batch, and will react and stir 1 hour, and wash with 1: 1 of 100mL saturated sodium-chlor/sodium bicarbonate with ice bath.Organic layer is obtained 7-chlorine furo [2,3-c] pyridine-5-carboxylic aldehyde (C6) with Anhydrous potassium carbonate drying, filtration and vacuum concentration, be flaxen solid (97% productive rate).C
8H
4ClNO
2MS (EI) m/z:181 (M)
+
(3.0g 16.5mmol) is dissolved among the 40Ml DMSO with C6.Add potassium primary phosphate (561mg, 6.5mL aqueous solution 4.1mmol).And add NaClO then
2(2.6g, 24mL aqueous solution 23.1mmol), and will react stirred overnight at room temperature.To react with the dilution of 200mL water, and pH will be adjusted to 9 with 2N sodium hydroxide, and any residual aldehyde is extracted in 3 * 50mL ether.With the pH regulator to 3 of 10% hydrochloric acid with water layer, and with 4 * 50mL ethyl acetate extraction.The organic layer drying, filtration and the vacuum concentration on sal epsom that merge are obtained white solid.Solid is washed with ether, and drying obtains 7-chlorine furo [2,3-c] pyridine-5-carboxylic acid (C7) (55% productive rate).C
8H
4ClNO
3MS (CI) m/z:198 (M+H).
Shake in the bottle at 250mL Parr, (980mg 4.98mmol) is dissolved in the 75mL methyl alcohol, comprises 500mG20% palladium hydroxide-charcoal with C7.With reaction mixture 20PSI hydrogenation 24 hours.Catalyzer is removed after filtration, and the filtrate vacuum concentration is obtained white solid.Solid is dissolved in the methyl alcohol, and loads on the 20mL Dowex 50W-X2 ion exchange resin (hydrogen ion type), the latter uses the methyl alcohol pre-wash.With post 50mL methanol-eluted fractions, the methanol solution wash-out with 5% TEA of 150mL obtains also [2,3-c] pyridine-5-carboxylic acid (C8) (74% productive rate) of 2,3 dihydro furan then.C
8H
7NO
3The HRMS of+H (FAB) calculated value: 166.0504, actual value 166.0498 (M+H).
Use C8 to prepare embodiment 3 (i-a) according to coupling method discussed here.
Following embodiment is prepared according to coupling method discussed here:
Embodiment 3 (i-a):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also
Embodiment 3 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also
Embodiment 3 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also
Embodiment 3 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also
Embodiment 3 (v):
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also for N-
Embodiment 3 (vi):
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also
Embodiment 4 (i):
N-(1-azabicyclic [2.2.1] heptan-3-yl)-7-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides:
Embodiment 4 (i) can-[2.2.1]-3-amine outer by coupling or interior-[2.2.1]-3-amine and 7-chlorine furo [2,3-c] pyridine-5-carboxylic acid (C7) prepare.
Following embodiment is prepared according to coupling method discussed here:
Embodiment 4 (i-a):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-7-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 4 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-7-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 4 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl)-7-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 4 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-7-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 4 (v):
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-7-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 5 (i):
N-(1-azabicyclic [2.2.1] heptan-3-yl)-3,3-dimethyl-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also:
Under nitrogen, (6.3g 22mmol) is dissolved among the 30Ml DMF with 2-chloro-6-(hydroxymethyl)-4-iodo-3-pyridine alcohol (C2) in dry flask.Flask is placed in the ice bath, and add 60% sodium hydride mineral oil (880mg, 22mmol).To react and stir 30 minutes, simultaneously flask be remained in the ice bath.Removed ice bath 30 minutes, and then flask is placed in the ice bath again with the cooling reaction.Add 3-bromine 2-methacrylic (23.1mmol), and will react stirred overnight at room temperature.To react with the dilution of 150mL ethyl acetate and with 4 * 50mL, 50% saturated 1: 1 sodium-chlor/sodium bicarbonate and wash.With organic layer with anhydrous sodium sulfate drying, filtration and then vacuum concentration obtain the oily matter of light color, crystallization obtains (6-chloro-4-iodo-5-[(2-methyl-2-propenyl) oxygen base from hexane]-the 2-pyridyl) methyl alcohol (C19) (86% productive rate).C
10H
11ClINO
2The HRMS of+H (FAB) calculated value: 339.9603, actual value 339.9604 (M+H).
Under nitrogen, with C19 (6.3g, 18.9mmol), sodium formiate (1.49g, 21.8mmol), TEA (8mL, 57.2mmol), acid chloride (202mg, 0.9mmol) and four (normal-butyl) ammonium muriate (5.25g 18.9mmol) joins among the 30mL DMF in the dry flask.To be reflected at 60 ℃ warm 5 hours, be poured in the 150mL ethyl acetate, and with 4 * 50mL, 50% saturated 1: 1 sodium-chlor/sodium bicarbonate washing.Organic layer is obtained light oily matter with anhydrous sodium sulfate drying, filtration and vacuum concentration.Thick material is carried out chromatography on 40g silica gel (Biotage), obtain (7-chloro-3,3-dimethyl-2,3 dihydro furan be [2,3-c] pyridine-5-yl also) methyl alcohol (C20) (54% productive rate) with 30% ethyl acetate/hexane wash-out.C
10H
12ClNO
2MS (EI), m/z:213 (M)
+
With C20 (2.11g, 9.9mmol) and the 10% Pd/C catalyzer of 600mg be placed on and be equipped with in the 30mL alcoholic acid 250mL Parr vibration bottle.Add then 2N sodium hydroxide (5mL, 10mmol) and with mixture 20PSI hydrogenation 2.5 hours.Remove catalyzer after filtration, and the filtrate vacuum concentration is obtained the aqueous solution of residue.Saturated sodium bicarbonate (20mL) is joined in the residue also with 4 * 20mL dichloromethane extraction.The organic layer that merges is obtained (3,3-dimethyl-2,3 dihydro furan is [2,3-c] pyridine-5-yl also) methyl alcohol (C21) (92% productive rate) with Anhydrous potassium carbonate drying, filtration and vacuum concentration.C
10H
13NO
2MS (EI), m/z:179 (M)
+
Under nitrogen, (869 μ L 9.9mmol) are dissolved in the 50mL methylene dichloride in the dry flask with oxalyl chloride.Flask is placed in-78 ℃ the dry ice/acetone batch, drips DMSO (1.41mL, 5mL dichloromethane solution 19.8mmol), and mixture stirred 20 minutes.Add C21 (1.53g, 5mL dichloromethane solution 8.5mmol), and will be reflected at-78 ℃ and stir 30 minutes then.(5.9mL 42.5mmol) also will be reflected at-78 ℃ and stir 20 minutes to add TEA.Remove dry ice/acetone batch, and will react and stir 1 hour, and will react saturated sodium bicarbonate washing with 25mL.With organic layer with Anhydrous potassium carbonate drying, filtration and then vacuum concentration obtain orange solids.Thick material is carried out chromatography on 40g silica gel (Biotage), obtain 3 with 25% ethyl acetate/hexane wash-out, 3-dimethyl-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic aldehyde C22 (92% productive rate) also.C
10H
11NO
2MS (EI), m/z:177 (M)
+
(1.35g 7.62mmol) is dissolved in 40mL tetrahydrofuran (THF), the 20mL trimethyl carbinol and the 20mL water with C22.Add potassium primary phosphate (3.11g, 22.9mmol) and NaClO
2(2.58g 22.9mmol), and will react stirring at room and spend weekend.To react vacuum concentration and obtain residue.Residue (is distributed between 2 * 50mL) at 20mL water and methylene dichloride.With the organic layer that merges with anhydrous sodium sulfate drying, filtration and then vacuum concentration obtain roughly 3,3-dimethyl-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid (C23) (99% productive rate) also.C
10H
11NO
3The HRMS of+H (FAB) calculated value: 194.0817, actual value 194.0808 (M+H).
Embodiment 5 (i) can prepare by utilizing coupling method discussed here to carry out coupling with outer-[2.2.1]-3-amine or interior-[2.2.1]-3-amine C23.
Following embodiment is prepared according to coupling method discussed here:
Embodiment 5 (i-a):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-3,3-dimethyl-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also
Embodiment 5 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-3,3-dimethyl-2,3 dihydrofuran is [2,3-c] pyridine-5-carboxylic acid amides also
Embodiment 5 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3,3-dimethyl-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also
Embodiment 5 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3,3-dimethyl-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also
Embodiment 5 (v):
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3,3-dimethyl-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also
Embodiment 6 (i):
N-(1-azabicyclic [2.2.1] heptan-3-yl)-2-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also:
Under nitrogen, in dry flask, with 2-chloro-6-(hydroxymethyl)-4-iodo-3-pyridine alcohol C2 (4.6g, 16mmol), propargyl trimethyl silyl (2g, 17.8mmol), two (triphenylphosphine) palladium dichloride (156mg, 0.21mmol), cuprous iodide (122mg, 0.64mmol) and piperidines (3.52mL is among the 25mL DMF that 26.6mmol) joins.With mixture 45 ℃ warm 7 hours, stirred overnight at room temperature, and dilute with the 150mL ethyl acetate.Mixture is washed with 4 * 50mL, 50% saturated 1: 1 sodium-chlor/sodium bicarbonate.With organic layer drying anhydrous sodium sulfate, filtration and then vacuum concentration obtain amber oily matter.Thick material is carried out chromatography on 40g silica gel (230-400 order), obtain (7-chloro-methyl furan is [2,3-c] pyridine-5-yl also) methyl alcohol C24 (44% productive rate) with 35% ethyl acetate/hexane wash-out.C
9H
8ClNO
2MS (CI), m/z:198 (M+H).
(2.0g 10.8mmol) joins and is equipped with in 500mg 10% Pd/C catalyzer and the 25mL alcoholic acid 250mL Parr vibration bottle with C24.(6mL 12mmol), and will be reflected at 20PSI hydrogenation 6 hours to add 2N sodium hydroxide.Remove catalyzer after filtration, and the filtrate vacuum concentration is obtained the aqueous solution of residue.Residue is distributed between saturated sodium-chlor of 50mL 50% and 30mL methylene dichloride.With organic layer with Anhydrous potassium carbonate drying, filtration and then vacuum concentration obtain (the 2-methyl furan is [2,3-c] pyridine-5-yl also) methyl alcohol (C25) (77% productive rate).C
9H
9NO
2MS (CI), m/z:164 (M+H).
Under nitrogen, in dry flask, (784 μ L 8.9mmol) are dissolved in the 25mL methylene dichloride with oxalyl chloride.To be placed in the flask in-78 ℃ the dry ice/acetone batch, and add DMSO (1.26mL, 5mL dichloromethane solution 17.8mmol).Mixture was stirred 20 minutes and add C25 (1.53g, 5mL dichloromethane solution 8.5mmol).And will react and stir 1 hour, (5.9mL 42.5mmol), and will be reflected at-78 ℃ of stirrings 30 minutes to add TEA.Flask is placed in the ice bath, and will reacts and stir 1 hour.Reaction is washed with the saturated sodium bicarbonate of 50mL.With organic layer with Anhydrous potassium carbonate drying, filtration and then vacuum concentration obtain the solid of brown.Thick material is carried out chromatography on 40g silica gel (Biotage), obtain also [2,3-c] pyridine-5-carboxylic aldehyde (C26) (99% productive rate) of 2-methyl furan with 25% ethyl acetate/hexane wash-out.C
9H
7NO
2MS (EI), m/z:161 (M)
+
(1.15g 7.1mmol) is dissolved in 40mL tetrahydrofuran (THF), the 20mL trimethyl carbinol and the 20mL water with C26.Add the 2-methyl-2-butene (6.5mL, 57.4mmol), and add then potassium primary phosphate (3.11g, 22.9mmol) and NaClO
2(2.58g, 22.9mmol).To react stirring at room 6 hours.To react vacuum concentration.(20ml) joins in the residue with water, white solid occurs.The collection white solid washes with water and washs with ether then and drying obtains also [2,3-c] pyridine-5-carboxylic acid (C27) (70% productive rate) of 2-methyl furan.C
9H
7NO
3MS (EI), m/z:177 (M)
+
Embodiment 6 (i) can by will outer-[2.2.1]-3-amine or interior [2.2.1]-3-amine carry out coupling with C27 and obtain preparing.
Following embodiment is prepared according to coupling method discussed here:
Embodiment 6 (i-a):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-2-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also
Embodiment 6 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-2-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also
Embodiment 6 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also
Embodiment 6 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also
Embodiment 6 (v):
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also for N-
Embodiment 7 (i):
(S)-N-(1-azabicyclic [2.2.1] heptan-3-yl)-3-methyl furan [2,3-c] pyridine-5-carboxylic acid amides fumarate also outward-4:
Under nitrogen, in dry flask, with 2-chloro-6-(hydroxymethyl)-4-iodo-3-pyridine alcohol (C2) (7.14g, 25.0mmol) among the dissolved DMF (50mL), (1.0g 25.0mmol), and will react stirring at room 1 hour to add sodium hydride (60% in mineral oil dispersion).Add allyl bromide 98 (2.38mL, 27.5mmol), and with reaction mixture stirring at room 48 hours.Mixture is washed with ethyl acetate (50mL) dilution and with 50% of 4 * 25mL saturated 1: 1 sodium-chlor/sodium bicarbonate of solution.Organic layer is dry on sal epsom, and filtering also, vacuum concentration obtains white solid.Solid is obtained 3-(allyloxy)-2-chloro-6-(hydroxymethyl)-4-iodine pyridine (C50) with hexane wash and drying, be white solid (68% productive rate).C
9H
9ClINO
2MS (EI), m/z:325 (M)
+
Under nitrogen, (5.51g is 16.9mmol) in the suspension benzene (30mL) with C50 in dry flask.(289mg 1.8mmol), quickly heats up to backflow with mixture, and adds tributyltin hydride (4.91mL, benzene 18.2mmol) (10mL) solution to add azo (two) isobutyryl nitrile.Solution was refluxed 1.5 hours, be cooled to room temperature and vacuum concentration.The residue that obtains is carried out chromatography on the silica gel that the 125g pulpous state is filled, obtain (7-chloro-3-methyl 2 with ethyl acetate/hexane (20%-60%) gradient elution, the 3-dihydrofuran is [2,3-c] pyridine-5-yl also) methyl alcohol (C51), be white solid (89% productive rate).For C
9H
10ClNO
2The MS of+H (ESI), m/z:200.1 (M+H).
In Parr vibration bottle, with C51 (3.00g, 15.0mmol) join 20% palladium hydroxide charcoal (800mg) and 2N sodium hydroxide (9.2mL, 18.2mmol) in.20PSI hydrogenation 3 hours, filtration over celite and vacuum concentration obtained residue with mixture.The residue that obtains (is distributed between 4 * 30mL) at water (50mL) and methylene dichloride.With the organic layer that merges through dried over mgso, filtration, and concentrate and obtain colourless oily matter, place after fixing, obtain (3-methyl-2,3 dihydro furan also [2 of 2.50g (greater than 100% productive rate), 3-c] pyridine-5-yl) methyl alcohol (C52), be white crystalline solid.For C
9H
11NO
2MS (EI): 165 (M)
+
(2.48g 15.03mmol) is dissolved in the pyridine (15mL), and (4.18mL, stirring at room is 16 hours 45.09mmol) and under nitrogen to add diacetyl oxide with C52.To react vacuum concentration, and residue is diluted with ethyl acetate (75mL), (4 * 30mL) wash, and use dried over mgso with 50% saturated sodium bicarbonate.Organic layer filtration and vacuum concentration are obtained (3-methyl-2,3 dihydrofuran is [2,3-c] pyridine-5-yl also) methyl acetic acid ester (C53), be colourless oily matter (92% productive rate).For C
11H
13NO
3MS (EI), m/z:207 (M)
+
(2.85g 13.8mmol) is dissolved in the two alkane (100mL), adds 2,3,5, and (3.72g 15.1mmol), and will react reflux 17 hours to the 6-tetrachlorobenzoquinone with C53.To react vacuum concentration.The brown solid that obtains with the washing of 1: 1 ethylacetate/ether (50mL), is removed by filter insoluble substance, filtrate concentrating obtained brown solid, be dissolved in the methyl alcohol (50mL), (16mL 32mmol) handles, and stirring at room 1 hour with 2N sodium hydroxide.Mixture is concentrated into dried, is dissolved in the 1N sodium hydroxide (75mL), and with methylene dichloride (4 * 50mL) extractions.The organic layer that merges is dry on salt of wormwood, filter, and concentrate and obtain white solid (2.0g).Thick material is adsorbed on silica gel (4g) goes up and on the Biotage of standard 40g post, carry out chromatography, obtain (the 3-methyl furan is [2,3-c] pyridine-5-yl also) methyl alcohol (C54), be white solid (84% productive rate) with 90% ethyl acetate/hexane wash-out.For C
9H
9NO
2MS (EI), m/z:163 (M)
+
Under-78 ℃ of dry ice/acetone batch, (1.16mL 13.2mmol) joins in the methylene dichloride (30mL) in the dry flask with oxalyl chloride under nitrogen.Slow adding DMSO (18.80mL, 26.5mmol).With solution stirring 20 minutes, and add C54 (1.88g, 11.5mmol).Mixture was stirred 1 hour at-78 ℃, stirred 30 minutes at 0-5 ℃ then.Material with saturated sodium bicarbonate (75mL) washing, is obtained xanchromatic solid (3.23g) at salt of wormwood drying, filtration and vacuum concentration.Thick material is adsorbed on silica gel (6g) goes up and on the 40gBiotage of standard post, carry out chromatography, obtain also [2,3-c] pyridine-5-carboxylic aldehyde (C55) of 3-methyl furan, be white solid (72% productive rate) with 25% ethyl acetate/hexane wash-out.For C
9H
7NO
2MS (EI), m/z:161 (M)
+
Under nitrogen, (1.33g 8.28mmol) is dissolved in tetrahydrofuran (THF) (50mL), tertiary butyl alcohol (25mL) and the water (25mL), and adds NaClO with C55
2(2.81g, 24.84mmol) and potassium primary phosphate (2.25g, 16.56mmol).With the reaction mixture stirred overnight at room temperature, be concentrated into driedly, be dissolved in the 50% saturated salt solution (60mL) and with ether extraction (3 *).Extract TLC shows acid and residual aldehyde exists, with organic layer and aqueous layer merging and alkaline to pH10 with the ammonium hydroxide adjusting.Layering also extracts residual aldehyde with ether.Water layer is acidified to pH3 with concentrated hydrochloric acid, uses methylene dichloride (4 *) extraction then.Most acid is retained in the water layer, therefore water layer is concentrated into dried.Solid is ground with chloroform (4 *), and use then 10% ethanol/methylene (4 *) with many acid extractions in supernatant liquor.The organic layer that merges is dry on sodium sulfate, filter, and concentrate the solid (1.69g is greater than 100% isolated yield) that obtains brown.With solid with chloroform dilution and reflux 3 hours.Flask is pined for removing from adding, make it slow cooling, filter then.Filtrate concentrating obtained brown solid (1.02g).Solid is ground with ether, and filtration and drying obtain also [2,3-c] pyridine-5-carboxylic acid (C56) of 3-methyl furan, are light brown solid (51% productive rate).For C
9H
7NO
3MS (CI), m/z:178 (M+H).
Embodiment 7 (i) utilize respectively shown in step 1 and 1b step by will be outer-(4S)-[2.2.1]-3-amine and C56 carry out coupling, forms fumarate then,, obtain embodiment 7 (i), productive rate 77%.For C
15H
18N
3O
2MS (ESI) m/e 272 (M+H).
Embodiment 7 (i-a):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-3-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also:
This embodiment is prepared according to coupling method discussed here.
Embodiment 7 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-3-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also:
This embodiment is prepared according to coupling method discussed here.
Embodiment 7 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also: this embodiment is prepared according to coupling method discussed here.
Embodiment 7 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also: this embodiment is prepared according to coupling method discussed here.
Embodiment 7 (v):
(outward)-N-[1-azabicyclic [3.2.1] oct-3-yl]-3-methyl furan [2,3-c] pyridine-5-carboxylic acid amides dihydrochloride also
With outer-[3.2.1]-amine (0.199g, 1.00mmol), C56 (0.177g, 1.00mmol), tetrahydrofuran (THF) (15mL), DIEA (0.53mL, 3.02mmol) and the mixture of DMF (4mL) carries out the ice bath cooling and with HATU (0.380g, 1.00mmol) processing.Mixture is warmed to envrionment temperature and evaporation.Residue is washed with the chloroform dilution and with aqueous sodium hydroxide solution (1N).With organic layer drying (sal epsom), filtration, evaporation and with the oily matter that obtains through rapid column chromatography (1: 7: 90; Dense ammonium hydroxide-methyl alcohol-chloroform) carry out purifying.Form dihydrochloride and obtain the product (0.110g, 30%) of needs with 2-propyl alcohol/acetone grinding.For C
16H
19N
3O
2The MS of+H (ESI) (M+H)
+M/z=286.
Embodiment 8 (i):
(S)-N-(1-azabicyclic [2.2.1] heptan-3-yl)-3-ethyl furan [2,3-c] pyridine-5-carboxylic acid amides fumarate also outward-4:
Rise and start from 1-chloro-2-butylene and 2-chloro-6-(hydroxymethyl)-4-iodo-3-pyridine alcohol (C2), prepare also [2,3-c] pyridine-5-carboxylic acid (C60) of corresponding 3-ethyl furan.C
10H
9NO
3The HRMS of+H (FAB) calculated value: 192.0661, measured value 192.0659 (M+H).
Embodiment 8 is by will outer-4-[2.2.1]-3-amine and C60 coupling, form fumarate then, as the method described in step 1a and the 1b, obtain embodiment 8 (i) respectively, productive rate is 87%.For C
16H
20N
3O
2MS (ESI) m/e 286 (M+H).
Following embodiment is prepared according to coupling method discussed here:
Embodiment 8 (i-a):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-3-ethyl furan is [2,3-c] pyridine-5-carboxylic acid amides also
Embodiment 8 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-3-ethyl furan is [2,3-c] pyridine-5-carboxylic acid amides also
Embodiment 8 is (iii):
N-2-azabicyclic [2.2.1] heptan-5-yl)-3-ethyl furan [2,3-c] pyridine-5-carboxylic acid amides also
Embodiment 8 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-ethyl furan is [2,3-c] pyridine-5-carboxylic acid amides also
Embodiment 8 (v):
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-ethyl furan is [2,3-c] pyridine-5-carboxylic acid amides also for N-
Embodiment 10 (i):
N-(1-azabicyclic [2.2.1] heptan-3-yl)-furo [2,3-b] pyridine-2-carboxylic acid amides:
(35.5mL, (15.8g 394mmol) 1, in the slurry in the 2-glycol dimethyl ether (400mL), is placed on flask in the ice bath 375mmol) slowly to add (with 20 minutes) sodium hydroxide with ethyl glycollate under nitrogen.Mixture is warmed to room temperature, and stirred 30 minutes, and with added in 10 minutes 2-chlorine apellagrin ethyl ester (27.84g, 150mmol) 1,2-glycol dimethyl ether (50mL) solution.To be reflected in 65 ℃ of oil baths warm 15 hours.Mixture is concentrated into dried, residue is dissolved in the water (500mL), with hexane (500mL) washing, with 5% hcl acidifying to pH3, and with chloroform extraction (4 * 400mL).The organic layer that merges is dry on sal epsom, filter, and concentrate and obtain the xanchromatic solid.Solid suspension is heated until being concentrated into the 40mL volume in ether (200mL) and in steam bath.Substance crystallization is spent the night, filter then and obtain 3-hydroxyl furo [2,3-b] pyridine-2-carboxylic acids ethyl esters (C40), be light orange solid (41% productive rate).Concentrated filtrate obtains other material.Secondary recrystallization obtains (C40) in ether, is flaxen solid (7.3% productive rate).For C
10H
9NO
4MS (EI), m/z:207 (M)
+
Under the room temperature with C40 (207mg, 1.0mmol) join TEA (139 μ L in methylene dichloride 1.0mmol) (5mL), and add 2-[N, two (trifluoromethyl sulfonyl) amino of N-]-the 5-chloropyridine (393mg, 1.0mmol).With solution stirring at room 1 hour, (2 * 15mL) washed with ethyl acetate (25mL) dilution and with 50% saturated salt solution.Organic layer is dry on sodium sulfate, filter, and concentrate and obtain xanchromatic oily matter, place after fixing.Thick material is adsorbed on silica gel (1.2g) upward and on the silica gel that the 25g pulpous state is filled carries out chromatography; obtain ([(trifluoromethyl) alkylsulfonyl] oxygen base) furo [2 with 20% ethyl acetate/hexane wash-out; 3-b] pyridine-2-carboxylic acids ethyl ester (C41), be the crystalline solid (98% productive rate) of white.C
11H
8F
3NO
6The theoretical value of S: C, 38.94; H, 2.38; N, 4.13, actual value: C, 38.84; H, 2.29; N, 4.11.
In 250mL Parr vibration bottle, (1.36g 4.0mmol) joins 10% Pd/C catalyzer (68mg) and sodium bicarbonate (336mg, ethanol 4.0mmol) (100mL)/water (5mL) with C41.Mixture 10PSI hydrogenation 5 hours, is filtered and the concentrated residue that obtains.Residue is distributed between 50% saturated sodium bicarbonate (80mL) and ethyl acetate (80mL).Organic layer is obtained colourless oily matter at dried over sodium sulfate, filtration and vacuum concentration, place after fixing (793mg).Thick material is carried out chromatography on the silica gel that the 40g pulpous state is filled, obtain furo [2,3-b] pyridine-2-carboxylic acids ethyl esters (C42), be white solid (90% productive rate) with 25% ethyl acetate/hexane wash-out.C
10H
9NO
3MS (EI), m/z:191 (M)
+
(758mg 3.96mmol) is dissolved in the methyl alcohol (20mL), and adds lithium hydroxide monohydrate (366mg, 6mL aqueous solution 8.7mmol) under nitrogen with C42.To react stirring at room 2 hours, be concentrated into dried, water (5mL) dilution and with 10% hcl acidifying to pH3.Filter and collect the solid that obtains, obtain furo [2,3-b] pyridine-2-carboxylic acids (C43), be white solid (97% productive rate) with other water washing and drying.For C
8H
5NO
3MS (EI), m/z:163 (M)
+
Embodiment 10 (i) can by will outer-[2.2.1]-3-amine or interior-[2.2.2.1]-3-amine carry out coupling with C43 and obtain preparing.
Following embodiment is prepared according to coupling method discussed here:
Embodiment 10 (i-a):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-furo [2,3-b] pyridine-2-carboxylic acid amides
Embodiment 10 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-furo [2,3-b] pyridine-2-carboxylic acid amides
Embodiment 10 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl)-furo [2,3-b] pyridine-2-carboxylic acid amides
Embodiment 10 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-furo [2,3-b] pyridine-2-carboxylic acid amides
Embodiment 10 (v):
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-furo [2,3-b] pyridine-2-carboxylic acid amides
Embodiment 10 (vi):
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-furo [2,3-b] pyridine-2-carboxylic acid amides
Embodiment 11 (i):
(S)-N-(1-azabicyclic [2.2.1] heptan-3-yl)-3-sec.-propyl furo [2,3-c] pyridine-5-carboxylic acid amides fumarate outward-4:
Utilize the method for preparing embodiment 7 (i) acid, without the change of any key, the preparation of 3-sec.-propyl furo [2,3-c] pyridine-5-carboxylic acid (C70) is from 1-chloro-3-methyl-2-butene and 2-chloro-6-(hydroxymethyl)-4-iodo-3-pyridine alcohol (C2.C
11H
11NO
3The HRMS of+H (FAB) calculated value: 206.0817, actual value 206.0817 (M+H)
+
Embodiment 11 (i) by will be outer-(4S)-[2.2.1]-3-amine and C70 carry out coupling, is transformed into fumarate then, respectively according to the method among step 1a and the 1b, obtains embodiment 11 (i), productive rate 89%.For C
17H
22N
3O
2MS (ESI) m/z:300 (M+H).
Following embodiment is prepared according to coupling method discussed here:
Embodiment 11 (i-a):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-3-sec.-propyl furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 11 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-3-sec.-propyl furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 11 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-sec.-propyl furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 11 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-sec.-propyl furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 11 (v):
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-sec.-propyl furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 12 (i):
N-(1-azabicyclic [2.2.1] heptan-3-yl)-7-(methylthio group) furo [2,3-c] pyridine-5-carboxylic acid amides:
Embodiment 12 (i) can prepare by following method: with embodiment 4 (i) (0.72mmol) and sulfo-sodium methylate (sodium thiomethoxide) (0.79mmol) join among the DMF (3mL) and stir to detect no longer with TLC and exist up to embodiment 4 (i).Then reaction mixture is diluted with methyl alcohol, and load on AG 50W-X2 resin (hydrogen ion type) post, use methanol wash, and with about 5%TEA/ methanol solution wash-out AMBERJET 4400 OH resin columns.The silica gel that thick material can further be filled at pulpous state carries out chromatography, with about 0.5% ammonium hydroxide/8% ethanol/methylene wash-out.
Following embodiment is prepared according to coupling method discussed here:
Embodiment 12 (a):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-7-(methylthio group) furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 12 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-7-(methylthio group) furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 22 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl)-7-(methylthio group) furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 12 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-7-(methylthio group) furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 12 (v):
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-7-(methylthio group) furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 13 (i):
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-b] pyridine-2-carboxylic acid amides:
The dry flask that to adorn tetrahydrofuran (THF) (200mL) under nitrogen cools off by flask being placed in-78 ℃ the dry ice/acetone batch.(125mL 200mmol), drips iodobenzene (11.19mL, tetrahydrofuran (THF) 100mmol) (10mL) solution then to drip butyllithium.Solution was stirred 30 minutes at-78 ℃.Drip diisopropylamine (0.70mL, (3mL) solution of tetrahydrofuran (THF) 5mmol) and 2-chloropyridine (9.46mL, tetrahydrofuran (THF) 100mmol) (30mL) solution, and solution stirred 1 hour at-40 ℃ successively.Drip formyl piperidine (11.1mL, tetrahydrofuran (THF) 100mmol) (25mL) solution, and solution stirred 1 hour at-40 ℃.The 6N hydrochloric acid of reaction with 40mL is stopped,, and add a spot of hypo solution to remove the color of iodine with the dilution of 250mL ether.With solution with the neutralization of saturated sodium bicarbonate, filter and with ether extraction (3 * 150mL).With organic layer drying, filtration and the vacuum concentration on sodium sulfate that merges.Thick material is carried out chromatography on the silica gel that the 600g pulpous state is filled, obtain 2-chlorine nicotine aldehyde (C90), be light orange solid (54% productive rate) with 20% ethyl acetate/hexane wash-out.For C
6H
4The MS of ClNO (EI), m/z:141 (M)
+
Under nitrogen, (1.41g 10.01mmol) is dissolved in DMF (10mL) and water (1mL) with C90.Add in batches salt of wormwood (1.56g, 11.27mmol) and the thioglycolic acid methyl esters (1.00mL, 11.25mmol).To be reflected at 35 ℃ and stir 24 hours, stop, and be placed in the ice bath to increase precipitation with cold water (75mL).The filtering separation precipitation obtains methyl-thieno-[2,3-b] pyridine-2-carboxylic acids esters (C101), is orange powder (40% productive rate).For C
9H
7NO
2The MS of S (EI), m/z:193 (M)
+
(0.700g 3.63mmol) is dissolved in methyl alcohol (15mL) and the 3mL water, and (1.82mL 3.63mmol), and will react stirring at room 24 hours to drip 2N sodium hydroxide with C101.To react vacuum concentration, and add entry (40mL) with dissolution residual substance.The solution that obtains is acidified to pH4 with concentrated hydrochloric acid, and the filtering separation precipitation, produce thieno-[2,3-b] pyridine-2-carboxylic acids (C102), be white powder (85% productive rate).For C
8H
5NO
2The MS of S (EI), m/z:179 (M)
+
Embodiment 13 (i) can be prepared by inciting somebody to action outer-[2.2.1]-3-amine or interior-[2.2.1]-3-amine and C102 coupling.
Following embodiment is prepared according to coupling method discussed here:
Embodiment 13 (i-a):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-b] pyridine-2-carboxylic acid amides
Embodiment 13 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[2,3-b] pyridine-2-carboxylic acid amides
Embodiment 13 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[2,3-b] pyridine-2-carboxylic acid amides
Embodiment 13 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[2,3-b] pyridine-2-carboxylic acid amides
Embodiment 13 (v):
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[2,3-b] pyridine-2-carboxylic acid amides
Embodiment 13 (vi):
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[2,3-b] pyridine-2-carboxylic acid amides
Embodiment 14 (i):
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-b] pyridine-5-carboxylic acid amides:
(33.76g 261.4mmol) is suspended in the concentrated hydrochloric acid (175mL) and is heated to 50 ℃ with the 2-nitrothiophene.Add tin protochloride (118.05g 523.2mmol), remains on temperature of reaction between 45-50 ℃ with ice bath, adds the recession deicing that finishes and bathes in batches.Solution was slowly cooled to 30 ℃ with 1 hour.Then with cooling of solution ice bath and filtration.Filter cake with dense HCl (20mL) washing, is used the airflow drying, and wash the chlordene stannate that (50mL) obtains the 2-aminothiophene, be brown solid (26% productive rate) with ether.
3,3-dimethyl-2-formyl radical propionitrile sodium (3.33g, 20.2mmol) easily according to Bertz, S.H., etc., J.Org.Chem., 47,22162217 (1982) method prepares.With 3,3-dimethyl-2-formyl radical propionitrile sodium is dissolved in the methyl alcohol (40mL), and (10.04g, methyl alcohol 19.1mmol) (130mL) solution slowly is added drop-wise in the mixture with the chlordene stannate of concentrated hydrochloric acid (4mL) and 2-aminothiophene.Add finish after, with mixture (80 ℃) reflux 4 hours in oil bath, add methyl alcohol (10mL) and concentrated hydrochloric acid (10mL) then.To react and continue to reflux 20 hours, and solution will be cooled to room temperature, and will react vacuum concentration.The residue of purple is dissolved in the water (60mL), and slurry is filtered.Be heated to 55 ℃ simultaneously with the filter cake grind into powder and with 5% methyl alcohol/chloroform (105mL) vigorous stirring.With mixture cooling and filtration, organic layer is concentrated the oily matter that obtains green.Thick material is carried out chromatography on the silica gel that the 130g pulpous state is filled, obtain thieno-[2,3-b] pyridine-5-nitrile (C105), be flaxen solid (24% productive rate) with 30% ethyl acetate/hexane wash-out.C
8H
4N
2The HRMS of S+H (FAB) calculated value: 161.0173, actual value 161.0173 (M+H).
(0.138g, (0.503g 3.14mmol) is dissolved in the solution of 70% ethanol/water (12mL) 3.45mmol) to join C105 with sodium hydroxide.With 100 ℃ of reflux of mixture 3 hours.To react vacuum concentration, and residue will be dissolved in the water (8mL), and, slurry be filtered and wash with ether with the concentrated hydrochloric acid neutralization.The initial NMR of separate substance shows and has the carboxylic acid amides intermediate, therefore material is suspended in the 1M sodium hydroxide (6mL) and stirs and spend the night.Add entry (10mL), and with solution with ether extraction (3 * 10mL), and mixture neutralize with dense HCl, wash with the slurry filtration and with ether, obtain thieno-[2,3-b] pyridine-5-carboxylic acid (C106), be pale solid (48% productive rate).C
8H
5NO
2The MS of S (EI), m/z:179 (M)
+
Embodiment 14 (i) can be prepared by inciting somebody to action outer-[2.2.1]-3-amine or interior-[2.2.1]-3-amine and C106 coupling.
Following embodiment is prepared according to coupling method discussed here:
Embodiment 14 (i-a):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-b] pyridine-5-carboxylic acid amides
Embodiment 14 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[2,3-b] pyridine-5-carboxylic acid amides
Embodiment 14 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[2,3-b] pyridine-5-carboxylic acid amides
Embodiment 14 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[2,3-b] pyridine-5-carboxylic acid amides
Embodiment 14 (v):
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) thieno-[2,3-b] pyridine-5-carboxylic acid amides
Embodiment 14 (vi):
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[2,3-b] pyridine-5-carboxylic acid amides
Embodiment 15 (i):
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides:
(12.9g 99.9mmol) is dissolved in the concentrated hydrochloric acid (200mL) and 30 ℃ of vigorous stirring with the 2-nitrothiophene.(25g 210mmol) slowly adds in batches with granulated tin.After tin dissolved fully, (6.1g, ethanol 44.7mmol) (70mL) suspension with mixture heating up to 85 ℃, and added mda two acetals (24mL, ethanol 100mmol) (30mL) solution to drip zinc chloride.Solution is continued to stir 1 hour at 85 ℃, and be poured on the ice (100g) and stop.Mixture is adjusted to pH10 with ammonium hydroxide, and the slurry filtration over celite that obtains is spent the night.With liquid with chloroform (3 * 300mL) extractions, and the organic layer that merges is dry on sal epsom, filter, and concentrate and obtain brown oil.Thick material is carried out chromatography on the silica gel that the 250g slurry is filled, obtain orange buttery thieno-[2,3-b] pyridines (C110) (26% productive rate) with 35% ethyl acetate/hexane wash-out.For C
7H
5The MS of NS (EI), m/z:135 (M)
+
(3.47g 25.7mmol) is dissolved in the acetate (12mL) and is heated to 85 ℃ with C110.Drip 30% hydrogen peroxide (9mL), and solution stirring is spent the night.To react cool to room temperature and stop up to carry out superoxide detection test with starch-iodine test paper negative with Paraformaldehyde 96.With solution with water (100mL) dilution and with the sodium bicarbonate neutralization, use chloroform re-extract (12 * 80mL, 6 * 50mL) then.With the organic layer that merges in dried over sodium sulfate, filtration, and concentrate and obtain brown solid.The silica gel that thick material is filled at the 70g pulpous state carries out chromatography, obtains thieno-[2,3-b] pyridine-7-oxide compound (C111) with 3.5% ethanol/methylene wash-out, is flaxen solid (22% productive rate).C
7H
5The MS of NOS (EI) m/z:151 (M)
+
(5mL, dichloromethane solution 2.5mmol) is with the dilution of 8mL methylene dichloride with the C111 of 0.5M under nitrogen.Drip dimethylcarbamyl chloride (0.27mL, 2.9mmol), then by syringe add the silica-based prussiate of trimethylammonium first (0.388mL, 2.9mmol).To react to stir and also stop in 9 days with 10% salt of wormwood (10mL).Make it layering, isolate organic layer, and with salt of wormwood drying, filtration, and concentrate and obtain brown solid.Thick material is carried out chromatography on the silica gel that the 25g pulpous state is filled, obtain thieno-[2,3-b] pyridine-6-nitrile (C112), be flaxen solid (100% productive rate) with 35% ethyl acetate/hexane wash-out.C
8H
4N
2The theoretical value of S: C, 59.98; H, 2.52; N, 17.49, actual value: C, 59.91; H, 2.57; N, 17.43.
(398mg, 9.95mmol) join C112 (674mg is in 70% ethanol/water (20mL) solution 4.2mmol) in batches with sodium hydroxide.Solution 100 ℃ of reflux 24 hours, and will be reacted vacuum concentration.Residue is dissolved in the water (15mL) and with ether washing (3 * 10mL).Regulate pH to 3.5 with concentrated hydrochloric acid, produce precipitation.Slurry is filtered, obtain thieno-[2,3-b] pyridine-6 carboxylic acids (C113), be white solid (45% productive rate).C
8H
5NO
2The MS of S (EI), m/z:179 (M)
+
Embodiment 15 (i) can obtain preparation by inciting somebody to action outer-[2.2.1]-3-amine or interior-[2.2.1]-3-amine and C113 coupling.
Following embodiment is prepared according to coupling method discussed here:
Embodiment 15 (i-a):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides
Embodiment 15 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides
Embodiment 15 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides
Embodiment 15 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides
Embodiment 15 (v):
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides
Embodiment 15 (vi):
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides
Embodiment 16 (i):
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-c] pyridine-2-carboxylic acid amides:
Under nitrogen, in dry flask, tetrahydrofuran (THF) (200mL) is cooled to-70 ℃, and the dropping n-Butyl Lithium (24.4mL, 55.0mmol).Be placed on reaction in the ice bath and drip DIA (7.71mL, tetrahydrofuran (THF) 55.0mmol) (20mL) solution.Solution is chilled to-70 ℃ again, drips 3-chloropyridine (4.75mL, tetrahydrofuran (THF) 50.0mmol) (20mL) solution.To be reflected at-70 ℃ and stir 4 hours, and add ethyl formate (4.44mL, tetrahydrofuran (THF) 55.0mmol) (20mL) solution.To react again and stir 3 hours, and water (500mL) stops at-70 ℃.Make it layering, and with water layer ethyl acetate extraction (3 * 250mL).With organic layer dried over mgso, filtration, the also concentrated dark brown solid that merges.Thick material is carried out chromatography on the silica gel that the 250g pulpous state is filled, obtain 3-chlorine isonicotine aldehyde (C120), be pale solid (55% productive rate) with 50% ethyl acetate/hexane wash-out.C
6H
4The MS of ClNO (EI), m/z:141 (M)
+
(2.12g 14.9mmol) is dissolved among the DMF (75mL) that contains less water (7.5mL) with C120.Add in batches the thioglycolic acid methyl esters (1.67mL, 18.7mmol) and salt of wormwood (2.59g 18.7mmol), and stirs mixture 24 hours at 45 ℃.To react with cold water (200mL) and stop, and with ethyl acetate extraction (3 * 150mL).With the organic layer that merges with 50% sodium chloride solution wash (3 * 150mL), dry on sal epsom, filter, the concentrated orange solids that obtains also.Thick material is carried out chromatography on the silica gel that the 40g pulpous state is filled, obtain thieno-[2,3-c] pyridine-2-carboxylic acids ethyl esters (C121), be flaxen solid (22% productive rate) with 50% ethyl acetate/hexane wash-out.
(577mg, 2.99mmol) (1.5mL 3.0mmol) mixes in methyl alcohol (15mL) and water (1.5mL) with 2M sodium hydroxide with C121.And will be reflected at stirring at room 24 hours.To react vacuum concentration and residue will be dissolved in the water (75mL).With concentrated hydrochloric acid solution is acidified to pH3.Slurry is filtered, water and ether washing, and dry, obtain thieno-[2,3-c] pyridine-2-carboxylic acids (C122), be pale solid (38% productive rate).C
8H
5NO
2The HHRMS of S+ (FAB) calculated value: 180.0119, actual value 180.0119 (M+H).
Embodiment 16 (i) can by will outer-[2.2.1]-3-amine or interior-[2.2.1]-3-amine and C122 coupling be prepared and obtain.
Following embodiment is prepared according to coupling method discussed here:
Embodiment 16 (i-a):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-c] pyridine-2-carboxylic acid amides
Embodiment 16 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[2,3-c] pyridine-2-carboxylic acid amides
Embodiment 16 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[2,3-c] pyridine-2-carboxylic acid amides
Embodiment 16 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[2,3-c] pyridine-2-carboxylic acid amides
Embodiment 16 (v):
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[2,3-c] pyridine-2-carboxylic acid amides
Embodiment 16 (vi):
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[2,3-c] pyridine-2-carboxylic acid amides
Embodiment 17 (i):
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-b] pyridine-2-carboxylic acid amides:
Be dissolved in 3-chloropyridine (9.5mL.99.9mmol) in the acetate (35mL) and be heated to 98 ℃.Drip 30% hydrogen peroxide (28mL), and will be reflected at 98 ℃ of stirrings 5 hours.To react cooling and add Paraformaldehyde 96, obtain negative superoxide test when testing to use starch-iodine test paper.On the silica gel that the 600g pulpous state is filled, carry out chromatography with solution for vacuum concentration and with rough mashed prod, 10% ethanol/methylene wash-out with 4% ethanol/methylene of 2% ethanol/methylene of 4L, 2L and final 1L obtains 3-chloropyridine 1-oxide compound (C125), is the oily matter (100% productive rate) of light color.
(10mL, 20mmol) solution mixes with other 90m methylene dichloride with the C125 of 2M.Drip dimethylcarbamyl chloride (2.03mL, 22.0mmol), then by syringe add the silica-based prussiate of trimethylammonium first (2.93mL, 22.0mmol).To react stirring at room also stopped with 10% salt of wormwood (100mL) in 10 days.Make it layering, and organic layer is dry on salt of wormwood, filter, and concentrate and obtain orange solids.Thick material is carried out chromatography on the silica gel that the 160g pulpous state is filled, obtain 3-chloropyridine-2-nitrile (C126), be white solid (59% productive rate) with 40% ethyl acetate/hexane wash-out.C
6H
3ClN
2MS (EI), m/z:138 (M)
+
With C126 (1.01g, 7.29mmol) and salt of wormwood (1.10g 7.96mmol) joins in DMF (10mL) and the water (1mL).(0.709mL 7.93mmol), and is heated to 40 ℃ and stirred 3 hours with solution to drip the thioglycolic acid methyl esters.To react with cold water (70mL) and stop and be placed on ice to increase precipitation.Slurry is filtered and filter cake is dissolved in the chloroform.Organic solution is dry on sal epsom, filter, and concentrate, obtain methyl 3-aminothiophene also [3,2-b] pyridine-2-carboxylic acids ester (C127 is xanchromatic solid (84% productive rate).C
9H
8N
2O
2The HRMS of S+H (FAB) calculated value: 209.0385, actual value 209.0383 (M+H).
(0.919g 4.42mmol) is dissolved in 50% Hypophosporous Acid, 50 (35mL) and cools off on ice bath with C127.(0.61g 8.84mmol) is dissolved in the minimum water and is added drop-wise in the aforementioned solution, and will be reflected in the ice bath and stir 3 hours with Sodium Nitrite.Regulate pH to 7.9 with 3M sodium hydroxide, and with solution ethyl acetate extraction (3 * 100mL).With the organic layer that merges in dried over mgso, filtration, and concentrate and obtain thieno-[3,2-b] pyridine-2-carboxylic acids methyl esters (C128), be xanchromatic solid (44% productive rate).For C
9H
7NO
2The MS of S (EI), m/z:193 (M)
+
With 2M sodium hydroxide (0.8mL, 1.6mmol) and C128 (300mg 1.55mmol) joins in methyl alcohol (8mL) and the water (1mL) and stirred 24 hours, will react vacuum concentration, and residue water (5mL) is dissolved.Regulate pH to 3.5 with 5%HCl, produce precipitation.Slurry is filtered and wash, obtain thieno-[3,2-b] pyridine-2-carboxylic acids (C129), be brown solid (67% productive rate) with ether.C
8H
5NO
2The HRMS of S+H (FAB) calculated value: 180.0119, actual value 180.0121 (M+H).
Embodiment 17 (i) can by will outer-[2.2.1]-3-amine or interior-[2.2.1]-3-amine and C129 coupling be prepared and obtain.
Following embodiment is prepared according to coupling method discussed here:
Embodiment 17 (i-a):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-b] pyridine-2-carboxylic acid amides
Embodiment 17 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[3,2-b] pyridine-2-carboxylic acid amides
Embodiment 17 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[3,2-b] pyridine-2-carboxylic acid amides
Embodiment 17 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[3,2-b] pyridine-2-carboxylic acid amides
Embodiment 17 (v):
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[3,2-b] pyridine-2-carboxylic acid amides
Embodiment 17 (vi):
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[3,2-b] pyridine-2-carboxylic acid amides
Embodiment 18 (i):
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides:
Embodiment 18 (i) can be prepared by thieno-[3, the 2-b] pyridine-5 carboxylic acid coupling with outer-[2.2.1]-3-amine or interior-[2.2.1]-3-amine and commercial offers and obtain.
Following embodiment is prepared according to coupling method discussed here:
Embodiment 18 (i-a):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides
Embodiment 18 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides
Embodiment 18 is (iii): N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides
Embodiment 18 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides
Embodiment 18 (v):
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides
Embodiment 18 (vi):
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides
Embodiment 19 (i):
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides:
With 3-ammonia thiophene-2-carboxylic acid methyl esters (1.52g, 9.68mmol) be dissolved in 2M sodium hydroxide (10mL, 20mmol) in and 115 ℃ of oil bath reflux 30 minutes.Mixture is cooled to room temperature, is placed in the ice bath, and use the concentrated hydrochloric acid acidifying carefully.Slurry is filtered and water (25mL) cleaning.Then filter cake is dissolved in the acetone (50mL), dry on sal epsom, filter, and concentrate and obtain dense thick mashed prod.With thick substance dissolves in 1-propyl alcohol (25mL), and add in batches oxalic acid (0.90g, 10.0mmol).Mixture 38 ℃ of heating 45 minutes, is cooled to room temperature, and dilutes with ether.Filter to isolate precipitation, and, obtain 3-amino-thiophene barkite (C135), be villous white solid (70% productive rate) with the ether washing.C
4H
5The HRMS of NS+H (FAB) calculated value: 100.0221, actual value 100.0229 (M+H).
With 3, (5.38g 32.6mmol) is dissolved in methyl alcohol (60mL) and the concentrated hydrochloric acid (6mL) 3-dimethyl-2-formyl radical propionitrile sodium.(6.16g 32.6mmol) is suspended in the methyl alcohol (200mL) and drops in the acidic solution, when adding other 20mL concentrated hydrochloric acid and 20mL water, with 80 ℃ of reflux of mixture 5 hours with C135; Mixture is continued to reflux 12 hours.With the mixture vacuum concentration, and residue is dissolved in the water (100mL).Filter out the precipitation and the drying of generation, obtain thieno-[3,2-b] pyridine-6-nitrile (C136), be brown solid (44% productive rate).C
8H
4N
2The HRMS of S+H (FAB) calculated value: 161.0173, actual value 161.0170 (M+H).
With C136 (1.99g 12.5mmol) is dissolved in 70% ethanol/water (20mL), and add in batches sodium hydroxide (0.52g, 13.0mmol).Mixture was heated 15 hours at 100 ℃, and be cooled to room temperature then.And with the mixture vacuum concentration.Residue is dissolved in the cold water (30mL), and solution is washed (3 * 10mL) with ether.PH is adjusted to 3.5 to precipitate the product that needs with concentrated hydrochloric acid, obtains thieno-[3,2-b] pyridine-6-carboxylic acid (C137), be brown solid (77% productive rate) through leaching.C
8H
5NO
2The HRMS of S+H (FAB) calculated value: 180.0119, actual value 180.0118 (M+H).
Embodiment 19 (i) can by will outer-[2.2.1]-3-amine or interior-[2.2.1]-3-amine and C137 coupling be prepared and obtain.
Following embodiment is prepared according to coupling method discussed here:
Embodiment 19 (i):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides
Embodiment 19 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides
Embodiment 19 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides
Embodiment 19 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides
Embodiment 19 (v):
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides
Embodiment 19 (vi):
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides
Embodiment 20 (i):
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-c] pyridine-2-carboxylic acid amides:
(15g is 99.9mmol) by stirring the form that became free alkali in 1 hour at 1: 1 of 1000mL in saturated sodium bicarbonate/ether with 4-chloropyridine hydrochloride.Make it layering, with water layer with ether extraction (2 * 175mL), and the organic layer that merges is dry on sal epsom, filter, and concentrate and obtain oily matter.Tetrahydrofuran (THF) (300mL) is cooled to-70 ℃ in dry flask.(105.1mL 168.2mmol), and is placed on mixture in the ice bath to drip n-Butyl Lithium.Drip tetrahydrofuran (THF) (50mL) solution of diisopropylamine (23.6mL.168.4mmol), and yellow solution was stirred 30 minutes, and reaction is cooled to-70 ℃.(9.55g 84.1mmol) is dissolved in the tetrahydrofuran (THF) (50mL) and drops in the cold yellow solution, dropwises the back crimson with the 4-chloropyridine oily matter of free alkali form.To be reflected at-70 ℃ stirred 2 hours.(13.6mL, tetrahydrofuran (THF) 168.3mmol) (25mL) drips of solution adds in the solution of-70 ℃ of dark colors with ethyl formate then.After 2 hours, reaction is warmed to-10 ℃ and water (450mL) termination.Make it layering, and water layer is extracted (3 * 200mL) with ether.The organic layer drying, filtration and the vacuum concentration on sal epsom that merge are obtained oily matter.Thick material is carried out chromatography on the silica gel that the 320g pulpous state is filled, obtain 4-chloropyridine-3-aldehyde (C140), be orange oily matter, obtain orange solids (21% productive rate) in vacuum solidification with 30% ethyl acetate/hexane wash-out.
With C140 (2.53g 17.9mmol) is dissolved in DMF (20mL) and the water (2mL), add in batches salt of wormwood (2.97g, 21.5mmol) and the thioglycolic acid methyl esters (1.92mL, 21.5mmol).To be reflected at 45 ℃ and stir 24 hours, and use cold water (100mL) to stop then, and flask will be placed in the ice to improve precipitation.Precipitation and dry is told in filtration, obtains thieno-[3,2-c] pyridine-2-carboxylic acids methyl esters, is white solid (92% productive rate).For C
9H
7NO
2The MS of S (EI), m/z:193 (M)
+
(2.65g 13.7mmol) is dissolved in methyl alcohol (70mL) and the water (5mL) with C141.(6.86mL 13.7mmol), and will react stirring at room 24 hours to drip 2N sodium hydroxide.To react vacuum concentration, and water (150mL) will be added dissolution residual substance.The salts solution that obtains is acidified to pH3.5 with concentrated hydrochloric acid, and filters to isolate precipitation and dry, obtain thieno-[3,2-c] pyridine-2-carboxylic acids (C142), be the powder (57% productive rate) of white.C
8H
5NO
2The HRMS of S+H (FAB) calculated value: 180.0119, actual value 180.0124 (M+H).
Embodiment 20 (i) can by will outer-[2.2.1]-3-amine or interior-[2.2.1]-3-amine and C142 coupling be prepared and obtain.
Following embodiment is prepared according to coupling method discussed here:
Embodiment 20 (i-a)
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-c] pyridine-2-carboxylic acid amides
Embodiment 20 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[3,2-c] pyridine-2-carboxylic acid amides
Embodiment 20 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[3,2-c] pyridine-2-carboxylic acid amides
Embodiment 20 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[3,2-c] pyridine-2-carboxylic acid amides
Embodiment 20 (v):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[3,2-c] pyridine-2-carboxylic acid amides
Embodiment 20 (vi):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[3,2-c] pyridine-2-carboxylic acid amides
Embodiment 21 (i):
(S)-N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides fumarate outward-4:
With the oxyacetic acid monohydrate (20.3g, 221mmol) and benzyl carbamate (30.6g 202mmol) joins in the ether (200mL).With solution stirring at room 24 hours.With the dense thick sedimentation and filtration that obtains, and residue washed with ether, obtain ([(benzyloxy) carbonyl] amino) (hydroxyl) acetate (C150), be white solid (47% productive rate).C
10H
22NO
5+H?MS(CI)m/z：226(M+H)。
(11.6g 51.5mmol) is dissolved in the absolute methyl alcohol (120mL) and cools off on ice bath with C150.The careful vitriol oil (2.0mL) that drips.Solution stirring was removed ice bath after 2 days.Reaction is poured in 500g ice and saturated sodium hydrogen carbonate solution (400mL) mixture and stops.With solution ethyl acetate extraction (3 * 300mL), and the organic layer that merges is dry on sal epsom, filter, and concentrate the oily matter that obtains light color, place post crystallization, obtain methyl ([(benzyloxy) carbonyl] amino) (methoxyl group) acetic ester (C151), be white solid (94% productive rate).C
12H
15NO
5Theoretical value: C, 56.91; H, 5.97; N, 5.53, actual value: C, 56.99; H, 6.02; N, 5.60.
(11.76g 46.4mmol) is dissolved in the toluene (50mL), and is heated to 70 ℃ with C151 under nitrogen.(23.2mL 46.4mmol), and stirs solution 18 hours at 70 ℃ to drip phosphorus trichloride by syringe.Drip then trimethyl phosphite (5.47mL, 46.4mmol), and again 70 ℃ continued restir 2 hours.The mixture vacuum concentration is obtained oily matter.And with thick substance dissolves in ethyl acetate (100mL), and with saturated sodium bicarbonate (3 * 50mL) washing.Organic layer is dry on sodium sulfate, filter, and concentrate the volume that obtains 30mL.Residual solution vigorous stirring is added hexane simultaneously up to forming precipitation.Filter out precipitation, obtain ([(benzyloxy) carbonyl] amino) (dimethoxy phosphoryl) methyl acetate (C152), be white solid (84% productive rate).C
13H
18NO
7The MS of P (EI), m/z:331 (M)
+
With C152 (12.65g, 38.2mmol) and diacetyl oxide (9.02mL, methyl alcohol 95.5mmol) (100mL) solution joins in the Parr flask.With solution with 10% Pd/C catalyzer (0.640g) 45PSI hydrogenation 3 hours.Remove by filter catalyzer, and the filtrate vacuum concentration is obtained oily matter.Oily matter is placed under reduced pressure, when applying decompression, solidified.Be dissolved in the residue of white in a spot of ethyl acetate and vigorous stirring adds pentane simultaneously up to beginning to form precipitation.Filter out precipitation and obtain methyl (acetylamino) (dimethoxy phosphoryl) acetic ester (C153), be white powder (87% productive rate).For C
7H
14NO
6The MS of P (CI), m/z:240 (M+H).
With 2, (1.40g 9.99mmol) is dissolved in the methylene dichloride (100mL) 3-thiophene dialdehyde, and flask is placed in the ice bath.(2.63g 11.0mmol) is dissolved in the methylene dichloride (50mL), adds 1, and (1.65mL 11.0mmol), and is added to this drips of solution in the ice-cold thiophene solution 8-diazabicylo [5.4.0] 11 carbon-7-alkene with C152.Reaction mixture was stirred 1 hour, simultaneously flask is placed in the ice bath, and stirred overnight at room temperature then.To react vacuum concentration, and thick material will be carried out chromatography on the silica gel that the 300g pulpous state is filled, with 50% ethyl acetate/hexane wash-out.Level part is gathered into 2 groups of different compounds needing to obtain.With each group level part merging and concentrated respectively.First group of level part obtains thieno-[2,3-c] pyridine-5-carboxylic acid methyl ester (C154), is white solid (41% productive rate) that second group of level part obtains thieno-[3,2-c] pyridine-6 carboxylic acid methyl ester (C155), is xanchromatic solid (38% productive rate).MS (EI) for C154 for C
9H
7NO
2S, m/z:193 (M)
+MS (EI) for C155 for C
9H
7NO
2S, m/z:193 (M)
+
(736mg 3.8mmol) is dissolved in the methyl alcohol (16mL) of moisture (2mL) with C154.(2.0mL is 4.0mmol) and with the solution stirring at room to drip 2M sodium hydroxide.(TLC detects the ester completely dissolve) will react vacuum concentration after 2 days.Residue is dissolved in the water (12mL), and with 10% HCl with pH regulator to 3.5.Filter out precipitated solid, and solid is washed with ether, obtain thieno-[2,3-c] pyridine-5-carboxylic acid (C156), be white solid (58% productive rate).C
8H
5NO
2The HRMS of S+H (FAB) calculated value: 180.0119, actual value 180.0123 (M+H).
Outside inciting somebody to action-(4S)-[2.2.1-amine and C156 coupling form fumarate then, and the step as describing among step 1a and the 1b obtains embodiment 21 (i) respectively, productive rate 84%.For C
14H
16N
3The MS of OS (ESI) m/e:274 (M+H).
Embodiment 21 (i-a):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides:
This embodiment is prepared according to coupling method discussed here.
Embodiment 21 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides:
This embodiment is prepared according to coupling method discussed here.
Embodiment 21 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides:
This embodiment is prepared according to coupling method discussed here.
Embodiment 21 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides:
This embodiment is prepared according to coupling method discussed here.
Embodiment 21 (v):
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides:
The productive rate of coupling is 66%.MS(EI)m/z?287(M+)。
Embodiment 21 (vi):
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides:
This embodiment is prepared according to coupling method discussed here.
Embodiment 22 (i):
Outward-4-N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides fumarate:
(678mg 3.5mmol) is dissolved in methyl alcohol (16mL) and the water (2mL) with thieno-[3,2-c] pyridine-6-carboxylic acid methyl ester (C155).Dropping 2M sodium hydroxide (1.8mL, 3.6mmol), and with the solution stirring at room.After 2 days (TLC detects the ester completely dissolve), with solution for vacuum concentration.Residue is dissolved in the water (12mL), and pH is adjusted to 3.5 with 10% HCl.Process leaches solid, and solid is washed with ether, obtains thieno-[3,2-c] pyridine-6-carboxylic acid C160, is white solid (43% productive rate).C
8H
5NO
2The HRMS of S+H (FAB) calculated value: 180.0119, actual value 180.0123 (M+H).
Embodiment 22 by will be outer-(4S)-[2.2.1]-3-amine and C160 coupling, form fumarate then and obtain, carried out embodiment 22 (i), productive rate 77% respectively as step 1a and the described step of 1b.For C
14H
16N
3The MS of SO (ESI) m/e:274 (M+H).
Embodiment 22 (i-a):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides:
This embodiment is prepared according to coupling method discussed here.
Embodiment 22 is (ii): N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides:
This embodiment is prepared according to coupling method discussed here.
Embodiment 22 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides:
This embodiment is prepared according to coupling method discussed here.
Embodiment 22 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides:
This embodiment is prepared according to coupling method discussed here.
Embodiment 22 (v):
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides:
Embodiment 22 is (v) by carrying out C160 coupling, utilize coupling step described herein with outer-[3.2.1]-amine.The coupling productive rate is 58%.MS(EI)m/z?287(M
+)。
Embodiment 22 (vi):
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides:
This embodiment is prepared according to coupling method discussed here.
Embodiment 23 (i):
N-(1-azabicyclic [2.2.1] heptan-3-yl)-1H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides:
Under nitrogen, with 2, (51.4mL 0.445mole) is added drop-wise to flask and is placed in the 250mL oleum in the ice bath 4-lutidine.(89.9g 0.889mole) handled with batch-wise saltpetre with solution with 15 minutes.To be reflected in the ice bath and stir 1 hour, stirring at room 2 hours stirred 5 hours in 100 ℃ of oil baths gradually, and stirred 4 hours in 130 ℃ of oil baths then.With mixture cooling, be poured in the 1000mL ice, and with mixture with the sodium bicarbonate neutralization (1,100g, 13.1mole).Sedimentary sodium sulfate is removed after filtration, solid is extracted with 4 * 500mL ether with the 500mL water washing and with filtrate.The organic layer that merges is obtained yellow oil (50g) with dried over mgso and vacuum concentration.With rough oily matter vacuum distilling with provide that 3 level part: 16g reclaim 2,4-lutidine (85 ℃), 16g 2,4 dimethyl-3-nitro-pyridine C169 contains 25% 2,4-dimethyl-5-nitropyridine (135-145 ℃), and 16g 2,4-dimethyl-5-nitro-pyridine (C170) contains 2,4-dimethyl-3-nitropyridine (145-153 ℃).C169's
1HNMR (CDCl
3) δ 2.33,2.54,7.10,8.43ppm.C170's
1HNMR (CDCl
3) δ 2.61,2.62,7.16,9.05ppm.
Under nitrogen, (5.64g, 37mmol) (8.2g 22.8mmol) mixes with 300mL two alkane with the benzene selenic anhydride with C170/C169 (75: 25) in flask.Reaction is warmed to backflow 10 hours, and cooling also concentrates the oily matter that obtains yellow black.Oily matter is carried out chromatography on 250g silica gel (230-400 order), obtain 2-formyl radical-4-methyl-5-nitro pyridine (C171) (66% productive rate) with 15% ethyl acetate/hexane wash-out.C
7H
6N
2O
3HRMS (EI) calculated value: 166.0378, actual value 166.0383 (M
+).
With C171 (1.15g, 6.9mmol), tosic acid (41mg, 0.22mmol) and ethylene glycol (1.41mL 25mmol) joins in the 25mL toluene, and flask is equipped with the Dean-Starke trap.Reaction is warmed to backflow 2 hours, be cooled to room temperature, and vacuum concentration obtains the buttery residue.Rough oily matter is carried out chromatography on 40g silica gel (Biotage), obtain 2-(1,3-two oxa-s penta ring-2-yl)-4-methyl-5-nitro pyridine (C172) (90% productive rate) with 20% ethyl acetate/hexane wash-out.For C
9H
10N
2O
4MS (EI), m/z:210 (M)
+
(1.3g, 6.2mmol) (1.12mL 8.4mmol) joins among the 15Ml DMF with the DMF dimethylacetal with C172 under nitrogen.To be reflected at 90 ℃ warm 3 hours, cooling and will be reacted vacuum concentration.In 250mL Parr vibration bottle, will mix in the 5% Pd/ barium sulfate of residue and 1.25g and the 20mL ethanol.And with mixture at ambient temperature hydrogenation stop up to absorption.Catalyzer is removed after filtration, and filtrate is mixed in 250mL Parr vibration bottle with 500mg 10% Pd/C catalyzer.With mixture hydrogenation 1 hour under environmental stress.Observe and no longer absorb hydrogen.Catalyzer is removed after filtration, and the filtrate vacuum concentration is obtained brown solid.Thick material is carried out chromatography on 50g silica gel (230-400 order), with 7% ethanol/methylene wash-out, with part merging of suitable level and concentrated 5-(1,3-two oxa-s penta ring-2-yl)-1H pyrrolo-[2, the 3-c] pyridines (C173) (69% productive rate) that obtain.For C
10H
10N
2O
2MS, (EI) m/z:190 (M)
+
(800mg 4.21mmol) is dissolved in 44mL 10% acetonitrile solution with C173.The adding tosic acid (630mg, 3.3mmol), and with mixture heating up backflow 5 hours.Mixture is cooled to room temperature, and vacuum concentration, and with the residue that the obtains saturated sodium bicarbonate dilution of 15mL.Collect flaxen solid, wash with water, and drying obtains 1H-pyrrolo-[2,3-c] pyridine-5-carboxylic aldehyde (C174) (81% productive rate).C
8H
6N
2The HRMS of O+H (FAB) calculated value: 147.0558, actual value 147.0564 (M+H).
(500mg 3.42mmol) is dissolved in the 1.5mL formic acid with C174.With solution ice bath cooling, (722 μ L 6.8mmol), and will be reflected in the ice bath and stir 1 hour, and spend the night 5 ℃ of placements to drip 30% aqueous hydrogen peroxide solution.With the mixture dilute with water,, wash with water and the dry pale solid that obtains 522mg solid collection.Formate is joined in the 7mL water, add the 2N sodium hydroxide of 3mL, and pH is adjusted to 3 with 5% hydrochloric acid.Collecting precipitation and drying obtain 1H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid (C176) (67% productive rate).C
8H
6N
2O
2The HRMS of+H (FAB) calculated value: 163.0508, actual value 163.0507 (M+H).
Embodiment 23 (i) can by will outer-[2.2.1]-3-amine or interior-[2.2.1]-3-amine and C176 coupling be prepared and obtain.
Following embodiment is prepared according to coupling method discussed here:
Embodiment 23 (i-a):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-1H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides
Embodiment 23 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-1H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides
Embodiment 23 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl)-1H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides
Embodiment 23 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-1H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides
Embodiment 23 (v):
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-1H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides
Embodiment 23 (vi):
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-1H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides
Embodiment 24 (i):
N-(1-azabicyclic [2.2.1] heptan-3-yl)-1-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides:
Under nitrogen, (1,3-two oxa-s penta ring-2-yl)-(1.05g 5.52mmol) is dissolved in the 20mL tetrahydrofuran (THF) 1H-pyrrolo-[2,3-c] pyridines (C173) with 5-in dry flask.(243mg 6.07mmol), and will react and stir 30 minutes, and (360 μ L 5.8mmol), and will react stirred overnight at room temperature to add methyl iodide to add 60% sodium hydride.(distribute between 4 * 10mL) at 10mL saturated sodium-chlor and methylene dichloride with the reaction vacuum concentration and with residue.The organic layer that merges is obtained the brown mashed prod at the dry also vacuum concentration of Anhydrous potassium carbonate.Rough thing is carried out chromatography with silica gel (230-400 order), with 5% ethanol/methylene wash-out.With part merging of suitable level and concentrated 5-(1,3-dioxolane-2-yl)-1-methyl isophthalic acid H pyrrolo-[2, the 3-c] pyridines (C175) (86% productive rate) that obtain.C
11H
12N
2O
2The HRMS of+H (FAB) calculated value: 205.0977, actual value 205.0983.
In flask, (920mg 4.5mmol) is dissolved in 25mL 10% acetonitrile solution with C175.Add tosic acid (630mg, 3.3mmol), and with 90 ℃ of heat of mixture 8 hours.Mixture is cooled to room temperature, vacuum concentration, and residue (distributed between 4 * 10mL) at saturated sodium bicarbonate of 15mL and methylene dichloride.The organic layer that merges is obtained 1-methyl-pyrrolo-[2,3-c] pyridine-5-carboxylic aldehyde (C177) (99% productive rate) at the dry also vacuum concentration of Anhydrous potassium carbonate.C
9H
8N
2The HRMS of O+H (FAB) calculated value: 161.0715, actual value 161.0711.
(690mg 4.3mmol) is dissolved in the 2mL formic acid with C177.With solution ice bath cooling, (970 μ L 8.6mmol), and will be reflected in the ice bath and stir 1 hour, and 5 ℃ of placements are spent the night to drip 30% aqueous hydrogen peroxide solution.Mixture is concentrated into dried, is suspended in the water, and pH is adjusted to 7 with 2N sodium hydroxide.Mixture is concentrated into dried, is dissolved in the methyl alcohol, and, use 200mL 5% triethylamine/methanol-eluted fractions then with the 200mL methanol-eluted fractions by 15mL 50W-X2 ion exchange resin (hydrogen ion type).The elutriant of alkalescence is concentrated into the dried 1-of obtaining methyl-pyrrolo-[2,3-c] pyridine-5-carboxylic acid (C178) (78% productive rate).C
9H
8N
2O
2The HRMS of+H (FAB) calculated value: 177.0664, actual value 177.0672 (M+H).
Embodiment 24 (i) can by will outer-[2.2.1]-3-amine or interior-[2.2.1]-3-amine and C178 coupling be prepared and obtain.
Following embodiment is prepared according to coupling method discussed here:
Embodiment 24 (i-a):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-1-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides
Embodiment 24 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-1-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides
Embodiment 24 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl)-1-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides
Embodiment 24 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-1-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides
Embodiment 24 (v):
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-1-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides
Embodiment 25 (i):
N-(outer-(4S)-1-azabicyclic [2.2.1] heptan-3-yl)-3-bromine furo [2,3-c] pyridine-5-carboxylic acid amides 1.5 fumarates
(5.17g 27.05mmol) is dissolved in the methylene dichloride (130mL), with saturated sodium bicarbonate (220mL) layering, uses BR with furo [2,3-c] pyridine-5-ethyl methyl acetic acid ester
2(8.36mL 162.3mmol) handles and stirring at room 4.5 hours very lentamente.With mixture vigorous stirring 30 minutes, with methylene dichloride (100mL) dilution and layering.With water layer with dichloromethane extraction (2 * 100mL) and the organic layer that merges is concentrated into small volume under nitrogen gas stream.Solution is diluted with ethanol (200mL), with salt of wormwood (22.13g, 160.1mmol) handle and stirring at room 2.5 days, mixture is concentrated into dried, (distribute between 5 * 200mL) at 50% saturated sodium-chlor (200mL) and methylene dichloride, dry on sodium sulfate, and vacuum concentration obtains xanchromatic solid (6.07g).Thick material is adsorbed on that silica gel (12g) is gone up and on the silica gel that the 250g pulpous state is filled chromatography, with 50% ethyl acetate/hexane～100% ethyl acetate gradient elution.Suitable level part merged and vacuum concentration obtains (3-bromine furo [2,3-c] pyridine-5 base) methyl alcohol of 5.02g (81%), be white solid.MS(EI)m/z：227(M
+)。
(1.77mL 20.1mmol) mixes in dry flask with methylene dichloride (60mL), is cooled to-78 ℃, and (2.86mL 40.25mmol) handles and stir 20 minutes to drip DMSO with oxalyl chloride under nitrogen.Cooling solution is dripped (3-bromine furo [2,3-c] pyridine-5-yl) methyl alcohol, and (4.0mg, tetrahydrofuran (THF) 17.5mmol) (50mL) solution is handled, and stirs 1 hour, drips triethylamine (12.2mL, 87.5mmol) processing then.Mixture was stirred 30 minutes at-78 ℃, stirred 30 minutes at 0 ℃ then.With saturated sodium bicarbonate (120mL) washing and with organism drying on salt of wormwood, vacuum concentration obtains the solid (3.91g) of deep yellow with mixture.Thick material is carried out chromatography on the silica gel that the 150g pulpous state is filled, with 30% ethyl acetate/hexane wash-out.Suitable level part merged and vacuum concentration obtains 3-bromine furo [2,3-c] pyridine-5-carboxylic aldehyde of 3.93g (99%), be white solid.MS(EI)m/z：225(M
+)。
(3.26g 14.42mmol) is dissolved in tetrahydrofuran (THF) (100mL)/t-BuOH (50mL)/water (50mL), with single part NaOCl with 3-bromine furo [2,3-c] pyridine-5-carboxylic aldehyde
2(4.89g, 43.3mmol) and potassium primary phosphate (3.92g 28.8mmol) handles, and stirring at room 18 hours, filter and collect white solid, and the filtrate vacuum concentration is to doing.Residue is suspended in the water (25mL), is acidified to pH 2, and filter and collect the solid that obtains with concentrated hydrochloric acid.With the solid collected in 50 ℃ of loft drier dry 18 hours and merge and obtain 3.52g (3-bromine furo [2,3-c] pyridine-5-carboxylic acid of 99% is white solid.MS(EI)m/z：241(M
+)。
To 3-bromine furo [2, the 3-c] pyridine-5-carboxylic acid that stirs (182mg, 0.75mmol) in DMF (10mL) suspension, add DIEA (400RL, 2.30mmol) and outer-4-[2.2.1]-3-amine (343mg, 0.75mmol).The mixture ice bath is cooled to 0 ℃, and a add HATU (286mg, 0.75mmol).Reaction mixture is warmed to room temperature and stirs spend the night.Vacuum is removed solvent, and residue is distributed between saturated wet chemical and chloroform methanol (95: 5).With water layer chloroform extraction (3 *).With the organic layer salt water washing that merges, dry on sodium sulfate, filtration and vacuum concentration obtain the acid amides of 50mg (20%), are white solid.
(50mg in methyl alcohol 0.15mmol) (5mL) solution, adds fumaric acid (66mg, methyl alcohol 0.35mmol) (5mL) solution to the above-mentioned acid amides that stirs.Vacuum is removed solvent, and residue is diluted with acetone (5mL).With the mixture stirred overnight at room temperature.Solid collected by filtration, with ether washing, and the dry vacuum embodiment 25 (i) that spends the night and obtain 53mg (70%), be white solid:
1HNMR (400MHz, CD
3OD) δ 8.97,8.36,8.31,6.72,4.354.34,3.78-3.72,3.55-3.36,3.28-3.25,3.09,2.25-2.17,1.92-1.85.
Following embodiment is prepared according to coupling method discussed here:
Embodiment 25 (i-a):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-3-bromine furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 25 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-3-bromine furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 25 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-bromine furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 25 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-bromine furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 25 (v):
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-bromine furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 26 (i):
N-[is outer-(4S)-and 1-azabicyclic [2.2.1] heptan-3-yl]-3-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides fumarate:
(7.70g 51.63mmol) is dissolved in the pyridine (45mL), and (14.36mL, 154.9mmol) processing and stirring at room are 18 hours with diacetyl oxide with furo [2,3-c] pyridine-5-base methyl alcohol.Vacuum is removed pyridine, and the residue that obtains is dissolved in the ethyl acetate (200mL), with 50% saturated sodium bicarbonate (4 * 90mL) washings, dried over mgso and vacuum concentration obtain the furo [2 of 9.32g (94%), 3-c] pyridine-5-ethyl methyl acetic acid ester, be xanchromatic oily matter.MS(EI)m/z：191(M
+)，277，148，119，118，86，84，77，63，51，50。
(956mg 5mmol) is dissolved in the methylene dichloride (40mL) and is cooled to 0 ℃ with furo [2,3-c] pyridine-5-ethyl methyl acetic acid ester.Chlorine was fed solution 15 minutes, remove cryostat immediately, and mixture was stirred 2 hours.Mixture is cooled to 0 ℃ again, saturated with chlorine, remove cryostat and solution is warmed to room temperature.With solution with saturated sodium bicarbonate (20mL) layering, stir 2 hours vigorous stirring 15 minutes then gently, mixture is diluted with saturated sodium bicarbonate (50mL), with dichloromethane extraction (1 * 40mL then 1 * 20mL), dry on the salt of wormwood and under nitrogen gas stream vacuum concentration to 20mL.Solution is diluted with ethanol (35mL), and (4.09g, 29.6mmol) processing and stirring at room are 18 hours with salt of wormwood.Add entry (7mL) and mixture was stirred 2 days.Mixture is concentrated into dried, (distribute between 4 * 50mL), the dry and vacuum concentration of salt of wormwood obtains brown solid (833mg) at 50% saturated sodium-chlor (50mL) and methylene dichloride.Thick material is carried out chromatography on standard 40g Biotage post, with 50% ethyl acetate/hexane wash-out.With part merging of suitable level, and concentrate (3-chlorine furo [2, the 3-c] pyridine-5 base) methyl alcohol that obtains 624mg (68%), be xanchromatic oily matter.
1HNMR(DMSO-d6)：δ4.69，5.56，7.69，8.55，8.93ppm。
(231 μ L 2.6mmol) mix with methylene dichloride (10mL), are cooled to-78 ℃, and (373 μ L 5.3mmol) handle and stir 20 minutes to drip DMSO with oxalyl chloride.Refrigerative solution is dripped (3-chlorine furo [2,3-c] pyridine-5-yl) methyl alcohol, and (420mg, tetrahydrofuran (THF) 2.3mmol) (5mL)/methylene dichloride (5mL) solution-treated stirred 1 hour, dripped triethylamine (1.59mL, 11.45mmol) processing then.Mixture was stirred 30 minutes at-78 ℃, stirred 30 minutes at 0 ℃ then.Mixture is washed with saturated sodium bicarbonate (20mL), and organism is dry on salt of wormwood, and vacuum concentration obtains xanchromatic solid (410mg).Thick material is carried out chromatography on the silica gel that the 20g pulpous state is filled,, suitable level part is merged 3-chlorine furo [2,3-c] pyridine-5-carboxylic aldehyde that vacuum concentration also obtains 322mg (77%), be the solid of white with 15% ethyl acetate/hexane wash-out.
1HNMR(CDCl
3)：δ7.89，8.33，9.02，10.18ppm。
(317mg 1.74mmol) is dissolved in tetrahydrofuran (THF) (10mL)/t-BuOH (5mL)/water (5mL) with 3-chlorine furo [2,3-c] pyridine-5-carboxylic aldehyde, with Textone (592mg, 5.24mmol) and potassium primary phosphate (473mg 3.48mmol) handles, and stirring at room 18 hours.The reaction mixture vacuum concentration to doing, is suspended in the water (10mL), is acidified to pH3.5 and stirring at room 2 hours with concentrated hydrochloric acid.Filter the solid that forms, wash with water and 40 ℃ of dry 3-chlorine furo [2,3-c] pyridine-5-carboxylic acids that obtained 364mg in 18 hours of vacuum drying oven, be white solid.MS(EI)m/z：197(M
+)。
To 3-chlorine furo [2, the 3-c] pyridine-5-carboxylic acid that stirs (99mg, add in dry DMF 0.5mmol) (10mL) solution DIEA (265 μ L, 1.52mmol) and outer-4 (S)-[2.2.1]-3-amine (228mg, 0.5mmol).Mixture is cooled to-5 ℃ at acetone/ice-water bath, and add once HATU (190mg, 0.5mmol).Reaction mixture is warmed to room temperature and stirs spend the night.Solvent removed in vacuo, and residue distributed between saturated wet chemical and chloroform.Water layer extracts with chloroform (2 *).With the organic layer salt water washing that merges, dry on sodium sulfate, filtration and vacuum concentration obtain acid amides, are white solid (125mg, 85%).
(125mg in the solution of acetone 0.43mmol) (5mL), adds warm fumaric acid (49.7mg, Virahol 0.43mmol) (5mL) solution to stirring above-mentioned acid amides.50 ℃ in mixture is warm 10 minutes.Vacuum is removed solvent, and remaining residue is diluted with acetone (5mL).With the mixture stirred overnight at room temperature.Solid filtering is collected, used washing with acetone, and dried overnight obtains the embodiment 26 (i) of 152mg (87%) under high vacuum, is white solid:
1HNMR (400MHz, CD
3OD) δ 8.98,8.42,8.32,6.71,4.32-4.29,3.73-3.68,3.50-3.35,3.26-3.20,3.07,2.22-2.13,1.89-1.81.
Following embodiment is prepared according to coupling method discussed here:
Embodiment 26 (i-a):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-3-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 26 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-3-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 26 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 26 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 26 (v):
N-((3R, 5R)-1-azabicyclic [32.1] oct-3-yl)-3-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides
Embodiment 27 (i):
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thionaphthene is [3,2-c] pyridine-3-carboxylic acid amides also:
Under nitrogen, (150.6ml 241mmol) is added drop-wise in-20 ℃ the ether (100ml) with n-Butyl Lithium.(10.5ml 80.3mmol) is dissolved in the ether (50ml) and is added drop-wise in the refrigerative solution cooling and stirring 0.5 hour with 3-bromine benzo-thiophene.With DMF (16.3ml 210mmol) drips and to be dissolved in the ether (75ml), and with solution-20 ℃ of restir 15 hours.To react 10% H with ice (300g)
2SO
4(200ml) suspension stops and stirs up to double-deck its colour changed into yellow.The slurry that obtains is filtered, and filter cake is dry in airflow, obtaining 1-thionaphthene-2,3-dicarboxyl aldehyde (C180) is xanchromatic solid (60% productive rate).C
10H
6O
2The HRMS of S+H (FAB) calculated value: 191.0167, actual value 191.0172 (M+H).
With 1-thionaphthene-2, (1.91g 10.0mmol) is dissolved in the methylene dichloride (100ml) and cools off on ice bath 3-dicarboxyl aldehyde (C180).With methyl (acetylamino) (dimethoxy phosphoryl) acetic ester (C152) (2.63g; 11.0mmol) be dissolved in the methylene dichloride (50ml), and add to 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (1.65ml; 11.0mmol) in, stirred 5 minutes.This drips of solution is added to refrigerative thiophene solution.Reaction mixture was stirred in ice bath 1 hour, then stirred overnight at room temperature.To react vacuum concentration, and thick material will be carried out chromatography at the silica gel of 500g pulpous state filling, obtain also [3,2-c] pyridine-3-carboxylic acid methyl ester (C181) of thionaphthene, be white solid (73% productive rate) with 50% ethyl acetate/hexane wash-out.For C
13H
9NO
2The MS of S (EI) m/z:243 (M)
+.
(1.43g 5.87mmol) is dissolved in the methyl alcohol (25ml) of band water (3ml) with C181.Dropping 2M sodium hydroxide (3.0ml, 6.0mmol), and with the solution stirring at room.(TLC detects the ester completely dissolve) will react vacuum concentration after 4 days.Residue is dissolved in the water (5ml) and with 10% hydrochloric acid with pH regulator to 3.It is complete to precipitation that solution stirring is spent the night.Slurry is filtered and filter cake is washed with ether, the thionaphthene that obtains 100% productive rate is [3,2-c] pyridine-3-carboxylic acids (C182) also, are white solid.C
12H
7NO
2The HRMS of S+H (FAB) calculated value 230.0276, actual value 230.0275 (M+H).
Embodiment 27 (i) can by will outer-[2.2.1]-3-amine or interior-[2.2.1]-3-amine be prepared with (C182) coupling and obtain.
Following embodiment is prepared according to coupling method discussed here:
Embodiment 27 (i-a):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thionaphthene is [3,2-c] pyridine-3-carboxylic acid amides also
Embodiment 27 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thionaphthene is [3,2-c] pyridine-3-carboxylic acid amides also
Embodiment 27 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thionaphthene is [3,2-c] pyridine-3-carboxylic acid amides also
Embodiment 27 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thionaphthene is [3,2-c] pyridine-3-carboxylic acid amides also
Embodiment 27 (v):
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thionaphthene is [3,2c] pyridine-3-carboxylic acid amides also for N-
Embodiment 27 (vi):
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thionaphthene is [3,2-c] pyridine-3-carboxylic acid amides also
Embodiment 28
N-(1-azabicyclic [2.2.1] heptan-3-yl) thieno-[3,4-c] pyridine-6-carboxylic acid amides:
Under nitrogen, with 3, the 4-dibromo thiophene (12.5ml, 113mmol) with CuCN (30.4g, 339mmol) and DMF (40ml) in dry flask, mix, utilize unsettled agitator.To be reflected at 180 ℃ refluxed 5 hours.Mixture with black is poured into FeCl then
3(113.6g in 1.7MHCl 700mmol) (200ml) solution, and 65 ℃ of heating 0.5 hour, uses unsettled agitator again.Reaction is cooled to room temperature and uses dichloromethane extraction (7 * 300ml).Each extraction liquid is used the 6MHCl (2 *), water of 200ml, saturated sodium bicarbonate and water washing individually.Then organism is merged, dry on sal epsom, filtration, also concentrated obtains 3 of 10.49g (69%), and 4-dicyano thiophene is fine hair shape brown solid.C
6H
2N
2The HRMS of S (EI) calculated value: 133.9939, actual value 133.9929 (M
+).
Under nitrogen, with 3, (5.0g 37.2mmol) is suspended in the benzene (150ml) of dry flask 4-dicyano thiophene, utilizes unsettled agitator.(82.0ml 82.0mmol), and will react stirring at room 2 hours to drip diisobutylaluminium hydride (toluene solution of 1.0M).To react and use methyl alcohol (5ml) to stop then carefully, and be poured over 30% H
2SO
4(60ml) and ice (200g) in.Slurry is stirred until all block dissolvings, layering.With water layer with ether (4 * 200ml) extractions, and with the organic layer that merges with dried over mgso, filtration and be adsorbed onto on the silica gel, thick material is carried out chromatography on the silica gel of 225g pulpous state filling, with 40% ethyl acetate/hexane wash-out.Suitable level part merged and concentrate obtain 3 of 1.88g (36%), 4-thiophene dialdehyde is flaxen solid.MS(EI)m/z：140(M+)。
With 3, (1.0g 7.13mmol) is dissolved in the methylene dichloride (40ml) and is cooled to 0 ℃ 4-thiophene dialdehyde.(1.88g 7.85mmol) is dissolved in the methylene dichloride (30ml), and (1.1ml 7.85mmol) mixes with DBU with methyl (acetylamino) (dimethoxy phosphoryl) acetic ester.Stir after 5 minutes and this drips of solution to be added to refrigerative thiophene solution.Reaction mixture was stirred 1 hour for 0 ℃, then stirred overnight at room temperature.Vacuum is removed volatile component, and thick material is carried out chromatography at the silica gel of 68g pulpous state filling, with 70% ethyl acetate/hexane wash-out.With part merging of suitable level and concentrated methyl alcohol (carbinol) intermediate that obtains 2.09g, be white foam.Intermediate is dissolved in the chloroform (50ml), and with DBU (1.32ml, 8.8mmol) and drip trifluoroacetic anhydride (1.24ml 8.8mmol) handles.To react stirred overnight at room temperature, and use saturated sodium hydrogen carbonate solution (50ml) to stop then.Layering, and with (2 * 50ml) extractions of water layer chloroform.The organism that merges is dry on sal epsom, filter, and concentrate and obtain xanchromatic oily matter.The silica gel that oily matter is filled at the 50g pulpous state carries out chromatography, with 90% ethyl acetate/hexane wash-out.With part merging of suitable level and concentrated thieno-[3, the 4-c] pyridine-6-carboxylic acid methyl ester that obtains 1.2g (88%), be the xanchromatic solid.MS(EI)m/z：193(M
+)。
(250mg 1.3mmol) is dissolved in methyl alcohol (7ml) and the water (1ml) with thieno-[3,4-c] pyridine-6-carboxylate methyl ester.Dropping 2M sodium hydroxide (0.72ml, 1.43mmol).To react stirred overnight at room temperature and monitor with TLC.Vacuum is removed volatile component and residue is dissolved in the water (2ml).Regulate pH to 3 with 10% HCl, will react stirred overnight at room temperature again.The aqueous solution is used ethyl acetate extraction (20 * 10ml) repeatedly.The organism that merges is dry on sal epsom, filter, and concentrate and obtain the xanchromatic solid.Therefore the product amount minimum (67mg) of extracting and separating concentrates water layer, and finds to comprise a large amount of products.The solid aqueous solution residue is obtained thieno-[3, the 4-c] pyridine-6-carboxylic acid of 225mg (97%) with ethyl acetate extraction, be the xanchromatic solid.MS(EI)m/z：179(M
+)。
Embodiment 28 (i) can utilize method discussed here to be prepared and to obtain by inciting somebody to action outer-[2.2.1]-3-amine or interior-[2.2.1]-3-amine and thieno-[3,4-c] pyridine-6-carboxylic acid coupling.
Following embodiment is prepared according to coupling method discussed here:
Embodiment 28 (i-a):
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl) thieno-[3,4-c] pyridine-6-carboxylic acid amides
Embodiment 28 is (ii):
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl) thieno-[3,4-c] pyridine-6-carboxylic acid amides
Embodiment 28 is (iii):
N-(2-azabicyclic [2.2.1] heptan-5-yl) thieno-[3,4-c] pyridine-6-carboxylic acid amides
Embodiment 28 is (iv):
N-(2-azabicyclic [2.2.1] heptan-6-yl) thieno-[3,4-c] pyridine-6-carboxylic acid amides
Embodiment 28 (v):
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) thieno-[3,4-c] pyridine-6-carboxylic acid amides
Embodiment 28 (vi):
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl) thieno-[3,4-c] pyridine-6-carboxylic acid amides
Measure the materials and methods of α 7 nAChR agonist activities
Measure α 7 nAChR agonist EC
50Cell analysis method
α 7-5HT
3The structure of acceptor and expression:
People α 7 nAChRN-that will encode hold 201 amino acid whose cDNA, and this zone comprises ion-channel ligands in conjunction with the territory, are fused to coding mouse 5HT
3Receptor hole forms on the cDNA in district, according to Eisele JL, etc., Chimaeric nicotinic-serotonergic receptor combines distinct ligand bindingand channel specificities, Nature (1993), Dec.2; 366 (6454): 479-83, and Groppi, etc., the improved method of WO00/73431 is carried out.With chimeric α 7-5HT
3Ionic channel is inserted among pGS175 and the pGS179, and the latter comprises the resistant gene of G-418 and hygromycin B respectively.The transfections simultaneously of two kinds of plasmids in the SH-EP1 cell, and are filtered out the clone that G-418 and hygromycin B is all had resistance.Determine the clone of expressing chimeric ionic channel by the binding ability of its cell surface combined with fluorescent α-bungatotoxin.Utilize Fluorescent Activated CellSorter (FACS) to isolate cell with maximum fluorescence α-bungatotoxin binding capacity.By measuring fluorescence α-bungatotoxin in conjunction with determining the chimeric α 7-5HT of stably express in cell growth back
3Clone, cell is grown in MEM, comprise nonessential amino acid, replenish 10% foetal calf serum, L-glutamine, 100 units/ml penicillin/streptomycin, 250ng/mg amphotericin B, 400 μ g/ml hygromycin B and 400 μ g/ml G-418 at 37 ℃ 6% CO
2At least 4 weeks of cultured continuously in standard mammalian cell incubator.
Chimeric α 7-5HT
3The mensuration of receptor active
In order to analyze α 7-5HT
3The activity of ionic channel merges expressing in each holes of the cell bed board 96 of passage or 384 orifice plates (Corning# 3614) and make it growth before analysis.On the same day of analyzing, anhydrous DMSO solution and 20% pluronic F-127 (Molecular Probes) mixture of 1: 1 2mM calcium of cell loading is green 1, AM (Molecular Probes).This solution is directly joined in the substratum in each hole so that final concentration is 2 μ M.Cell and dyestuff were cultivated 60 minutes at 37 ℃, and then with Earle ' s balanced salt solution (MMEBSS) washing with modification, described in WO00/73431.The ion condition of regulating MMEBSS is so that by chimeric α 7-5HT
3Ionic channel calcium ionic current maximum is described in WO00/73431.Analysis of compounds is to chimeric α 7-5HT on FLIPR
3The activity of ionic channel.With 500 milliwatt power instrument being arranged to excitation wavelength is 488 nanometers.Measure fluorescent emission being higher than 525 nanometers, with suitable F-aperture to keep the signal to noise ratio of maximum.The agonist activity of each compound is measured according to following method: express chimeric α 7-5HT by directly compound being joined
3Also measure the increase of the intracellular Ca2+ that produces in the cell of ionic channel, the latter is caused by the activation of the chimeric ionic channel of agonist-inductive.This analysis is quantitative, so the concentration dependent increase of intracellular Ca2+ can be determined as the concentration dependent change of calcium green fluorescence.The needed compound effective concentration of 50% maximum increase that causes intracellular Ca2+ is defined as EC
50Measured its EC of following embodiment
50Value is from about 40nM～about 1200nM: embodiment 1 (i), embodiment 1 (i-b), embodiment 1 (i-d), embodiment 1 (v), embodiment 1 (vi), embodiment 2 (v), embodiment 7 (i), embodiment 7 (v), embodiment 8 (i), embodiment 11 (i), embodiment 21 (i), embodiment 21 (v), embodiment 22 (i), embodiment 22 (v), embodiment 25 (i) and embodiment 26 (i).
Binding constant
The another kind of mode of measuring α 7 nAChR agonist activities is to measure the binding constant of potential agonist in competitive binding analysis.For α 7 nAChR agonists, utilizing chimeric α 7-5HT
3Ionic channel is as the functional EC of drug targets
50There is good dependency between value and compound the binding affinity to endogenous α 7 nAChR.
Membrane prepare
With male Sprague-Dawley rat (300-350g) sacrificed by decapitation, and brain (full brain deduct cerebellum) cut fast, weigh and in the ice-cold 0.32M sucrose/g weight in wet base of 9 times of volumes, carry out homogenate, utilize rotary pestle, be provided with 50 (10 times impact up and down).With homogenate 4 ℃ at 1,000 * g centrifugal 10 minutes.Collect supernatant liquor and 4 ℃ at 20,000 * g centrifugal 20 minutes.It is 1-8mg/mL that the precipitation resuspending that obtains is made proteic concentration.5mL homogenate five equilibrium is frozen until analysis at-80 ℃.The same day of analyzing, with branch room temperature freeze thawing such as homogenate, and dilute with Kreb ' s-20mM Hepes pH of buffer 7.0 (room temperatures), the latter comprises 4.16mM sodium bicarbonate, 0.44mM potassium primary phosphate, 127mM sodium-chlor, 5.36mM Repone K, 1.26mM calcium chloride and 0.98mM magnesium chloride, like this 25-150 μ g protein is joined in each testing tube.Measure albumen with Bradford method (Bradford, M.M., Anal.Biochem., 72,248-254,1976), use bovine serum albumin as standard.
Binding analysis
In order to carry out saturated research, the 0.4mL homogenate is joined in the testing tube, the latter comprises the radio-labeled part of damping fluid and various concentration, and cultivates 1 hour at 25 ℃ with the 0.5mL final volume.In following method, measure non-specific binding: 0.05mls MLA final concentration be under the 1 μ M condition abreast with tissue culture, before radioligand, add.In competitiveness research, adding 0.05mls[
3H]-mode of medicine with cumulative concentration added in the testing tube before the MLA, so that final concentration is 3.0～4.0nM.Cultivate by the quick centrifugal termination of Whatman GF/B glass filter paper, filter paper is placed on the 48 hole Brandel cell harvestors.With filter submergence in advance in the poly-second diimine of 50mM Tris HCl pH7.0-0.05%.With the cold 0.9% salt solution Rapid Cleaning twice of filter, and with liquid flash of light spectrometer radioactivity is counted then with the 5mL five equilibrium.
Data analysis
Competitive in conjunction with research in, from concentration dependent [
3H]-the MLA bonded calculates in suppressing and suppresses constant (Ki), and the nonlinear regression and fitting of concentration-inhibition is according to Cheng-Prusoff equation program (Cheng, Y.C. and Pmssoff, W.H., Biochem.Pharmacol., 22, p.3099-3108,1973).(GraphPad Prism sigmoidal dose-response with variable slope) obtains the Hill coefficient with non-linear regression.
Claims (60)
1. the compound of formula I:
Formula I
Wherein Azabicyclo is
W is
Or
Condition is-C (=X)-chemical bond between group and the W group can connect as at R
3, R
6And R
15Any in the W group that provides becomes on the key carbon atom;
X is O or S;
R
0Be H, low alkyl group, replacement low alkyl group or junior alkyl halides;
Each R
1Be H, alkyl, cycloalkyl, haloalkyl, substituted-phenyl or substituted naphthyl;
Each R
2Be alkyl, cycloalkyl, aryl, F, Cl, Br, the I of alkyl, haloalkyl, replacement, or R
2Do not exist, condition is k
2, k
5Or k
6Be 0;
R
2-3Alkyl, haloalkyl, F, Cl, Br or I for H, alkyl, replacement;
k
2Be 0 or 1;
k
5And k
6Independently 0,1 or 2;
A---A '---A " is N (R
4)-C (R
3)=C (R
3), N=C (R
3)-C (R
15)
2, C (R
3)=C (R
3)-N (R
4), C (R
3)
2-N (R
4)-C (R
3)
2, C (R
15)
2-C (R
3)=N, N (R
4)-C (R
3)
2-C (R
3)
2, C (R
3)
2-C (R
3)
2-N (R
4), O-C (R
3)=C (R
3), O-C (R
3)
2-C (R
3)
2, C (R
3)
2-O-C (R
3)
2, C (R
3)=C (R
3)-O, C (R
3)
2-C (R
3)
2-O, S-C (R
3)=C (R
3), S-C (R
3)
2-C (R
3)
2, C (R
3)
2-S-C (R
3)
2, C (R
3)=C (R
3)-S or C (R
3)
2-C (R
3)
2-S;
Each R
3The chemical bond condition that links to each other for core element is to have only a R independently
3And there is not R
6Or R
5Also be this chemical bond, H, alkyl, replacement alkyl, haloalkyl, alkenyl, substituted alkenyl base, halogenated alkenyl, alkynyl, substituted alkynyl, halo alkynyl ,-CN ,-NO
2, F, Br, Cl, I ,-OR
19,-C (O) N (R
10)
2,-N (R
10)
2,-SR
19,-S (O)
2R
19,-C (O) R
19,-CO
2R
19, aryl, R
7Or R
9
J, L, M and Q are N or C (R
6), condition is to have only to be a N among J, L, M or the Q, and other groups are C (R
6), and further condition is that Q is C (H) when core element connects pyridyl in the M position, and further condition is only to exist one to be connected with core element;
G and Y are C (R
6), condition is when molecule is connected to the phenyl composition at the Y place, G is CH;
R
4Alkyl, cycloalkyl, halogenated cycloalkyl, the cycloalkyl of replacement, Heterocyclylalkyl, halogenated heterocycloalkyl, substituted heterocycle alkyl, R for H, alkyl, haloalkyl, replacement
7Or R
9
Each R
5Be H, low alkyl group or low-grade alkenyl independently;
Each R
6Be independently H, F, Br, I, Cl ,-CN ,-CF
3,-OR
5,-SR
5,-N (R
5)
2, with the chemical bond condition of core element bonding be to have only a R
6And there is not R
3Or R
15Be described key;
V is selected from O, S or N (R
4);
R
7Be the assorted fragrant monocycle composition of 5-person, comprise 1-3 in the ring to be independently selected from=N-,-N (R
17)-,-O-and-heteroatoms of S-, and have 0-1 and be selected from R
18Substituting group and further have 0-3 substituting group, described substituting group is independently selected from F, Cl, Br or I, or R
7Be fused to 9-person's fused rings composition that 5-person encircles for having 6-person's ring, comprise following formula
G wherein
1Be O, S or NR
17,
Wherein G is C (R
16) or N, and each G
2And G
3Be independently selected from C (R
16)
2, C (R
16), O, S, N and N (R
18), condition is G
2And G
3Be not O simultaneously, be not S simultaneously, or be not O and S simultaneously, or
Wherein G is C (R
16) or N, and each G
2And G
3Be independently selected from C (R
16)
2, C (R
16), O, S, N and N (R
17), each 9-person's fused rings composition has 0-1 and is selected from R
18Substituting group, and further have the substituting group that 0-3 is independently selected from F, Cl, Br or I, wherein R
7During composition is connected to suc as formula I under the condition that valence link allows on defined other substituting groups on any position of arbitrary ring;
Each R
8Be alkyl, cycloalkyl, halogenated cycloalkyl, the cycloalkyl of replacement, Heterocyclylalkyl, halogenated heterocycloalkyl, substituted heterocycle alkyl, the R of H, alkyl, haloalkyl, replacement independently
7, R
9, phenyl or substituted-phenyl;
R
9Be the assorted fragrant monocycle composition of 6-person, in ring, comprise 1-3 to be selected from=heteroatoms of N-and have 0-1 and be selected from R
18Substituting group and the 0-3 substituting group that is independently selected from F, Cl, Br or I, or R
9Be 10 Yuans assorted fragrance two ring compositions, in one or two ring, comprise 1-3 to be selected from=heteroatoms of N-, include but not limited to that quinolyl or isoquinolyl, each 10-person's fused rings composition have 0-1 and be selected from R
18Substituting group and the 0-3 substituting group that is independently selected from F, Cl, Br or I, and when valence link allows, have the valence link that directly or indirectly links to each other with core element;
Each R
10Be H, alkyl, cycloalkyl, Heterocyclylalkyl independently, be selected from R by 1
13The alkyl that replaces of substituting group, be selected from R by 1
13The cycloalkyl that replaces of substituting group, be selected from R by 1
13The substituting group Heterocyclylalkyl, haloalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, phenyl or the substituted-phenyl that replace;
Each R
11Be H, alkyl, cycloalkyl, Heterocyclylalkyl, haloalkyl, halogenated cycloalkyl or halogenated heterocycloalkyl independently;
R
12For-NO
2The alkyl of ,-CN, alkyl, cycloalkyl, Heterocyclylalkyl, haloalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, replacement, the cycloalkyl of replacement, substituted heterocycle alkyl ,-OR
11,-SR
11,-NR
11R
11,-C (O) R
11,-C (O) NR
11R
11,-NR
11C (O) R
11,-S (O)
2NR
11R
11Or-NR
11S (O)
2R
11
R
13For-CN ,-CF
3,-NO
2,-OR
11,-SR
11,-NR
11R
11,-C (O) R
11,-C (O) NR
11R
11,-NR
11C (O) R
11,-S (O)
2NR
11R
11Or-NR
11S (O) R
11
Each R
14For the alkyl of H, alkyl, replacement, haloalkyl, alkenyl, substituted alkenyl base, halogenated alkenyl, alkynyl, substituted alkynyl, halo alkynyl, F, Br, Cl, I ,-CN ,-NO
2,-OR
19,-C (O) N (R
10)
2,-N (R
10)
2,-SR
19,-S (O)
2R
19,-C (O) R
19,-CO
2R
19, aryl, R
7Or R
9
Each R
15Be independently alkyl, replacement alkyl, haloalkyl, alkenyl, substituted alkenyl base, halogenated alkenyl, alkynyl, substituted alkynyl, halo alkynyl, F, Br, Cl, I ,-CN ,-NO
2,-OR
19,-C (O) N (R
10)
2,-N (R
10)
2,-SR
19,-CO
2R
19, aryl, R
7, R
9, with the valence link of core element bonding, condition is to have only a R
15And there is not R
6Or R
3Be described valence link;
Each R
16Be independently alkyl, the replacement of H, alkyl, cycloalkyl, Heterocyclylalkyl, haloalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, replacement cycloalkyl, substituted heterocycle alkyl, F, Cl, Br, I ,-NO
2,-CN ,-OR
11,-SR
11,-NR
11R
11,-C (O) R
11,-C (O) NR
11R
11,-NR
11C (O) R
11,-S (O)
2NR
11R
11,-NR
11S (O)
2R
11, the valence link that directly or indirectly links to each other with core element, condition is only to have a described valence link that links to each other with core element in 9-person's fused rings composition, other condition is that the fused rings composition has 0-1 substituting group, described substituting group be selected from alkyl, the replacement of alkyl, cycloalkyl, Heterocyclylalkyl, haloalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, replacement cycloalkyl, substituted heterocycle alkyl ,-OR
11,-SR
11,-NR
11R
11,-C (O) R
11,-NO
2,-C (O) NR
11R
11,-CN ,-NR
11C (O) R
11,-S (O)
2NR
11R
11Or-NR
11S (O) R
11, and other condition is that the fused rings composition has 0-3 substituting group that is selected from F, Cl, Br or I;
R
17For the cycloalkyl of the alkyl of H, alkyl, haloalkyl, replacement, cycloalkyl, halogenated cycloalkyl, replacement, phenyl ,-SO
2R
8Or have 1 and be selected from R
18Substituting group and further have 0-3 and be independently selected from the substituent phenyl of F, Cl, Br or I;
R
18For alkyl, cycloalkyl, Heterocyclylalkyl, haloalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl ,-OR
11,-SR
11,-NR
11R
11,-C (O) R
11,-C (O) NR
11R
11,-CN ,-NR
11C (O) R
11,-S (O)
2NR
11R
11,-NR
11S (O)
2R
11,-NO
2, be independently selected from F, Cl, Br, I or R by 1-4
13The alkyl that replaces of substituting group, be independently selected from F, Cl, Br, I or R by 1-4
13The cycloalkyl that replaces of substituting group or be independently selected from F, Cl, Br, I or R by 1-4
13The Heterocyclylalkyl that replaces of substituting group;
R
19Alkyl, haloalkyl, substituted-phenyl or substituted naphthyl for H, alkyl, cycloalkyl, replacement;
Or its pharmacologically acceptable salt, racemic mixture and pure enantiomorph.
2. according to the compound of claim 1, wherein X is O.
3. according to the compound of claim 2, R wherein
1Be H, alkyl or cycloalkyl.
4. according to the compound of claim 3, wherein W is (a).
5. according to the compound of claim 4, wherein (a) is thieno-[2,3-b] pyridine-2-base, thieno-[2,3-b] pyridine-5-base, thieno-[2,3-b] pyridine-6-base, thieno-[3,2-b] pyridine-2-base, thieno-[3,2-b] pyridine-5-base, thieno-[3,2-b] pyridine-6-base, thieno-[2,3-c] pyridine-2-base, thieno-[2,3-c] pyridine-5-base, thieno-[3,2-c] pyridine-2-base, thieno-[3,2-c] pyridine-6-base, furo [3,2-c] pyridine-2-base, furo [3,2-c] pyridine-6-base, furo [2,3-b] pyridine-2-base, furo [2,3-c] pyridine-2-base, furo [2,3-c] pyridine-5-base, 2,3 dihydro furan is [2,3-c] pyridine-5-base or 1H-pyrrolo-[2 also, 3-c] pyridine-5-base
Randomly be substituted on 4 different carbon atoms at the most under the valence link permission situation, and by F, Br in the W definition, Cl, I ,-CN ,-NO
2,-CF
3,-OR
5,-OR
19,-SR
5,-SR
19,-N (R
5)
2,-N (R
10)
2,-C (O) R
19,-CO
2R
19,-C (O) N (R
10)
2,-S (O)
2R
19, alkyl, the alkyl of replacement, haloalkyl, alkenyl, substituted alkenyl base, halogenated alkenyl, alkynyl, substituted alkynyl, halo alkynyl, aryl, R
7, R
9Replace,
And further choose wantonly on nitrogen by alkyl, haloalkyl, the alkyl of replacement, cycloalkyl, halogenated cycloalkyl, the cycloalkyl of replacement, Heterocyclylalkyl, halogenated heterocycloalkyl, substituted heterocycle alkyl, R in the W definition
7Or R
9Replace,
Condition is to use a carbon atom that W is bonded on the core element.
6. according to the compound of claim 5, wherein Ren Xuan substituting group be selected from F, Br, Cl, I ,-CN ,-CF
3,-OR
5,-SR
5,-N (R
5)
2,-C (O) R
5,-CO
2R
5,-C (O) N (R
10)
2,-S (O)
2R
5, low alkyl group, rudimentary substituted alkyl or low-grade alkynyl, wherein R
10Be H, low-grade halogenated alkyl or low alkyl group, optional quilt-CN ,-CF
3,-NO
2,-OR
11,-SR
11,-NR
11R
11,-C (O) R
11,-C (O) NR
11R
11,-NR
11C (O) R
11,-S (O)
2NR
11R
11Or-NR
11S (O)
2R
11Replace, wherein R
11Alkyl for H, low alkyl group, low-grade halogenated alkyl or rudimentary replacement.
7. according to the compound of claim 6, wherein Azabicyclo is II, V or VI.
8. according to the compound of claim 7, each k wherein
2, k
5And k
6Be 0 or 1 independently.
9. compound according to Claim 8, wherein R
2Be the alkyl of alkyl, haloalkyl, replacement, or existence condition not k
2, k
5Or k
6Be 0.
10. according to the compound of claim 9, R wherein
1Be H or low alkyl group, and R wherein
2For low alkyl group or not existence condition be k
2, k
5Or k
6Be 0.
11. according to the compound of claim 10, wherein compound is
(S)-N-(1-azabicyclic [2.2.1] heptan-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides outward-4;
(R)-N-(1-azabicyclic [2.2.1] heptan-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides outward-4;
Outward-N-(1-azabicyclic [2.2.1] heptan-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
In (+)-N-[-and 1-azabicyclic [2.2.1] heptan-3-yl] furo [2,3-c] pyridine-5-carboxylic acid amides;
In (-)-N-[-and 1-azabicyclic [2.2.1] heptan-3-yl] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-[(is outer)-azabicyclic [2.2.1] heptan-3-yl] furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(1-azabicyclic [2.2.1]-heptan-3-yl)-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-7-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-7-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-7-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-3,3-dimethyl-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-3,3-dimethyl-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3,3-dimethyl-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-2-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-2-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
(S)-N-(1-azabicyclic [2.2.1] heptan-3-yl)-3-methyl furan [2,3-c] pyridine-5-carboxylic acid amides also outward-4;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-3-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
(outward)-N-[1-azabicyclic [3.2.1] oct-3-yl]-3-methyl furan [2,3-c] pyridine-5-carboxylic acid amides also;
(3R, 5R)-N-[1-azabicyclic [3.2.1] oct-3-yl]-3-methyl furan [2,3-c] pyridine-5-carboxylic acid amides also;
(S)-N-(1-azabicyclic [2.2.1] heptan-3-yl)-3-ethyl furan [2,3-c] pyridine-5-carboxylic acid amides also outward-4;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-3-ethyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-ethyl furan is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-furo [2,3-b] pyridine-2-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-furo [2,3-b] pyridine-2-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-furo [2,3-b] pyridine-2-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-furo [2,3-b] pyridine-2-carboxylic acid amides;
(S)-N-(1-azabicyclic [2.2.1] heptan-3-yl)-3-sec.-propyl furo [2,3-c] pyridine-5-carboxylic acid amides outward-4;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-3-sec.-propyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-sec.-propyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-7-(methylthio group) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-7-(methylthio group) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-7-(methylthio group) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-b] pyridine-2-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-b] pyridine-2-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[2,3-b] pyridine-2-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[2,3-b] pyridine-2-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-b] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-b] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) thieno-[2,3-b] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[2,3-b] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-c] pyridine-2-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-c] pyridine-2-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[2,3-c] pyridine-2-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[2,3-c] pyridine-2-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-b] pyridine-2-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-b] pyridine-2-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[3,2-b] pyridine-2-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[3,2-b] pyridine-2-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-c] pyridine-2-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-c] pyridine-2-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[3,2-c] pyridine-2-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[3,2-c] pyridine-2-carboxylic acid amides;
Outward-4-N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides; N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
(S)-N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides outward-4;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides; N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-1H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides; N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-1H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-1H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-1H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-1-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-1-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-1-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides;
N-(outer-(4S)-1-azabicyclic [2.2.1] heptan-3-yl)-3-bromine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-3-bromine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-bromine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-[is outer-(4S)-and 1-azabicyclic [2.2.1] heptan-3-yl]-3-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-3-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
Or its pharmacologically acceptable salt, wherein compound is its pure enantiomorph or its racemic mixture.
12. according to the compound of claim 11, wherein compound is
(S)-N-(1-azabicyclic [2.2.1] heptan-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides outward-4;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-[(is outer-(4S)-1-azabicyclic [2.2.1] heptan-3-yl] furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-2-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-2-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
(S)-N-(1-azabicyclic [2.2.1] heptan-3-yl)-3-methyl furan [2,3-c] pyridine-5-carboxylic acid amides also outward-4;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-3-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
(outward)-N-[1-azabicyclic [3.2.1] oct-3-yl]-3-methyl furan [2,3-c] pyridine-5-carboxylic acid amides also;
(3R, 5R)-N-[1-azabicyclic [3-2.1] oct-3-yl]-3-methyl furan [2,3-c] pyridine-5-carboxylic acid amides also;
(S)-N-(1-azabicyclic [2.2.1] heptan-3-yl)-3-ethyl furan [2,3-c] pyridine-5-carboxylic acid amides also outward-4;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-3-ethyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-ethyl furan is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-b] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-b] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) thieno-[2,3-b] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[2,3-b] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides;
(S)-N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides outward-4;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outward-(4S)-N-(1-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-[is outer-(4S)-and 1-azabicyclic [2.2.1] heptan-3-yl]-3-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-3-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
Or its pharmacologically acceptable salt, wherein compound is racemic mixture or its pure enantiomorph.
13. according to the compound of claim 10, wherein compound is
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-vinyl furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-ethynyl furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-third-1-alkynyl furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(3-hydroxyl third-1-alkynyl) furo [3,2-c] pyridine-6-carboxylic acid amides;
3-(outer-4 (the S)-1-azabicyclics [2.2.1] of 6-{[heptan-the 3-base is amino] carbonyl } furo [3,2-c] pyridine-2-yl) third-2-acetylenic acid methyl esters;
2-(3-amino-3-oxo third-1-alkynyl)-N-[is outer-(4S)-1-azabicyclic [2.2.1] heptan-3-yl] furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-cyano group furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-chlorine furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-fluorine furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-iodofuran [3,2-c] pyridine-6-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-trifluoromethyl furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(methylthio group) furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(methylamino) furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(formyl radical amino) furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-[formyl radical (methyl) amino] furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-the 2-[(trifluoroacetyl group) amino] furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-6-[heptan-3-yl] furo [3,2-c] pyridine-2, the 6-dicarboxamide;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-formylfuran [3,2-c] pyridine-6-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(trifluoroacetyl group) furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(methyl sulphonyl) furo [3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of 6-{[heptan-the 3-base is amino] carbonyl } furo [3,2-c] pyridine-2-carboxylic acids methyl esters;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-vinyl thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-thiophene acetylene [3,2-c] pyridine-6-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-third-1-alkynyl thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(3-hydroxyl third-1-alkynyl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
3-(outer-4 (the S)-1-azabicyclics [2.2.1] of 6-{[heptan-the 3-base is amino] carbonyl } thieno-[3,2-c] pyridine-2-yl) third-2-acetylenic acid methyl esters
Outer-4 (the S)-1-azabicyclics [2.2.1] of 2-(3-amino-3-oxo third-1-alkynyl)-N-[heptan-3-yl] thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-cyano thiophene [3,2-c] pyridine-6-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-chlorothiophene [3,2-c] pyridine-6-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-fluorine thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-iodothiophen [3,2-c] pyridine-6-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-trifluoromethyl thiophene [3,2-c] pyridine-6-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(methylthio group) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(methylamino) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(formyl radical amino) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-[formyl radical (methyl) amino] thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-the 2-[(trifluoroacetyl group) amino] thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(cyclopropyl amino) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-the 2-[dimethylamino] thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-6-[heptan-3-yl] thieno-[3,2-c] pyridine-2, the 6-dicarboxamide;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-formyl radical thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of 2-ethanoyl-N-[heptan-3-yl] thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(trifluoroacetyl group) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(methyl sulphonyl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of 6-{[heptan-the 3-base is amino] carbonyl } thieno-[3,2-c] pyridine-2-carboxylic acids methyl esters;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-vinyl furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-ethynyl furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-third-1-alkynyl furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(3-hydroxyl third-1-alkynyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
3-(outer-4 (the S)-1-azabicyclics [2.2.1] of 5-{[heptan-the 3-base is amino] carbonyl } furo [2,3-c] pyridin-3-yl) third-2-acetylenic acid methyl esters;
Outer-4 (the S)-1-azabicyclics [2.2.1] of 3-(3-amino-3-oxo third-1-alkynyl)-N-[heptan-3-yl] furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-cyano group furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-fluorine furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-iodofuran [2,3-c] pyridine-5-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-trifluoromethyl furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(methylthio group) furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(methylamino) furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(formyl radical amino) furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-[formyl radical (methyl) amino] furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-the 3-[(trifluoroacetyl group) amino] furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(cyclopropyl amino) furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-the 3-[dimethylamino] furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-5-[heptan-3-yl] furo [2,3-c] pyridine-3, the 5-dicarboxamide;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-formylfuran [2,3-c] pyridine-5-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(trifluoroacetyl group) furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(methyl sulphonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of 5-{[heptan-the 3-base is amino] carbonyl } furo [2,3-c] pyridine-3-carboxylic acid methyl esters;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-vinyl thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-thiophene acetylene [2,3-c] pyridine-5-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-third-1-alkynyl thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(3-hydroxyl third-1-alkynyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
3-(outer-4 (the S)-1-azabicyclics [2.2.1] of 5-{[heptan-the 3-base is amino] carbonyl } thieno-[2,3-c] pyridin-3-yl) third-2-acetylenic acid methyl esters;
Outer-4 (the S)-1-azabicyclics [2.2.1] of 3-(3-amino-3-oxo third-1-alkynyl)-N-[heptan-3-yl] thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-cyano thiophene [2,3-c] pyridine-5-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-chlorothiophene [2,3-c] pyridine-5-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-fluorine thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-iodothiophen [2,3-c] pyridine-5-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-trifluoromethyl thiophene [2,3-c] pyridine-5-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(methylthio group) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(methylamino) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(formyl radical amino) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-[formyl radical (methyl) amino] thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-the 3-[(trifluoroacetyl group) amino] thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(cyclopropyl amino) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-the 3-[dimethylamino] thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-5-[heptan-3-yl] thieno-[2,3-c] pyridine-3, the 5-dicarboxamide;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-formyl radical thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(trifluoroacetyl group) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(methyl sulphonyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of 5-{[heptan-the 3-base is amino] carbonyl } thieno-[2,3-c] pyridine-3-carboxylic acid methyl esters;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(phenylacetylene base) furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(3,3,3-trifluoropropyl-1-alkynyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(3,3-difluoro third-1-alkynyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(phenylacetylene base) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(3,3,3-trifluoropropyl-1-alkynyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-3-(3,3-difluoro third-1-alkynyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(phenylacetylene base) thieno-[3,2-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(3,3,3-trifluoropropyl-1-alkynyl) thieno-[3,2-c] pyridine-5-carboxylic acid amides;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl]-2-(3,3-difluoro third-1-alkynyl) thieno-[3,2-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-methyl-furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-methyl-furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-ethyl-furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-ethyl-furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-4-methyl-furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-4-methylthio group-furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-4-methoxyl group-furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-4-chloro-furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-vinyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-ethynyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-third-1-alkynyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-cyano group furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-ethynyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-third-1-alkynyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-cyano group furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-fluorine furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-chlorine furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-bromine furo [3,2-c] pyridine-6-carboxylic acid amides;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-iodofuran is [3,2-c] pyridine-6-carboxylic acid amides also for N-;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-trifluoromethyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-trifluoromethyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-sulfydryl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(methylthio group) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(methylamino) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(formyl radical amino) furo [3,2-c] pyridine-6-carboxylic acid amides;
2-(acetylamino)-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
2-(ethanoyl (methyl) amino)-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 2-[(trifluoroacetyl group) amino] furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(benzoyl-amido) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(diethylamino) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(diisopropylaminoethyl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(tetramethyleneimine-1-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(piperidines-1-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(morpholine-4-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(thiomorpholine-4-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(piperazine-1-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(4-methylpiperazine-1-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(cyclopropyl amino) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 2-[dimethylamino] furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(tetramethyleneimine-1-base carbonyl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(piperidines-1-base carbonyl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(piperazine-1-base carbonyl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-[(4-methylpiperazine-1-yl) carbonyl] furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(morpholine-4-base carbonyl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(thiomorpholine-4-base carbonyl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(azetidin-1-base carbonyl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(azetidin-1-base carbonyl) furo [3,2-c] pyridine-6-carboxylic acid amides;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-formylfuran is [3,2-c] pyridine-6-carboxylic acid amides also for N-;
2-ethanoyl-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(trifluoroacetyl group) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 2-[(phenyl) alkylsulfonyl] furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(methyl sulphonyl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-4-methyl-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-4-methylthio group-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-4-methoxyl group-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-4-chloro-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-vinyl thieno-[3,2-c] pyridine-6-carboxylic acid amides;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-thiophene acetylene is [3,2-c] pyridine-6-carboxylic acid amides also for N-;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-third-1-alkynyl thieno-[3,2-c] pyridine-6-carboxylic acid amides;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-cyano thiophene is [3,2-c] pyridine-6-carboxylic acid amides also for N-;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-fluorine thieno-[3,2-c] pyridine-6-carboxylic acid amides;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-chlorothiophene is [3,2-c] pyridine-6-carboxylic acid amides also for N-;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-bromothiophene is [3,2-c] pyridine-6-carboxylic acid amides also for N-;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-iodothiophen is [3,2-c] pyridine-6-carboxylic acid amides also for N-;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-trifluoromethyl thiophene is [3,2-c] pyridine-6-carboxylic acid amides also for N-;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-mercapto-thiophene is [3,2-c] pyridine-6-carboxylic acid amides also for N-;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(methylthio group) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(methylamino) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(formyl radical amino) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
2-(acetylamino)-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
2-(ethanoyl (methyl) amino)-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 2-[(trifluoroacetyl group) amino] thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(benzoyl-amido) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(diethylamino) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(diisopropylaminoethyl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(tetramethyleneimine-1-yl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(piperidines-1-yl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(morpholine-4-yl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(thiomorpholine-4-yl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(piperazine-1-yl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(4-methylpiperazine-1-yl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(cyclopropyl amino) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 2-[dimethylamino] thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(tetramethyleneimine-1-base carbonyl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(piperidines-1-base carbonyl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(piperazine-1-base carbonyl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-[(4-methylpiperazine-1-yl) carbonyl] thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(morpholine-4-base carbonyl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(thiomorpholine-4-base carbonyl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(azetidin-1-base carbonyl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(azetidin-1-base carbonyl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-formyl radical thieno-[3,2-c] pyridine-6-carboxylic acid amides;
2-ethanoyl-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(trifluoroacetyl group) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 2-[(phenyl) alkylsulfonyl] thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(methyl sulphonyl) thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-vinyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-7-methyl-furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-7-methoxyl group-furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-ethynyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-third-1-alkynyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-cyano group furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-fluorine furo [2,3-c] pyridine-5-carboxylic acid amides;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-iodofuran is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-trifluoromethyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-sulfydryl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(methylthio group) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(methylamino) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(formyl radical amino) furo [2,3-c] pyridine-5-carboxylic acid amides;
3-(acetylamino)-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
3-(ethanoyl (methyl) amino)-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 3-[(trifluoroacetyl group) amino] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(benzoyl-amido) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(diethylamino) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(diisopropylaminoethyl) furo [2,3-c] pyridine-5-carboxylic acid amides
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(tetramethyleneimine-1-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(piperidines-1-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(morpholine-4-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(thiomorpholine-4-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(piperazine-1-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(4-methylpiperazine-1-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(cyclopropyl amino) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 3-[dimethylamino] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(tetramethyleneimine-1-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(piperidines-1-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(piperazine-1-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-[(4-methylpiperazine-1-yl) carbonyl] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(morpholine-4-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(thiomorpholine-4-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(azetidin-1-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(azetidin-1-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-formylfuran is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
3-ethanoyl-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(trifluoroacetyl group) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 3-[(phenyl) alkylsulfonyl] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(methyl sulphonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-ethyl-furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-ethynyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-third-1-alkynyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-cyano group furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-fluorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-bromine furo [2,3-c] pyridine-5-carboxylic acid amides;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-iodofuran is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-trifluoromethyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-sulfydryl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(methylthio group) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(methylamino) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(formyl radical amino) furo [2,3-c] pyridine-5-carboxylic acid amides;
2-(acetylamino)-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
2-(ethanoyl (methyl) amino)-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 2-[(trifluoroacetyl group) amino] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(benzoyl-amido) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(diethylamino) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(diisopropylaminoethyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(tetramethyleneimine-1-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(piperidines-1-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(morpholine-4-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(thiomorpholine-4-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(piperazine-1-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(4-methylpiperazine-1-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(cyclopropyl amino) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 2-[dimethylamino] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(tetramethyleneimine-1-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(piperidines-1-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(piperazine-1-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-[(4-methylpiperazine-1-yl) carbonyl] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(morpholine-4-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(thiomorpholine-4-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(azetidin-1-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(azetidin-1-base carbonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-formylfuran is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
2-ethanoyl-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(trifluoroacetyl group) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 2-[(phenyl) alkylsulfonyl] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-2-(methyl sulphonyl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-7-methyl-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-7-methylthio group-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-7-methoxyl group-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-7-chloro-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-vinyl thieno-[2,3-c] pyridine-5-carboxylic acid amides;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-thiophene acetylene is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-third-1-alkynyl thieno-[2,3-c] pyridine-5-carboxylic acid amides;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-cyano thiophene is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-fluorine thieno-[2,3-c] pyridine-5-carboxylic acid amides;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-chlorothiophene is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3 bromo thiophene is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-iodothiophen is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-trifluoromethyl thiophene is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-mercapto-thiophene is [2,3-c] pyridine-5-carboxylic acid amides also for N-;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(methylthio group) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(methylamino) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(formyl radical amino) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
3-(acetylamino)-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
3-(ethanoyl (methyl) amino)-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 3-[(trifluoroacetyl group) amino] thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(benzoyl-amido) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(diethylamino) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(diisopropylaminoethyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(tetramethyleneimine-1-yl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(piperidines-1-yl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(morpholine-4-yl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(thiomorpholine-4-yl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(piperazine-1-yl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(4-methylpiperazine-1-yl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(cyclopropyl amino) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 3-[dimethylamino] thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(tetramethyleneimine-1-base carbonyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(piperidines-1-base carbonyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(piperazine-1-base carbonyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-[(4-methylpiperazine-1-yl) carbonyl] thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(morpholine-4-base carbonyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(thiomorpholine-4-base carbonyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(azetidin-1-base carbonyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(azetidin-1-base carbonyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-formyl radical thieno-[2,3-c] pyridine-5-carboxylic acid amides;
3-ethanoyl-N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(trifluoroacetyl group) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-the 3-[(phenyl) alkylsulfonyl] thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-3-(methyl sulphonyl) thieno-[2,3-c] pyridine-5-carboxylic acid amides;
Or its pharmacologically acceptable salt, wherein compound is racemic mixture or its pure enantiomorph.
14. according to the compound of claim 6, wherein Azabicyclo is I, III or IV.
15. according to the compound of claim 14, wherein Azabicyclo is I and R wherein
2Be the alkyl of alkyl, haloalkyl or replacement, or wherein Azabicyclo is III or IV and R wherein
2-3Alkyl for H, alkyl or replacement.
16. according to the compound of claim 15, wherein compound is
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-7-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-7-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-7-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-3,3-dimethyl-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3,3-dimethyl-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3,3-dimethyl-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-2-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-3-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-3-ethyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-ethyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-ethyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-furo [2,3-b] pyridine-2-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-furo [2,3-b] pyridine-2-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-furo [2,3-b] pyridine-2-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-3-sec.-propyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-sec.-propyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-sec.-propyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-7-(methylthio group) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-7-(methylthio group) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-7-(methylthio group) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[2,3-b] pyridine-2-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[2,3-b] pyridine-2-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[2,3-b] pyridine-2-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[2,3-b] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[2,3-b] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[2,3-b] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[2,3-c] pyridine-2-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[2,3-c] pyridine-2-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[2,3-c] pyridine-2-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[3,2-b] pyridine-2-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[3,2-b] pyridine-2-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[3,2-b] pyridine-2-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[3,2-c] pyridine-2-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[3,2-c] pyridine-2-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[3,2-c] pyridine-2-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-1H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-1H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-1H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-1-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-1-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-1-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-3-bromine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-bromine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-bromine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-3-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-chlorine furo [2,3-c] pyridine-5-carboxylic acid amides;
Or its pharmacologically acceptable salt, wherein compound is its pure enantiomorph or its racemic mixture.
17. according to the compound of claim 16, wherein compound is
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-2,3 dihydro furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-2-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-3-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-methyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-3-ethyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-ethyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-ethyl furan is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[2,3-b] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[2,3-b] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[2,3-b] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[2,3-b] pyridine-6-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[3,2-b] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[3,2-b] pyridine-6-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[2,3-c] pyridine-5-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thieno-[3,2-c] pyridine-6-carboxylic acid amides;
Or its pharmacologically acceptable salt, wherein compound is its pure enantiomorph or its racemic mixture.
18. according to the compound of claim 15, wherein compound is
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-2-ethynyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-2-third-1-alkynyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-2-cyano group furo [3,2-c] pyridine-6-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-2-fluorine furo [3,2-c] pyridine-6-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-2-chlorine furo [3,2-c] pyridine-6-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-2-bromine furo [3,2-c] pyridine-6-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-2-iodofuran [3,2-c] pyridine-6-carboxylic acid amides also;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-2-trifluoromethyl furo [3,2-c] pyridine-6-carboxylic acid amides;
2-(acetylamino)-N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl] furo [3,2-c] pyridine-6-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-2-(tetramethyleneimine-1-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-the 2-[dimethylamino] furo [3,2-c] pyridine-6-carboxylic acid amides;
N-6-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl] furo [3,2-c] pyridine-2, the 6-dicarboxamide;
2-ethanoyl-N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl] furo [3,2-c] pyridine-6-carboxylic acid amides;
6-{[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl amino] carbonyl } furo [3,2-c] pyridine-2-carboxylic acids methyl esters;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-3-vinyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-3-ethynyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-3-third-1-alkynyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-3-cyano group furo [2,3-c] pyridine-5-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-3-fluorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-3-iodofuran [2,3-c] pyridine-5-carboxylic acid amides also;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-3-trifluoromethyl furo [2,3-c] pyridine-5-carboxylic acid amides;
3-(acetylamino)-N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-3-(tetramethyleneimine-1-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-the 3-[dimethylamino] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-5-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl] furo [2,3-c] pyridine-3, the 5-dicarboxamide;
N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl]-3-formylfuran [2,3-c] pyridine-5-carboxylic acid amides also;
3-ethanoyl-N-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl] furo [2,3-c] pyridine-5-carboxylic acid amides;
5-{[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl amino] carbonyl } furo [2,3-c] pyridine-3-carboxylic acid methyl esters;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2-ethynyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2-third-1-alkynyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2-cyano group furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2-fluorine furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2-chlorine furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2-bromine furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2-iodofuran is [3,2-c] pyridine-6-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2-trifluoromethyl furo [3,2-c] pyridine-6-carboxylic acid amides;
2-(acetylamino)-N-(2-azabicyclic [2.2.1] heptan-5-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2-(tetramethyleneimine-1-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-2-[dimethylamino] furo [3,2-c] pyridine-6-carboxylic acid amides;
N-6-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl] furo [3,2-c] pyridine-2, the 6-dicarboxamide;
2-ethanoyl-N-(2-azabicyclic [2.2.1] heptan-5-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
6-[(2-azabicyclic [2.2.1] heptan-5-base is amino) carbonyl] furo [3,2-c] pyridine-2-carboxylic acids methyl esters;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-vinyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-ethynyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-third-1-alkynyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-cyano group furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-fluorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-iodofuran is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-trifluoromethyl furo [2,3-c] pyridine-5-carboxylic acid amides;
3-(acetylamino)-N-(2-azabicyclic [2.2.1] heptan-5-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-(tetramethyleneimine-1-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-[dimethylamino] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-5-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl] furo [2,3-c] pyridine-3, the 5-dicarboxamide;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-3-formylfuran is [2,3-c] pyridine-5-carboxylic acid amides also;
3-ethanoyl-N-(2-azabicyclic [2.2.1] heptan-5-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
5-[(2-azabicyclic [2.2.1] heptan-5-base is amino) carbonyl] furo [2,3-c] pyridine-3-carboxylic acid methyl esters;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2-ethynyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2-third-1-alkynyl furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2-cyano group furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2-fluorine furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2-chlorine furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2-bromine furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2-iodofuran is [3,2-c] pyridine-6-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2-trifluoromethyl furo [3,2-c] pyridine-6-carboxylic acid amides;
2-(acetylamino)-N-(2-azabicyclic [2.2.1] heptan-6-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2-(tetramethyleneimine-1-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-2-[dimethylamino] furo [3,2-c] pyridine-6-carboxylic acid amides;
N-6-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl] furo [3,2-c] pyridine-2, the 6-dicarboxamide;
2-ethanoyl-N-(2-azabicyclic [2.2.1] heptan-6-yl) furo [3,2-c] pyridine-6-carboxylic acid amides;
6-[2-azabicyclic [2.2.1] heptan-6-base is amino) carbonyl] furo [3,2-c] pyridine-2-carboxylic acids methyl esters;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-vinyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-ethynyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-third-1-alkynyl furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-cyano group furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-fluorine furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-iodofuran is [2,3-c] pyridine-5-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-trifluoromethyl furo [2,3-c] pyridine-5-carboxylic acid amides;
3-(acetylamino)-N-(2-azabicyclic [2.2.1] heptan-6-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-(tetramethyleneimine-1-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-[dimethylamino] furo [2,3-c] pyridine-5-carboxylic acid amides;
N-5-[1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl] furo [2,3-c] pyridine-3, the 5-dicarboxamide;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-3-formylfuran is [2,3-c] pyridine-5-carboxylic acid amides also;
3-ethanoyl-N-(2-azabicyclic [2.2.1] heptan-6-yl) furo [2,3-c] pyridine-5-carboxylic acid amides;
5-[2-azabicyclic [2.2.1] heptan-6-base is amino) carbonyl] furo [2,3-c] pyridine-3-carboxylic acid methyl esters;
Or its pharmacologically acceptable salt, wherein compound is its pure enantiomorph or its racemic mixture.
19. according to the compound of claim 3, wherein W is (b).
20. according to the compound of claim 19, wherein (b) is thieno-[3,4-c] pyridine-6-base,
Choose wantonly under the condition that valence link allows 4 different carbon atoms at the most be substituted and by F, Br in the W definition, Cl, I ,-CN ,-NO
2,-CF
3,-OR
5,-OR
19,-SR
5,-SR
19,-N-(R
5)
2,-N-(R
10)
2,-C (O) R
19,-CO
2R
19,-C (O) N-(R
10)
2,-S (O)
2R
19, alkyl, the alkyl of replacement, haloalkyl, alkenyl, substituted alkenyl base, halogenated alkenyl, alkynyl, substituted alkynyl, halo alkynyl, aryl, R
7, R
9Replace, and further choose wantonly on nitrogen by alkyl, haloalkyl, the alkyl of replacement, cycloalkyl, halogenated cycloalkyl, the cycloalkyl of replacement, Heterocyclylalkyl, halogenated heterocycloalkyl, substituted heterocycle alkyl, R in the W definition
7Or R
9Replace, condition is to utilize a carbon atom that W is bonded to core element.
21. according to the compound of claim 20, wherein Azabicyclo is II, V or VI.
22. according to the compound of claim 21, each k wherein
2, k
5And k
6Be 0 or 1 independently.
23. according to the compound of claim 22, wherein R
2For the alkyl of alkyl, haloalkyl, replacement or not existence condition be k
2, k
5Or k
6Be 0.
24. according to the compound of claim 23, wherein R
1Be H or low alkyl group, and R wherein
2For low alkyl group or not existence condition be k
2, k
5Or k
6Be 0.
25. the compound of claim 24, wherein compound is
N-(1-azabicyclic [2.2.1] heptan-3-yl) thieno-[3,4-c] pyridine-6-carboxylic acid amides;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl) thieno-[3,4-c] pyridine-6-carboxylic acid amides;
N-((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl) thieno-[3,4-c] pyridine-6-carboxylic acid amides;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl) thieno-[3,4-c] pyridine-6-carboxylic acid amides;
Or its pharmacologically acceptable salt, wherein compound is racemic mixture or its pure enantiomorph.
26. according to the compound of claim 20, wherein Azabicyclo is I, III or IV.
27. according to the compound of claim 26, wherein Azabicyclo is I and R wherein
2Be the alkyl of alkyl, haloalkyl or replacement, or wherein Azabicyclo is III or IV and R wherein
2-3Alkyl for H, alkyl or replacement.
28. according to the compound of claim 27, wherein compound is
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl) thieno-[3,4-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-5-yl) thieno-[3,4-c] pyridine-6-carboxylic acid amides;
N-(2-azabicyclic [2.2.1] heptan-6-yl) thieno-[3,4-c] pyridine-6-carboxylic acid amides;
Or its pharmacologically acceptable salt, wherein compound is its pure enantiomorph or its racemic mixture.
29. according to the compound of claim 3, wherein W is (c).
30. compound according to claim 29, wherein (c) is thionaphthene also [3,2-c] pyridin-3-yl, thionaphthene also [2,3-c] pyridin-3-yl, cumarone also [3,2-c] pyridin-3-yl or cumarone also [2,3-c] pyridin-3-yl, choose wantonly under the condition that valence link allows on 4 different carbon atoms at the most by F, Br in the W definition, Cl, I ,-CN ,-NO
2,-CF
3,-OR
5,-OR
19,-SR
5,-SR
19,-N-(R
5)
2,-N-(R
10)
2,-C (O) R
19,-CO
2R
19,-C (O) N-(R
10)
2,-S (O)
2R
19, alkyl, the alkyl of replacement, haloalkyl, alkenyl, substituted alkenyl base, halogenated alkenyl, alkynyl, substituted alkynyl, halo alkynyl, aryl, R
7, R
9Replace, and further choose wantonly on nitrogen by alkyl, haloalkyl, the alkyl of replacement, cycloalkyl, halogenated cycloalkyl, the cycloalkyl of replacement, Heterocyclylalkyl, halogenated heterocycloalkyl, substituted heterocycle alkyl, R in the W definition
7Or R
9Replace, condition is to utilize a carbon atom that W is bonded to core element.
31. according to the compound of claim 30, wherein Azabicyclo is II, V or VI.
32. according to the compound of claim 31, each k wherein
2, k
5And k
6Be 0 or 1 independently.
33. according to the compound of claim 32, wherein R
2For the alkyl of alkyl, haloalkyl, replacement or not existence condition be k
2, k
5Or k
6Be 0.
34. according to the compound of claim 33, wherein R
1Be H or low alkyl group, and R wherein
2The disappearance or for low alkyl group or not existence condition be k
2, k
5Or k
6Be 0.
35. the compound of claim 34, wherein compound is
N-(1-azabicyclic [2.2.1] heptan-3-yl)-thionaphthene is [3,2-c] pyridine-3-carboxylic acid amides also;
N-(1-(6-methyl)-azabicyclic [2.2.1] heptan-3-yl)-thionaphthene is [3,2-c] pyridine-3-carboxylic acid amides also;
((3R, 5R)-1-azabicyclic [3.2.1] oct-3-yl)-thionaphthene is [3,2-c] pyridine-3-carboxylic acid amides also for N-;
N-(1-azabicyclic [3.2.2] ninth of the ten Heavenly Stems-3-yl)-thionaphthene is [3,2-c] pyridine-3-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl] [1] cumarone [2,3-c] pyridine-3-carboxylic acid amides also;
Outer-4 (the S)-1-azabicyclics [2.2.1] of N-[heptan-3-yl] [1] thionaphthene [2,3-c] pyridine-3-carboxylic acid amides also;
Or its pharmacologically acceptable salt, wherein compound is racemic mixture or its pure enantiomorph.
36. according to the compound of claim 30, wherein Azabicyclo is I, III or IV.
37. according to the compound of claim 36, wherein Azabicyclo is I and R wherein
2Be the alkyl of alkyl, haloalkyl or replacement, or wherein azabicyclic is III or IV, and R wherein
2-3Alkyl for H, alkyl or replacement.
38. according to the compound of claim 37, wherein compound is
N-(1-(6-methyl)-azabicyclic [2.2.2] oct-3-yl)-thionaphthene is [3,2-c] pyridine-3-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-5-yl)-thionaphthene is [3,2-c] pyridine-3-carboxylic acid amides also;
N-(2-azabicyclic [2.2.1] heptan-6-yl)-thionaphthene is [3,2-c] pyridine-3-carboxylic acid amides also;
Or its pharmacologically acceptable salt, wherein compound is its pure enantiomorph or its racemic mixture.
39. a pharmaceutical composition comprises according to each compound, a kind of antipsychotics and pharmaceutically acceptable excipient in the claim 1～38.
40. according to the pharmaceutical composition of claim 39, wherein said compound and described medicine per rectum, part, oral, hypogloeeis or parenteral independently carry out administration to keep the effective timed interval of treatment.
41. according to the pharmaceutical composition of claim 39, wherein said compound carries out administration with the dosage of the described weight of mammal of about 0.001～about 100mg/kg every day.
42. according to the pharmaceutical composition of claim 39, wherein said compound carries out administration with the dosage of the described weight of mammal of about 0.1～about 50mg/kg every day.
43., comprise according to each compound and pharmaceutically acceptable excipient in the claim 1～38 according to the pharmaceutical composition of claim 39.
44. according to the pharmaceutical composition of claim 43, wherein said compound per rectum, part, oral, hypogloeeis or parenteral carry out administration to keep the effective timed interval of treatment.
45. according to the pharmaceutical composition of claim 43, wherein said compound carries out administration with the dosage of the described weight of mammal of about 0.001～about 100mg/kg every day.
46. according to the pharmaceutical composition of claim 43, wherein said compound carries out administration with the dosage of the described weight of mammal of about 0.1～about 50mg/kg every day.
47. in the purposes of the medicine that is used for preparing treatment disease or illness, wherein said Mammals is received treatment, and symptom will alleviate behind the alpha 7 nicotinic acetyl choline receptor agonists of significant quantity according to each compound in the claim 1～38.
48. according to the purposes of claim 47, wherein said disease or illness be Alzheimer's cognition and attention deficit syndrome, with disease for example Alzheimer's, the nerve retrograde affection that is associated of old dementia (mild cognitive impairment) or senile dementia early.
49. according to the purposes of claim 47, wherein said disease or illness are schizophrenia or psychosis.
50. the purposes of claim 49, wherein Mammals receive treatment the alpha 7 nicotinic acetyl choline receptor agonists of significant quantity and antipsychotics treat the effective timed interval after symptom will alleviate.
51. according to the purposes of claim 47, wherein said disease or illness are dysthymia disorders, anxiety disorder, generalized anxiety disorder imbalance and hinder back pressure imbalance.
52. according to the purposes of claim 47, wherein said disease or illness are attention deficit imbalance or attention deficit superfunction imbalance.
53. according to the purposes of claim 47, wherein said disease or illness are mood and emotionality imbalance, amyotrophic lateral sclerosis, the borderline personality imbalance, traumatic brain injury, behavior that generality and cerebral tumor are associated and cognitive question, the AIDS chronic brain syndrome, the dementia that mongolism is associated, the dementia that Lu Yiti is associated, the Heng Yandunshi disease, Parkinson's disease, tardive dyskinesia, creutzfeldt jakob disease, the ingestion of food imbalance comprises exessive appetite and anorexia nervosa, smoking cessation and dependent drug are given up the withdrawal symptoms that is associated, lucky tired this moral Latourette Cotard, the macula lutea degenerative change relevant with the age, glaucoma, the syndrome that nerve retrograde affection that glaucoma is associated or pain are associated.
54. method for the treatment of disease in the Mammals that needs treatment or illness, disease symptoms will alleviate after wherein Mammals is accepted the alpha 7 nicotinic acetyl choline receptor agonists, comprise the compound that uses in the claim 1～38 of treatment significant quantity each to Mammals.
55. according to the method for claim 54, wherein said disease or illness are alzheimer's cognition and attention deficit syndrome, disease for example Alzheimer's, the nerve retrograde affection that is associated of old dementia (mild cognitive impairment) or senile dementia early.
56. according to the method for claim 54, wherein said disease or illness are schizophrenia or psychosis.
57. according to the method for claim 56, wherein Mammals receive treatment the alpha 7 nicotinic acetyl choline receptor agonists of significant quantity and antipsychotics treat the effective timed interval after disease symptoms will alleviate.
58. according to the method for claim 54, wherein said disease or illness are dysthymia disorders or anxiety disorder and common anxiety disorder imbalance and the pressure imbalance of wound back.
59. according to the method for claim 54, wherein said disease or illness are attention deficit or attention deficit superfunction imbalance.
60. according to the method for claim 54, wherein said disease or illness are mood and disorder of affect, amyotrophic lateral sclerosis, the borderline personality imbalance, traumatic brain injury, behavior that generality and cerebral tumor are associated and cognitive question, the AIDS chronic brain syndrome, the dementia that mongolism is associated, the dementia that Lu Yiti is associated, the Heng Yandunshi disease, Parkinson's disease, tardive dyskinesia, creutzfeldt jakob disease, the ingestion of food imbalance comprises exessive appetite and anorexia nervosa, smoking cessation and dependent drug are given up the withdrawal symptoms that is associated, lucky tired this moral Latourette Cotard, the macula lutea degenerative change relevant with the age, glaucoma, the syndrome that nerve retrograde affection that glaucoma is associated or pain are associated.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US32656501P | 2001-10-02 | 2001-10-02 | |
| US60/326,629 | 2001-10-02 | ||
| US60/326,565 | 2001-10-02 | ||
| US60/334,886 | 2001-11-15 | ||
| US60/339,633 | 2001-12-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1871235A true CN1871235A (en) | 2006-11-29 |
Family
ID=37444451
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 02824179 Pending CN1871235A (en) | 2001-10-02 | 2002-10-01 | Azabicyclic-substituted fused heteroaryl compounds for the treatment of disease |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN1871235A (en) |
| EC (1) | ECSP045043A (en) |
| ZA (1) | ZA200402171B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584816A (en) * | 2011-01-11 | 2012-07-18 | 华东理工大学 | Method for preparing polycycle tertiary amine |
-
2002
- 2002-10-01 CN CN 02824179 patent/CN1871235A/en active Pending
-
2004
- 2004-03-18 ZA ZA200402171A patent/ZA200402171B/en unknown
- 2004-04-01 EC ECSP045043 patent/ECSP045043A/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584816A (en) * | 2011-01-11 | 2012-07-18 | 华东理工大学 | Method for preparing polycycle tertiary amine |
| CN102584816B (en) * | 2011-01-11 | 2014-07-30 | 华东理工大学 | Method for preparing polycycle tertiary amine |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200402171B (en) | 2006-08-30 |
| ECSP045043A (en) | 2004-04-28 |
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