CN101238107A - Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation - Google Patents
Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation Download PDFInfo
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- CN101238107A CN101238107A CNA2006800285688A CN200680028568A CN101238107A CN 101238107 A CN101238107 A CN 101238107A CN A2006800285688 A CNA2006800285688 A CN A2006800285688A CN 200680028568 A CN200680028568 A CN 200680028568A CN 101238107 A CN101238107 A CN 101238107A
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Abstract
The present invention relates to novel cannabinoid receptor modulators, in particular cannabinoid 1 (CBl) or cannabinoid 2 (CB2) receptor modulators, and uses thereof for treating diseases, conditions and/or disorders modulated by a cannabinoid receptor (such as pain, neurodegenative disorders, eating disorders, weight loss or control, and obesity).
Description
The application requires Indian patent application 659/MUM/2005 number (application on June 2nd, 2005), U.S. Provisional Application the 60/696th, No. 433 (application on July 1st, 2005), Indian patent application 370/MUM/2005 number (application on October 10th, 2005), Indian patent application 344/MUM/2006 number (application on March 9th, 2006), U.S. Provisional Application the 60/744th, the interests of No. 071 (application on March 31st, 2006) and Indian patent application 689/MUM/2006 number (application on May 3rd, 2006), all these patent applications all are hereby incorporated by.
Invention field
The present invention relates to new Cannibinoid receptor modulators, particularly cannaboid 1 (CB1) or cannaboid 2 (CB2) receptor modulators, and be used for the treatment of the disease of regulating, situation by Cannabined receptor and/or unusual (such as, pain, neurodegenerative disease, eating disorder, weight loss or control, and obesity) purposes.
Background of invention
The Endocannabinoids system comprises two kinds of principal recipient (CB1 and CB2), and several parts (comprising Endocannabinoids (anandamide) and novel Endocannabinoids (virodhamine)), they produce maximum activity (Jonathan A W﹠amp on Cannabined receptor; Louis J A, Obes Man., 5-19,20f05).The Endocannabinoids that is produced by the postsynaptic is the main lipid acid that relates in this system.It can enter extracellular space and activate the CB1 Cannabined receptor that is positioned on the presynaptic nerve ending.This activation causes the presynaptic of γ-An Jidingsuan or glutaminate to suppress by suppressing calcium channel, and disturbs vesica to discharge and activated potassium channels simultaneously.
But Endocannabinoids is easy to by the quick hydrolysis of enzyme.This is its critical defect as medicinal application, because facile hydrolysis cracked material is in changing in gi tract.
The CB1 acceptor mainly is positioned at brain and other neurone, and the CB2 acceptor mainly is positioned at immunocyte.These are known from experience maincenter and the peripheral effect that influences fat in the fatty tissue and glucose metabolism known stimulation, and the most notably are, can help to regulate ingestion of food, energy balance and nicotine dependence, and regulate fear and anxiety.
Evidence suggests that CB1 agonist or antagonist can increase or reduce motivation (Gallate J E and McGregor I S, the Psychopharmacology that carries out work in order to obtain ambrosia respectively, 142,302-308,1999, with Gallate J E, Saharov T, Mallet P E and McGregor I S, 1999, Eur.J.Pharmacol., 370,233-240,1999).As if cannaboid can be by acting on diet processes, making food stimulus outstanding more and bring out diet rapidly and directly stimulate diet, even also be (Williams C M and Kirkham TC, Physiol.Behav., 76 like this in full animal, 241-250,2002).
Present data presentation cannaboid by stimulating the CB2 acceptor control agent outward and intravital inflammation suppress people such as (, J.Neuroinflammation, 2,29,2005) Ehrhart J.The inflammatory conditioning agent is played an important role in the neuronal cell injury relevant with microgliacyte as a nitrogenize nitrogen, cytokine and chemokine.Activated microgliacyte and multiple neurodegenerative disease comprise that Alzheimer's disease, multiple sclerosis, HIV and dementia are relevant.
The compound that can regulate cannaboid (CB) receptor active can be used for treating the syndrome of being regulated by the CB acceptor, disease or unusual comprises appetite, metabolism, diabetes, obesity, glaucoma dependency intraocular pressure, mood disorder, epileptic seizures, substance abuse, learning disorder, cognitive disorder, dysmnesia, organ shrinks, muscle spasm, dyspnoea, the locomotor activity obstacle, dyskinesia, dysimmunity, inflammation, cell growth abnormity, eye illness, allergy and anaphylaxis, pain, anxiety, the spirit suffering, the brain pathological state, gastrointestinal disorders, feel sick, vomiting, dizzy, uropoiesis and reproductive problems, cardiovascular disorder, the neuritis disease, central nervous system disease, neurodegenerative syndrome, disease and unusual, the sleeping eyes obstacle, dermatological diseases, the obstacle relevant with leukocyte activation, autoimmune disease, kidney disease, tardy property or the anaphylaxis of the speed property sent out, infectivity parasitosis and virus and bacteriosis.
Now, existing multiple CB conditioning agent is described to agonist, inverse agonist or the antagonist of CB1 and/or CB2 acceptor.These conditioning agents comprise naphthalene-1-base-(4-amyl group oxygen base-naphthalene-1-yl) ketone (being considered to SAB-378); 4-(2; 4-dichlorophenyl amino)-N-(tetrahydrochysene-pyrans-4-ylmethyl)-2-trifluoromethyl-benzamide (GW-842166X); N-(piperidino)-5-(4-chloro-phenyl-)-1-(2; the 4-dichlorophenyl)-4-methylpyrazole-3-methane amide (SR141716A); 3-(4-chloro-phenyl--N '-(4-chloro-phenyl-) alkylsulfonyl-N-methyl-4-phenyl-4; 5-dihydro-1 h-pyrazole-1-methane amide (SLV-319); and (R)-(+)-[2; 3-dihydro-5-methyl-3-[4-morpholinyl methyl ］ pyrrolo-[1; 2; 3]-1,4-benzoxazine-6-yl] (1-naphthyl) ketone (WIN55212-2).
SAB-378 (CB1 agonist) GW-842166X (CB2 agonist)
SR-141716A SLV-319 (WIN?55212-2)
(CB1 inverse agonist) (CB1 antagonist)
These conditioning agents have entered the advanced stage of the clinical trial that is used for the treatment of pain, neurodegenerative disease, mental anomaly, neural system syndrome, disease or unusual, eating disorder, Alzheimer's disease, alcohol dependence, diabetes, obesity and/or smoking cessation.
United States Patent (USP) the 5th, 624,941,6,028,084 and 6,509, No. 367, PCT announces WO98/31227, WO 98/41519, WO 98/43636 and WO 98/43635, and bulletin EP in Europe discloses some for No. 0658546 and has the pyrazole compound of the active replacement of antagonism Cannabined receptor.United States Patent (USP) the 6th, 355,631 and 6,479, No. 479, reach PCT and announce that WO 01/64632,01/64633 and 01/64634 discloses some azetidine derivatives, they are cannaboid antagonists.
Other Cannabined receptor is regulated compound and is disclosed in United States Patent (USP) the 4th, 973,587,5,013,837,5,081,122,5,112,820,5,292,736 and 5,532, No. 237, and PCT announces WO 97/29079, WO 98/37061, WO 99/02499, WO 00/10967, WO 00/10968, WO 01/58869, WO 01/70700, WO 02/076949, WO 03/026647, WO 03/026648, WO03/027069, WO 03/027076, WO 03/027114, WO 03/077847, WO 03/088968, WO 04/13120, WO 04/69837, WO 04/058145, WO 04/26301, WO04/058744, WO 04/096763 and WO06/030124.
Can't satisfy the demand for the treatment of alcohol abuse at present.Comprise impaired motion control with excessive drinking associated health crisis and make decision, cancer, hepatic diseases, inborn defect, heart disease, medicine/drug interaction, pancreatitis and interpersonal relation problem.Studies show that the situation of Endocannabinoids is played an important role in the picked-up of control alcoholic acid.Endogenous CB1 receptor antagonist SR-141716A demonstrated the spontaneous alcohol panning that can block rat and mouse (referring to, Arnone, M. wait the people, "---antagonist of central cannaboid (CB1) acceptor---selectivity suppresses sucrose and alcoholic acid picked-up to pass through SR141716 " (Selective Inhibition of Sucrose and Ethanol Intake bySR141716, an Antagonist of Central Cannabinoid (CB1) Receptors), Psychopharmacol, 12,104-106 (1997)).Review article is referring to Hungund, B.L and B.S.Basavarajappa, " be Endocannabinoids and Cannabined receptor relevant with the ethanol tolerance? the summary of relevant testimony " (Are Anadamide and Cannabnoid Receptors involved inEthanol Tolerance? A Review of the Evidence), Alcohol﹠amp "; Alcoholism, 35 (2) 126-133,2000.
Treatment for alcohol abuse or dependence at present exists compliance difference or the hepatotoxic problem of potential usually.Still the method that needs more efficiently treatment alcohol abuse/dependence.
Simultaneously, still need for the disease of regulating, situation by Cannabined receptor and/or unusual (such as, pain, obesity), comprise disease, situation and/or the unusual safer and more effective methods of treatment of being regulated by CB1 or CB2 acceptor.
Summary of the invention
The present invention relates to the Cannibinoid receptor modulators of following formula:
Its analogue, pharmacologically acceptable salts, the acceptable ester of its pharmacy, its tautomer, its regional isomer, its steric isomer, its enantiomorph, its diastereomer, polymorphic, or its pharmacy acceptable solvent thing,
Wherein,
Dotted line in the formula (1) is represented two keys of choosing wantonly independently of one another;
U and V are C or N independently of one another;
W, X and Y be independently of one another C, N, O, S or-C (O)-, condition be have at least among U, V, W, X or the Y two be independently from each other N, O ,-C (O)-or S;
R, R
1And R
2Can be identical or different, and be independently of one another hydrogen, nitro, cyano group, formyl radical, ethanoyl, halogen ,-OR
3,-SR
3Oxo, sulfo-, replace or unsubstituted alkyl, replace or unsubstituted thiazolinyl, replace or unsubstituted alkynyl, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkylalkyl, replace or unsubstituted cycloalkenyl group, replace or unsubstituted cycloalkenyl alkyl, replace or unsubstituted aryl, replace or unsubstituted arylalkyl, replace or unsubstituted heteroaryl, replace or unsubstituted heteroarylalkyl, replace or unsubstituted heterocyclic, replace or the unsubstituted heterocyclic alkyl,-NR
3R
4,-C (=B)-R
3,-C (O) O-R
3,-C (O) NR
3R
4,-S (O)
m-R
3,-S (O)
m-NR
3R
4, or protecting group, or R
1And R
2Can be combined together to form optional 3 to 7 Yuans the saturated or undersaturated ring that replaces, it can randomly comprise at least two and be selected from O, NR
3Or the heteroatoms of S;
R
3And R
4Can be identical or different when occurring at every turn, and be independently of one another hydrogen, nitro, halogen, cyano group ,-OR
a,-SR
aOxo, sulfo-, replace or unsubstituted alkyl, replace or unsubstituted thiazolinyl, replace or unsubstituted alkynyl, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkylalkyl, replace or unsubstituted cycloalkenyl group, replace or unsubstituted cycloalkenyl alkyl, replace or unsubstituted aryl, replace or unsubstituted arylalkyl, replace or unsubstituted heteroaryl, replace or unsubstituted heteroarylalkyl, replace or unsubstituted heterocyclic, replace or the unsubstituted heterocyclic alkyl,-C (=B)-R
a,-C (O) O-R
a,-C (O) NR
aR
b,-S (O)
m-R
a,-S (O)
m-NR
aR
b,-NR
aR
b, or protecting group, or R
3And R
4Can be bonded together when combining with the common atom forms optional 3 to 7 Yuans the saturated or undersaturated ring that replaces, and it can randomly comprise at least two and be selected from O, NR
3Or the heteroatoms of S;
R
aAnd R
bCan be identical or different when occurring at every turn, and be independently of one another hydrogen, halogen, nitro, cyano group, formyl radical, ethanoyl, oxo, sulfo-,-C (O)-R
c,-C (O) O-R
c,-C (O) NR
cR
d,-S (O)
m-R
c,-S (O)
m-NR
cR
d,-NR
cR
d,-OR
c,-SR
c, protecting group, replacement or unsubstituted alkyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted alkynyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted cycloalkylalkyl, replacement or unsubstituted cycloalkenyl group, replacement or unsubstituted cycloalkenyl alkyl, replacement or unsubstituted aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted heterocyclic, replacement or unsubstituted heterocyclic alkyl, or replacement or unsubstituted heteroarylalkyl;
R
cAnd R
dCan be identical or different when occurring at every turn, and be hydrogen independently of one another, halogen, nitro, cyano group, formyl radical, ethanoyl, oxo, sulfo-, protecting group, replace or unsubstituted alkyl, replace or unsubstituted thiazolinyl, replace or unsubstituted alkynyl, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkylalkyl, replace or unsubstituted cycloalkenyl group, replace or unsubstituted cycloalkenyl alkyl, replace or unsubstituted aryl, replace or unsubstituted arylalkyl, replace or unsubstituted heteroaryl, replace or unsubstituted heterocyclic, replace or the unsubstituted heterocyclic alkyl, or replacement or unsubstituted heteroarylalkyl;
B is O, S or NR at every turn independently of one another when occurring
3
P and m are 0,1 or 2 independently of one another;
A is
Wherein:
Dotted line among the A is represented two keys of choosing wantonly independently of one another;
R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13And R
14Be independently of one another hydrogen, nitro, cyano group, formyl radical, ethanoyl, halogen ,-OR
15,-SR
15Oxo, sulfo-, replace or unsubstituted alkyl, replace or unsubstituted thiazolinyl, replace or unsubstituted alkynyl, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkylalkyl, replace or unsubstituted cycloalkenyl group, replace or unsubstituted cycloalkenyl alkyl, replace or unsubstituted aryl, replace or unsubstituted arylalkyl, replace or unsubstituted heteroaryl, replace or unsubstituted heteroarylalkyl, replace or unsubstituted heterocyclic, replace or the unsubstituted heterocyclic alkyl,-NR
15R
16,-C (=B)-R
15,-C (O) O-R
15,-C (O) NR
15R
16,-S (O)
m-R
15,-S (O)
m-NR
15R
16, or protecting group; R
5And R
6Can be combined together to form optional 3 to 11 Yuans saturated or undersaturated monocycle or two rings that replace, it can randomly comprise at least one and be selected from O, NR
3Or the heteroatoms of S;
R
9And R
10Can be combined together to form optional 3 to 11 Yuans saturated or undersaturated monocycle or two rings that replace, it can randomly comprise at least one and be selected from O, NR
3Or the heteroatoms of S;
R
5And R
9Can be combined together to form optional 3 to 11 Yuans saturated or undersaturated monocycle or two rings that replace, it can randomly comprise at least one and be selected from O, NR
3Or the heteroatoms of S;
R
7And R
10Can be combined together to form optional 3 to 11 Yuans saturated or undersaturated monocycle or two rings that replace, it can randomly comprise at least one and be selected from O, NR
3Or the heteroatoms of S;
R
15And R
16Can be identical or different when occurring at every turn, and be independently of one another hydrogen, nitro, halogen, cyano group ,-OR
3,-SR
3Oxo, sulfo-, replace or unsubstituted alkyl, replace or unsubstituted thiazolinyl, replace or unsubstituted alkynyl, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkylalkyl, replace or unsubstituted cycloalkenyl group, replace or unsubstituted cycloalkenyl alkyl, replace or unsubstituted aryl, replace or unsubstituted arylalkyl, replace or unsubstituted heteroaryl, replace or unsubstituted heteroarylalkyl, replace or unsubstituted heterocyclic, replace or the unsubstituted heterocyclic alkyl,-C (=B)-R
3,-C (O) O-R
3,-C (O) NR
3R
4,-S (O)
m-R
3,-S (O)
m-NR
3R
4,-NR
3R
4, or R
15And R
16Can be combined together to form optional 3 to 7 Yuans the saturated or undersaturated ring that replaces when combining with a common atom, it can randomly comprise at least two and be selected from O, NR
3Or the heteroatoms of S, wherein, R
3And R
4As defined above;
N is 1,2,3 or 4; And
A b, c, d and e are selected from 0 to 4 integer independently of one another,
Condition is that described conditioning agent does not have following formula:
Wherein, R
1And R
2As defined above.
Preferred wherein U and V are formula (1) compounds of C.
Further preferably wherein Y and X be N, and W is C.
Further preferably wherein-C (B) NR
1R
2B in the group is O.
Further preferably wherein R be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted aryl.
Further preferably wherein R be methyl, phenyl, 2-chloro-phenyl-, 4-chloro-phenyl-, 2,4-dichlorophenyl, 2-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 2,4 difluorobenzene base, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 2-(4-chloro-phenyl-) phenyl or 5-chloropyridine-2-base.
Further preferred R wherein
1Be hydrogen.
Further preferred R wherein
2Be replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted cycloalkylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heterocyclic, replacement or unsubstituted heteroaryl, replacement or unsubstituted heteroarylalkyl, or NR
3R
4
Further preferred R wherein
2It is the tertiary butyl, n-pentyl, cyclopentyl, cyclohexyl, diamantane-1-base, 2-methyl adamantane-2-base, 3-hydroxyadamantane-1-base, 1,3,3-trimethylammonium two ring [2.2.1] heptan-2-base, the 1-phenycyclopropyl, cyclohexyl methyl, phenyl, the 3-chloro-phenyl-, the 4-chloro-phenyl-, the 3-bromophenyl, the 2-p-methoxy-phenyl, the 4-tert-butyl-phenyl, 2, the 4-difluorophenyl, benzyl, 2-benzyl chloride base, 4-benzyl chloride base, 2, the 4-dichloro benzyl, the 2-luorobenzyl, the 4-luorobenzyl, 2, the 4-difluorobenzyl, 2, the 6-difluorobenzyl, the 2-bromobenzyl, the 4-bromobenzyl, the 4-trifluoromethyl benzyl, the 1-phenylethyl, 1-methyl isophthalic acid-phenylethyl, the 2-phenylethyl, 1-(2-chloro-phenyl-) ethyl, 2-(4-fluorophenyl) ethyl, the 1-phenyl propyl, 1-ethyl-1-phenyl propyl, 1-(2-chloro-phenyl-)-1-methylethyl, the aminomethyl phenyl acetic ester, 2-hydroxyl-1-phenylethyl, piperidyl, morpholinyl, pyridyl, 1,2,4-triazole-4-base, the 2-pyridylmethyl, 3-pyridylmethyl, or 4-pyridylmethyl.
Further preferred R wherein
1And R
2Be combined together to form optional 3 to 7 Yuans the saturated or undersaturated ring that replaces, it can randomly comprise at least two and be selected from O, NR
3Or the heteroatoms of S.
Further preferred R wherein
1And R
2With forming piperidines-1-base or morpholinyl (for example, morpholine-1-yl) with its bonded nitrogen-atoms.
Further preferred R wherein
2Be NR
3R
4Wherein, R
3And R
4Can be identical or different when occurring at every turn, and be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl independently of one another, or R
3And R
4Be combined together to form optional 3 to 7 Yuans the saturated or undersaturated ring that replaces, it can randomly comprise at least two and be selected from O, NR
3Or the heteroatoms of S.
Further preferred R wherein
3Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted aryl, or replacement or unsubstituted cycloalkyl.
Further preferred R wherein
3Be methyl, phenyl or cyclohexyl.
Further preferred R wherein
4Be selected from replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, or replacement or unsubstituted cycloalkyl.
Further preferred R wherein
4Be phenyl, 2-chloro-phenyl-, 4-chloro-phenyl-, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4 difluorobenzene base, 3,4-difluorophenyl, 2-bromophenyl, 3-chloropyridine-2-base, 5-chloropyridine-2-base or cyclohexyl.
Further preferred R wherein
2Be-NR
3R
4, wherein, R
3And R
4Be combined together to form optional 3 to 7 Yuans the saturated or undersaturated ring that replaces, it can randomly comprise at least two and be selected from O, NR
3Or the heteroatoms of S;
Further preferred R wherein
3And R
4Be combined together to form piperidines-1 base or morpholine-4-base.
Further preferably wherein A be
Wherein
R
5To R
14Be hydrogen or methyl independently of one another; And
R
8Be to replace or unsubstituted phenyl.
Further preferred R wherein
8It is the 4-chloro-phenyl-.
Further preferred a=b=c=d=e=1 wherein.
More preferably U and V are C, and X and Y are N, and W is-C (O) NR
1R
2
Further preferred p=1.
According to an embodiment, when A is 1,7,7-trimethylammonium-two ring [2.2.1] heptane and p are 1 o'clock, and then R does not represent unsubstituted phenyl.
According to an embodiment preferred, Y is N, and U is C, and one of W, V and X are that N and remaining two are C ,-C (B) NR
1R
2B in the group is O, and A, R, R
1And R
2As defined above.
Another embodiment relates to the Cannibinoid receptor modulators of formula 1A,
Or its analogue, its pharmacologically acceptable salts, the acceptable ester of its pharmacy, its tautomer, its regional isomer, its steric isomer, its enantiomorph, its diastereomer, its polymorphic, or its pharmacy acceptable solvent thing,
Wherein
R, R
1And R
2Can be identical or different, and be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted cycloalkylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heterocyclic, replacement or unsubstituted heteroaryl independently of one another, or replacement or unsubstituted heteroarylalkyl, or R
1And R
2Can be combined together to form optional 3 to 7 Yuans the saturated or undersaturated ring that replaces, it can randomly comprise at least two and be selected from O, NR
3Or the heteroatoms of S, or NR
3R
4
R
3And R
4Can be identical or different when occurring at every turn, and be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl independently of one another, or replacement or unsubstituted heterocyclic, or R
3And R
4Can be combined together to form optional 3 to 7 Yuans the saturated or undersaturated ring that replaces, it can randomly comprise at least two and be selected from O, NR
3Or the heteroatoms of S;
P is 1; And
A is
Wherein
Dotted line among the A is represented two keys of choosing wantonly independently of one another, and
R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13And R
14Can be identical or different when occurring and be selected from hydrogen, replacement or unsubstituted alkyl at every turn, or replacement or unsubstituted aryl; Condition is that this compound does not have following formula:
Wherein, R
1And R
2As defined above.
According to an embodiment, when A is 1,7,7-trimethylammonium-two ring [2.2.1] heptane and p are 1 o'clock, and then R does not represent unsubstituted phenyl.
According to an embodiment preferred, R replaces or unsubstituted aryl.
Further preferred wherein R is by the aryl of halogen, replacement or unsubstituted alkyl, replacement or unsubstituted alkoxyl group or replacement or the replacement of unsubstituted aryl.
Further preferably wherein R be 2-chloro-phenyl-, 4-chloro-phenyl-, 2,4 dichloro benzene base, 2-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 2,4 difluorobenzene base, 4-aminomethyl phenyl, 4-p-methoxy-phenyl or 2-(4-chloro-phenyl-) phenyl.
Further preferably wherein R be 2,4 dichloro benzene base or 2,4 difluorobenzene base.
Another embodiment preferred relates to the Cannibinoid receptor modulators of formula I (a) to I (g),
Wherein, R, R
1, R
2And R
8As defined above, and the R in the formula 1 (c) be not unsubstituted phenyl.
According to an embodiment preferred, the phenyl that R is replaced by at least one halogen atom.More preferably, R is by the phenyl (for example, 2,4 difluorobenzene base or 2,4 dichloro benzene base) of one or two halogen atom replacement.
Another embodiment relates to the selectivity CB2 agonist (that is, can not suppress or activate the CB2 agonist of CB1 acceptor basically) of following formula
Wherein, R, R
1And R
2As defined above.R preferably replaces or unsubstituted aryl, is more preferably to replace or unsubstituted phenyl, and is more preferably the phenyl of replacement.More preferably, R is by the phenyl (that is, 2,4 difluorobenzene base or 2,4 dichloro benzene base) of one or two halogen atom replacement.These compounds are specially adapted to treat the disease that mediates by exciting CB2 acceptor, include but not limited to eye disease, respiratory disease, exempt from the disease disease (such as, exempt from disease from body), inflammation, pain (such as, neuropathic pain), and the syndrome relevant with nerve degeneration.Therefore, the present invention comprises that also the compound of one or more formulas 1 (b) by the administering therapeutic significant quantity treats the method for these diseases in the individuality of needs is arranged.
Following listed representative compounds of the present invention only is illustrative, is not to limit the scope of the invention.
101.N (7)-and piperidyl-5-(2-bromophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
102.N (7)-and benzyl-5-(2-bromophenyl)-5,6-diaza Fourth Ring [7.3.1.13,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
103.N (7)-and morpholinyl-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
104.N (7)-and (3-pyridylmethyl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
105.N (7)-and (4-pyridylmethyl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
106.N (7)-and cyclohexyl-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,110
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
107.N (7)-and (N-cyclohexyl-N-methylamino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
108.N (7)-and cyclohexyl methyl-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
109.N (7)-and (diamantane-1-yl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
110.N (7)-(1S, in 2-1,3,3-trimethylammonium-two ring [2.2.1] heptan-2-yl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
111.N (7)-and (2-benzyl chloride base)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
112.N (7)-and (4-benzyl chloride base)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
113.N (7)-and (4-luorobenzyl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
114.N (7)-and (2, the 4-difluorobenzyl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
115.N (7)-and (2, the 6-difluorobenzyl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
116.N (7)-and (4-trifluoromethyl benzyl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
117.N (7)-(1-phenylethyl))-and 5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
118.N (7)-(R-1-phenylethyl))-and 5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
119.N (7)-(1-methyl isophthalic acid-phenylethyl))-and 5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
120.N (7)-and (2-pyridylmethyl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
121.N (7)-(N '-phenyl amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,110
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
122.N (7)-(N '-phenyl amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,110
4,8] 14 carbon 4 (8), 6-diene-7-carboxamide hydrochloride,
123.N (7)-and (2-chloro-phenyl-amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
124.N (7)-and (2-chloro-phenyl-amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-carboxamide hydrochloride,
125.N (7)-[(4-chloro-phenyl-) amino]]-and 5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,110
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
126.N (7)-and (2,4 dichloro benzene base amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,110
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
127.N (7)-[(2,4 dichloro benzene base-N '-methylamino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
128.N (7)-[(2,4 dichloro benzene base-N '-methylamino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-carboxamide hydrochloride,
129.N (7)-and (2,4 dichloro benzene base-N '-cyclohexyl amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
130.N (7)-and (4-fluorophenyl amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
131.N (7)-and (4-fluorophenyl amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-carboxamide hydrochloride,
132.N (7)-and (2,4 difluorobenzene base amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
133.N (7)-and (3-fluorophenyl amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11,04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
134.N (7)-and (3-chloro-2-pyridinylamino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
135.N (7)-and (5-chloro-2-pyridinylamino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
136.N (7)-and (2-phenylethyl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
137.N (7)-(N ', N '-diphenyl amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,110
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
(138.N7-[1-2-chloro-phenyl-) ethyl]-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
139.N (7)-and benzyl-5-(4 '-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
140.N (7)-and piperidyl-5-(4 '-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
(141.7-4 '-chloro-phenyl-)-6,7-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-5-diene-5-base-piperidinyl ketone,
142.N (7)-and phenyl-5-(4 '-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
143.N (7)-and piperidyl-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
144.N (7)-and (diamantane-1-yl)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
145.N (7)-(1S, in 2-1,3,3-trimethylammonium-two ring [2.2.1] heptan-2-yl)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
146.N (7)-(S-1-phenylethyl))-and 5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
147.N (7)-and (R-1-phenylethyl)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
148.N (7)-and (1-methyl isophthalic acid-phenylethyl)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
149N (7)-(2-benzyl chloride base)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
150.N (7)-and (2,4 dichloro benzene base amino)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
151.N (7)-and [1-(2-chloro-phenyl-) ethyl]-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
152.N (7)-[(S)-the 1-phenyl propyl]-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
(153.N7-[1-2-chloro-phenyl-)-1-methylethyl]-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1
3,11.0
4.8] 14 carbon-4 (8), 6-diene-7-methane amide,
154. (2R)-and 2-[7-(2,4 difluorobenzene base)-6,7-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 5-diene-5-base formamido group]-2-phenylacetic acid methyl esters,
155. (2S)-and 2-[7-(2,4 difluorobenzene base)-6,7-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 5-diene-5-base formamido group]-2-phenylacetic acid methyl esters,
(156.N7-3-hydroxyadamantane-1-yl)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
157.N (7)-and (1-methyl isophthalic acid-phenylethyl)-5-(4-fluorophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
158.N (7)-and (diamantane-1-yl)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
(158a.N7-diamantane-2-yl)-5-(4-fluorophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,110
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
(159.N7-1,3,3-trimethylammonium two ring [2.2.1] heptan-2-yl)-5-(4-fluorophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,110
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
160.N (7)-and piperidyl-5-(4-aminomethyl phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
161.N (7)-and (2,4 dichloro benzene base amino)-5-(4-aminomethyl phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
162.N (7)-and (2-benzyl chloride base)-5-(4-aminomethyl phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
163.N (7)-and piperidyl-5-(4-p-methoxy-phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
(164.N7-2-benzyl chloride base)-5-(4-p-methoxy-phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
165.N (7)-and (2,4 dichloro benzene base amino)-5-(4-p-methoxy-phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
166.N (7)-and piperidyl-5-[(2-chloro-phenyl-) phenyl]-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
167.N (7)-and [(2,4 dichloro benzene base) amino]-5-phenyl-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
168.N (7)-and phenyl-5-phenyl-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
169.N (7)-and piperidyl-5-phenyl-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
170.N (7)-and benzyl-5-phenyl-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
171.N (7)-and phenyl-6,7-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-5-diene-5-base-piperidinyl ketone,
172.N (7)-and (4-luorobenzyl)-5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
173.N (7)-and phenyl amino-5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
174.N (7)-and (2-chloro-phenyl-amino)-5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
175.N (7)-and (2,4 dichloro benzene base amino)-5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
176.N (7)-and (2-bromophenyl amino)-5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
177.N (7)-(N ', N '-diphenyl amino)-5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
178.N (7)-and (2-phenylethyl)-5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14-4 (8), 6-diene-7-methane amide,
179.N (7)-and benzyl-5-(2 ', 4 '-dichlorophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
180.N (7)-and piperidyl-5-(2 ', 4 '-dichlorophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
181.N (7)-and (2,4 dichloro benzene base amino)-5-(2-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
182.N (7)-and benzyl-5-(2 '-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
183.N (7)-and cyclohexyl-5-(2 '-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
184.N (7)-and piperidyl-5-(2 '-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
(185.N7-2-benzyl chloride base)-5-(5-chloro-2-pyridyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4.8] 14 carbon-4 (8), 6-diene-7-methane amide,
186.N (7)-and benzyl-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
187.N (7)-and piperidyl-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
188.6,7-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-5-diene-5-base-piperidinyl ketone,
189a.N (7)-and piperidyl-6-methyl-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
189b.N (7)-and piperidyl-5-methyl-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
190a.N (7)-and (1-methyl isophthalic acid-phenylethyl)-6-amyl group-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4,7-alkene-7-methane amide,
190b.N (7)-and (1-methyl isophthalic acid-phenylethyl)-5-amyl group-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
191.N (7)-[(1R)-2-hydroxyl-1-phenylethyl]-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
192.N (7)-[(1S)-2-hydroxyl-1-phenylethyl]-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
201.N (3)-and piperidines-1-base-1-phenyl-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
202.N (3)-and cyclohexyl-1-phenyl-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
203.N (3)-and benzyl-1-phenyl-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
204.N (3)-and phenyl amino-1-phenyl-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
205.N (3)-and piperidines-1-base-1-(2-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
206.N (3)-and cyclohexyl-1-(2-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
207.N (3)-and benzyl-1-(2-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
208.N (3)-and phenyl amino-1-(2-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
209.N (3)-and piperidines-1-base-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
(210.1-4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-phenylpiperidines base ketone,
211.N (3)-and cyclohexyl-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
212.N (3)-and cyclopentyl-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
213.N (3)-and [(N-cyclohexyl-N-methyl) amino]-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
214.N (3)-and phenyl-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
215.N (3)-and (3-chloro-phenyl-)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
216.N (3)-and (4-chloro-phenyl-)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
217.N (3)-and (3-bromophenyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
218.N (3)-and (2-p-methoxy-phenyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
219.N (3)-and (4-tert-butyl-phenyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
220.N (3)-and benzyl-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
221.N (3)-and (2-benzyl chloride base)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
222.N (3)-and (4-benzyl chloride base)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
223.N (3)-and (2, the 4-dichloro benzyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
224.N (3)-and (2-bromobenzyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
225.N (3)-and (4-bromobenzyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide.
226.N (3)-and (4-luorobenzyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
227.N (3)-and (4-trifluoromethyl benzyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
228.N (3)-and phenyl amino-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
229.N (3)-and [(4-chloro-phenyl-) amino]-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
230.N (3)-and [(2,4 dichloro benzene base) amino]-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
231.N (3)-and [(3, the 4-dichlorophenyl) amino]-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
232.N (3)-and [(2-fluorophenyl) amino]-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
233.N (3)-and [(3-fluorophenyl) amino]-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
234.N (3)-and [(4-fluorophenyl) amino]-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
235.N (3)-and [(2,4 difluorobenzene base) amino]-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
236.N (3)-(N ', N '-diphenyl amino-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
237.N (3)-and cyclohexyl-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
238.N (3)-and cyclohexyl methyl-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
239.N (3)-and (N, N-dicyclohexyl amino)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
240.N (3)-and (4H-1,2,4-triazole-4-yl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
241.N (3)-and (1,3,3-trimethylammonium two ring [2.2.1] heptan-2-yl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
242.N (3)-and (diamantane-1-yl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
243.N (3)-and phenyl-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
244.N (3)-and (2,4 difluorobenzene base)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
245.N (3)-and (2-luorobenzyl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
246.N (3)-and (4-luorobenzyl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
247.N (3)-and (2, the 4-difluorobenzyl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
248.N (3)-and (2, the 6-difluorobenzyl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
249.N (3)-and (2-benzyl chloride base)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
250.N (3)-and (4-benzyl chloride base)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
251.N (3)-and (2, the 4-dichloro benzyl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
252.N (3)-and [S-(1-phenylethyl)]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
253.N (3)-and [R-(1-phenylethyl)]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
254.N (3)-and (2-phenylethyl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
255.N (3)-and [2-(4-fluorophenyl) ethyl]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
256.N (3)-and phenyl amino-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
257.N (3)-and [(2-chloro-phenyl-) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
258.N (3)-and [N-(2-chloro-phenyl-)-N-methylamino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
259.N (3)-and [(4-chloro-phenyl-) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
260.N (3)-and [(2,4 dichloro benzene base) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
261.N (3)-and [(2,4 dichloro benzene base)-N-methylamino]-1-(2, the 4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
262.N (3)-and [(3, the 4-dichlorophenyl) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
263.N (3)-and [(2-bromophenyl) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
264.N (3)-and [(2-fluorophenyl) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
265.N (3)-and [(2,4 difluorobenzene base) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
266.N (3)-and [(3-fluorophenyl) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
267.N (3)-and [(3-chloropyridine-2-yl) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
268.N (5)-and piperidyl-3-(2 ', 4 '-dichlorophenyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide;
269.N (5)-and benzyl-3-(2 ', 4 '-dichlorophenyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
270.N (3)-and piperidines-1-base-1-(2-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
271.N (3)-and cyclohexyl-1-(2-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
272.N (3)-and benzyl-1-(2-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
273.N (3)-and phenyl amino-1-(2-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
274.N (3)-and piperidines-1-base-1-(4-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
275.N (3)-and cyclohexyl-1-(4-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
276.N (3)-and benzyl-1-(4-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
277.N (3)-and phenyl amino-1-(4-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
278.N (3)-and [(2-fluorophenyl) amino]-1-(4-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
279.N (3)-and cyclohexyl-1-(4-fluorophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
280.N (3)-and benzyl-1-(4-fluorophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
(281.N5-diamantane-2-yl)-3-(4-fluorophenyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
(282.N5-1-methyl isophthalic acid-phenylethyl)-3-(4-fluorophenyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
(283.N5-diamantane-1-yl)-3-(4-fluorophenyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
284.N (3)-and phenyl amino-1-(4-fluorophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
285.N (3)-and phenyl amino-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
286.N (3)-and [(2-chloro-phenyl-) amino]-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
287.N (3)-and [(2-bromophenyl) amino]-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
288.N (3)-and [(2-fluorophenyl) amino]-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
289.N (3)-and piperidines-1-base-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
290.N (3)-and cyclohexyl-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
291.N (3)-and (cyclohexyl methyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
292.N (3)-and [S-(1-phenylethyl)]-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
293.N (3)-and (R-1-phenylethyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
294.N (3)-and (1-methyl isophthalic acid-phenylethyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
(295.N5-[1-2-chloro-phenyl-)-1-methylethyl]-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
296.N (3)-and (1,3,3-trimethylammonium bi ring [2.2.1] heptan-2-yl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
(297.N5-2-benzyl chloride base)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
(298.N5-4-benzyl chloride base)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
(299.N5-1-ethyl-1-phenyl propyl)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
300.N5-[(1S)-1-phenyl propyl]-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
301. (2S)-and 2-[5-(2,4 difluorobenzene base)-4,5-diaza tricyclic [5.2.1.0.
2,6] last of the ten Heavenly stems-2 (6), 3-diene-3-base formamido group]-2-phenylacetic acid methyl esters,
302.N5-[(1S)-2-hydroxyl-1-phenylethyl]-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0.
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
303.N (3)-and (tertiary butyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide.
304. (4R, 7S)-or (4S, 7R)-N (3)-(tertiary butyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
305. (4S, 7R) or (4R, 7S)-N (3)-(tertiary butyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
306.N5-n-pentyl-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
(307.N5-2, the 4-dichloro benzyl)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
(308.N5-1-phenycyclopropyl)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
(309.N5-2-adamantyl)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
(310.N5-2-methyl-2-adamantyl)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
(311.N7-3-hydroxyadamantane-1-yl)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
(312.4-[5-2,4 difluorobenzene base)-4,5-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 3-diene-3-base formamido group] morpholine,
313.N (3)-and (tert-pentyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
314.N (3)-and ring third methyl isophthalic acid-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
315.N (3)-and cyclobutyl-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
316.N (3)-and (tetrahydrochysene-2H-4-pyrans methyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
317.N (3)-and cyclopropyl-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
318.N (3)-and (4-methylpiperazine base)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
319. (2R)-and 2-[5-(2,4 difluorobenzene base)-4,5-diaza tricyclic [5.2.1.0.
2,6] last of the ten Heavenly stems-2 (6), 3-diene-3-base formamido group]-2-phenylacetic acid methyl esters,
320.N (3)-[(1R)-2-hydroxyl-1-phenylethyl]-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
321.N (3)-and (tertiary butyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
322.N (3)-and (tetrahydrochysene-2-furyl methyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
323.N (3)-and (tertiary butyl)-1-(4-fluorophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
324.N (3)-and (tertiary butyl)-1-(4-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
325.N (3)-and (tertiary butyl)-1-(3, the 4-dichlorophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
326. (2S)-and 2-[5-(2,4 difluorobenzene base)-4,5-diaza tricyclic [5.2.1.0.
2,6] last of the ten Heavenly stems-2 (6), 3-diene-3-base formamido group]-2-(4-fluorophenyl) methyl acetate,
327.N (3)-and (tertiary butyl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
328.N (3)-and (4-hydroxy phenyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
329.N (3)-and (tertiary butyl)-1-(2-oxyethyl group, 4-fluorophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
330.N (3)-and (2-furyl methyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
331.N (3)-and (2-thenyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
332.N (3)-[(1S)-2-hydroxyl-1-(4-fluorophenyl) ethyl]-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
333. methyl-(2S)-2-[5-(2,4 difluorobenzene base)-4,5-diaza tricyclic [5.2.1.0.
2,6] last of the ten Heavenly stems-2 (6), 3-diene-3-base formamido group]-4-methylpent acid esters:
334.N (3)-and (diamantane-1-yl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
335a.N (3)-and (tertiary butyl)-1-(4-luorobenzyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
335b.N (3)-and (tertiary butyl)-2-(4-luorobenzyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
336a.N (3)-and (tertiary butyl)-1-(4-methyl-benzyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
336b.N (3)-and (tertiary butyl)-2-(4-methyl-benzyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
337.N (3)-and (2-hydroxyethyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
338.N (3)-and (thienyl ethyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
339.N (3)-and (sec.-propyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
340.N (3)-[(1S)-2-methoxyl group-1-phenylethyl]-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
401.N (3)-and phenyl-1-(2,4 dichloro benzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
402.N (3)-and [(2-fluorophenyl) amino]-1-(2,4 dichloro benzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
403.N (3)-and [(2,4 difluorobenzene base) amino]-1-(2,4 dichloro benzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
404.N (3)-and [(3-chloropyridine-2-yl) amino]-1-(2,4 dichloro benzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
405.N (3)-and (diamantane-1-yl)-1-(2,4 difluorobenzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
406.N (3)-and (1,3,3-trimethylammonium two ring [2.2.1] heptan-2-yl)-1-(2,4 difluorobenzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
407.N (3)-(1-methyl isophthalic acid-phenylethyl))-and 1-(2,4 difluorobenzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
408. (4R, 7S)-N (the 3)-tertiary butyl-1-(2,4 difluorobenzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-methylene radical-indazole-3-methane amide,
409. (2R)-and 2-[1-(2,4 difluorobenzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formamido group]-2-phenylacetic acid methyl esters,
410.N (3)-[(1R)-2-hydroxyl-1-phenylethyl]-1-(2,4 difluorobenzene base)-7,8, the 8-trimethylammonium)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
411. (4S, 7R)-N (the 3)-tertiary butyl-1-(2,4 difluorobenzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-methylene radical-indazole-3-methane amide,
412.N (3)-and amyl group-1-(2,4 difluorobenzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-methylene radical-indazole-3-methane amide
501.N (12)-and benzyl-10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide,
502.N (12)-and piperidyl-10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide,
503.N (12)-and piperidyl-10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide, hydrogenchloride,
504.N (12)-[(N '-cyclohexyl-N '-methyl) amino]-10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,70
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide,
505.N (12)-N '-[(2,4 dichloro benzene base)-N '-methyl] amino }-10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide,
506.N (12)-and (diamantane-1-yl)-10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide,
(507.N12-1,3,3-trimethylammonium two ring [2.2.1] heptan-2-yl)-10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2 (7), 3,5,9 (13), 11-pentaene-12-methane amide,
(508.N12-1-methyl isophthalic acid-phenylethyl)-10-(2,4, dichlorophenyl)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9.13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide,
(509.N12-1-methyl isophthalic acid-phenylethyl)-10-(2,4 difluorobenzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9.13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide,
601.N (12)-and benzyl-16-(4-chloro-phenyl-)-10-(2,4 dichloro benzene base)-15,17-dioxo-10,11,16-three azepine five rings [6.5.5.0
2,7.0
9,13.0
14,18] 18 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide,
602.N (12)-and piperidyl-16-(4-chloro-phenyl-)-10-(2,4 dichloro benzene base)-15,17-dioxo-10,11,16-three azepine five rings [6.5.5.0
2,7.0
9,13.0
14,18] 18 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide,
701.N12-benzyl-10-(2,4 difluorobenzene base)-10,11-diaza Fourth Ring [6.5.1.0
2,7.0
9,13] 14 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide,
702.N (12)-and the tertiary butyl-10-(2,4 difluorobenzene base)-10,11-diaza Fourth Ring [6.5.1.0
2,7.0
9,13] 14 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide,
(703.N12-1-methyl isophthalic acid-phenylethyl)-10-(2,4 difluorobenzene base)-10,11-diaza Fourth Ring [6.5.1.0
2,7.0
9,13] 14 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide,
(801.N5-the tertiary butyl)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.2.0
2,6] 11 carbon-2 (6), 4-diene-5-methane amide,
802.N (5)-and (tert-pentyl)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.2.0
2,6] 11 carbon-2 (6), 4-diene-5-methane amide.
I(a)
* represent HCl salt
Table (Ib)
Table 1 (c)
Table 1 (d)
Table (1e)
Table (1f)
Table (1g)
Another embodiment of the invention relate to comprise at least a compound of the present invention and the acceptable vehicle of pharmacy (such as, pharmaceutically acceptable carrier or thinner) pharmaceutical composition.Preferably, described pharmaceutical composition comprises the The compounds of this invention for the treatment of significant quantity.
Another embodiment relates to a kind of prevention in the individuality of needs is arranged, improve or treatment by the method for the disease of Cannabined receptor mediation, unusual or syndrome (such as disease, unusual or syndrome) by mediating with CB1 or CB2 acceptor interaction, this method comprises the The compounds of this invention to described individual administering therapeutic significant quantity.
Described illness includes but not limited to that abnormal food appetite, metabolic disturbance, katabolism are unusual, diabetes, obesity, eye disease, obstacle, mood disorder, epileptic seizures, substance abuse, learning disorder, cognitive disorder, dysmnesia, organ contraction, muscle spasm, dyspnoea and the disease relevant, locomotor activity obstacle, moving obstacle, dysimmunity with social activity (such as, the autoimmunization obstacle), the growth of inflammation, cell, pain, and the syndrome relevant with nerve degeneration.
Preferred illness is pain, eye disease, dyspnoea, exempt from the disease obstacle (such as, exempt from the disease obstacle from body), inflammation, cell growth, and the syndrome relevant with nerve degeneration.
Another embodiment relates to a kind of prevention in the individuality of needs is arranged, improve or the treatment abnormal food appetite, with social relevant obstacle, autoimmunization or inflammation, pain or with nerve degeneration relevant syndrome, unusually or disease; or the method for substance abuse, this method comprises the The compounds of this invention to described individual administering therapeutic significant quantity.
Another embodiment relates to a kind ofly prevents in the individuality of needs is arranged; improvement or treatment appetite are diseases related; unusual or syndrome (such as; obesity; overweight state; apositia; disease of eating too much at one meal; dislike physique; misadjustment appetite; obesity dependency syndrome; unusually; disease or symptom (include but not limited to by heredity; diet; food intake; metabolic syndrome; unusual or disease; hypothalamic unusual or disease; age; unusual liparitosis distributes; unusual fatty lattice chamber distributes; mandatory eating disorder; or motivation (comprises consumption sugar unusually; carbohydrate; wine or medicine or any desire with composition of enjoyment sexual valence value) obesity that causes; and/or reactivity reduction) method, this method comprises the The compounds of this invention to described individual administering therapeutic significant quantity.
Another embodiment relates to a kind ofly prevents in the individuality of needs is arranged; improvement or treatment and social diseases associated; unusual or syndrome (includes but not limited to dysthymia disorders and all kinds thereof; the bipolarity dysthymia disorders; the unipolarity dysthymia disorders; has or do not have the vain hope feature; nervous feature; melancholy feature; the depressed incident of atypical characteristics or the single of sending out at the beginning of postpartum or recurrent severe; seasonal affective disorder; have and early send out or tardy and have or do not have a light strongly fragrant disease of atypical characteristics; nervous depression and social phobia; follow the dysthymia disorders of dementia; anxiety disorder; psychosis; social affective disorder; and/or cognitive disorder) method, this method comprises the The compounds of this invention to described individual administering therapeutic significant quantity.
Another embodiment relates to a kind ofly prevents in the individuality of needs is arranged; improvement or treatment autoimmunization or inflammation are diseases related; unusual or syndrome (includes but not limited to psoriasis; lupus erythematosus; connective tissue disease; siogren's syndrome; stiff property arthritis vertebralis; rheumatoid arthritis; reactive arthritis; the undifferentiated type arthritis vertebralis; behcet disease; autoimmune hemolytic anemia; multiple sclerosis; the amyotrophic lateral sclerosis funiculus lateralis is just changed disease; albuminoid degeneration; transplant rejection or influence the disease of plasma cell system; anaphylactic disease (such as; delayed or type; allergic rhinitis; contact dermatitis or anaphylaxis conjunctivitis; the infectivity parasitosis); viral or bacteriosis (such as; AIDS and meningitis); inflammatory diseases (such as; joint disease; include but not limited to sacroiliitis; rheumatoid arthritis; osteoarthritis; spondylitis; gout; vasculitis; Crohn disease; inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS)) and the method for osteoporosis, this method comprises the The compounds of this invention to described individual administering therapeutic significant quantity.
Another embodiment relates to a kind ofly prevents in the individuality of needs is arranged; improve or treatment pain or the syndrome relevant with nerve degeneration; unusual or disease (includes but not limited to the pain of maincenter and peripheral approach mediation; bone and arthralgia; migraine; cancer pain; toothache; dysmenorrhoea; antenatal throe; chronic inflammatory pain; with allergy; rheumatoid arthritis; the pain that dermatitis or immune deficiency are relevant; chronic neuropathic pain (comprises and diabetic neuropathy; sciatica; nonspecific property back pain; fibromyalgia and the relevant pain of HIV dependency DPN); postherpetic neuralgia; trigeminal neuralgia; by the health wound; amputation; cancer; the pain that toxin or chronic inflammatory state cause; He Jiejinshi disease; myasthenia gravis; nephrotic syndrome; scleroderma and thyroiditis) method, this method comprises the The compounds of this invention to described individual administering therapeutic significant quantity.
Another embodiment relates to a kind ofly prevents in the individuality of needs is arranged; the syndrome that improvement or treatment are relevant with substance abuse; unusual or disease (includes but not limited to drug abuse and drug withdrawal; wherein; abuse or dependency material are for example alcohol; Amphetamine; Amphetamine sample material; caffeine; hemp; Cocaine; psychedelia; inhalation; opiate; Nicotine (and/or tobacco product); the heroine abuse; barbiturates; phencyclidine (or phencyclidine sample compound); sedative hypnotics; benzodiazepine derivatives; or the mixture of abuse material) method, this method comprises the The compounds of this invention to described individual administering therapeutic significant quantity.
Another embodiment relates to a kind of method that reduces the demand of tobacco in the individuality of needs is arranged, this method comprises the The compounds of this invention to described individual administering therapeutic significant quantity.
Another embodiment relates to a kind ofly treats nicotine dependence, habituation, gives up in the individuality of needs is arranged, or helps to give up or reduce the method that tobacco is used, and this method comprises the The compounds of this invention to described individual administering therapeutic significant quantity.
Another embodiment relates to the method for the compound of a kind of preparation formula (1), and wherein, Y is N, and U is C, and one of W, V and X are that N and all the other two are C, and B is O, and A, R, R
1, R
2With p as defined above.This method comprises makes formula HNR
1R
2Amine and the step of the compound coupling of following formula:
Wherein, L
2Be leaving group, thus the compound of the formula of formation (1).
Another embodiment relates to the method for the compound of a kind of preparation formula (1), and wherein, W and Y are N, and U, V and X are C, and B is O, and A, R, R
1, R
2And p as defined above.This method comprises as follows
Step:
(a) make the compound oxidation of formula K:
The compound of production B:
(b) make the compound of formula B carry out reductive amination process to form the ortho position diamines of formula C:
(c) make the ortho position diamines of formula C carry out single acylation reaction to form single N-acyl group diamines of formula D:
Wherein, pg is a protecting group;
(d) make the compound of formula D carry out cyclization to form the compound of formula E:
(e) make the compound of formula E carry out dehydrogenation reaction to form the compound of formula F:
(f) make the compound derivation of formula F form compound G1, compound G2, or their mixture:
(g) make compound G1, compound G2 or the two hydrolysis form compound H 1, compound H 2 or the two:
(h) make formula HNR
1R
2Amine and compound H 1, compound H 2 or the two coupling compound that forms formula (1).
Another embodiment relates to the method for the compound of a kind of preparation formula (1), and wherein, X and Y are N, and U, V and W are C, and B is O, and A, R, R
1, R
2With p as defined above.This method comprises the steps:
(a) make the compound of formula K carry out the deprotonation reaction:
Carry out the compound of acylation reaction production L subsequently:
(b) make compound and the formula RNHNH of formula L
2Hydrazine reaction form compound M, compound N or the two:
(c) compound M, compound N or the two are hydrolyzed and with formula HNR
1R
2The amine coupling form the compound of formula (1).
Another embodiment relates to the method for the compound of a kind of preparation formula (1), and wherein, V and Y are N, and U, W and X are C, and B is O, and p is 0 or 1, and A, R, R
1And R
2As defined above.This method comprises the steps:
(a) make the compound of formula O:
Transform the compound of accepted way of doing sth P:
(b) make the amine coupling of Compound P and formula Q:
Form the compound of formula R:
(c) make the compound of formula R go protection, form the compound of formula S with after:
(d) make formula S compound hydrolysis and with formula HNR
1R
2The amine coupling form the compound of formula (1).
Brief Description Of Drawings:
Fig. 1 is with carrier, 100mg/kg gabapentin, or 0.01,0.1,0.3 or the compound administration of 1mg/kg embodiment 294 after the mean percentage that reverses of the neuropathic hyperpathia of measuring by Seltzer model (plan V) in 0.5 and 1 hour (± SEM) stick plot.
Fig. 2 is with carrier, 100mg/kg gabapentin, or the mean percentage that reverses of the neuropathic hyperpathia of measuring by the chronic narrow injury pattern (plan V I) that contracts of sciatic nerve in 0.5 and 1 hour behind the compound administration of 0.1mg/kg embodiment 294 (± SEM) stick plot.
Fig. 3 is with carrier, 3mg/kg (i.p.) WIN 55212-2, or 0.3,1 or the compound administration of 3mg/kg (i.p.) embodiment 294 after 1,3,6,12 and 18 hour by dodging maximum possible analgesia (MPE) mean percentage that tail method (plan V II) measures (± SEM) stick plot.
Detailed Description Of The Invention
Definition
Term " aryl " refers to have the aromatic group of 6 to 14 carbon atoms, such as, phenyl, naphthyl, tetralyl, indanyl, and xenyl.
Term " aryl alkyl " refers to directly the as defined above aryl of being combined with alkyl as defined above, for example, and-CH2C
6H
5With-C2H
5C
6H
5。
Term " heterocycle " refers to be selected from 3 to 15 Yuans stable cyclic groups that the hetero atom of nitrogen, phosphorus, oxygen and sulphur forms by carbon atom and 1 to 5. For purpose of the present invention, described heterocyclic radical can be monocycle shape, two ring-types, or the loop systems of three ring-types, it can comprise that condense, bridge joint or the volution system, and the nitrogen in the heterocyclic group, phosphorus, carbon, oxygen or sulphur atom optionally are oxidized to various oxidation state. In addition, nitrogen-atoms is optionally by season; And this cyclic group can be partially or completely saturated (that is, heterocycle or heteroaryl). The example of described heterocyclic group includes but not limited to azetidinyl, acridinyl, the benzo dioxolyl, benzo two alkyl, benzofuranyl, carbazyl, the cinnolines base, dioxolanyl, the indolizine base, the naphthyridines base, perhydrogenate azacyclo-heptantriene base, phenazinyl, phenothiazinyl, fen piperazine base, phthalazinyl, pyridine radicals, pteridyl, purine radicals, quinazolyl, quinoxalinyl, quinolyl, isoquinolyl, tetrazole radical, imidazole radicals, tetrahydric quinoline group, piperidyl, piperazinyl, 2-oxo piperazinyl, 2-oxo-piperidine base, 2-oxo-pyrrolidine base, 2-oxo aza ring heptantriene base, azacyclo-heptantriene base, pyrrole radicals, the 4-piperidone base, pyrrolidinyl, pyrazinyl, pyrimidine radicals, pyridazinyl, azoles base, azoles quinoline base, the oxazolidinyl, triazolyl, indanyl, different azoles base, different oxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, the peaceful cyclic group of quinoline, the isothiazole alkyl, indyl, isoindolyl, the indoline base, the isoindoline base, the octahydro indyl, the octahydro isoindolyl, quinolyl, isoquinolyl, the Decahydroisoquinolinpreparation base, benzimidazolyl, thiadiazolyl group, benzopyranyl, benzothiazolyl, the benzoxazol base, furyl, tetrahydrofuran base, THP trtrahydropyranyl, thienyl, benzothienyl, the thiomorpholine base, thiomorpholine base sulfoxide, thiomorpholine base sulfone, dioxa phospholane base, the di azoly, chromanyl and isochroman base. Heterocyclic group can be connected on the main structure in any hetero atom or carbon atom place that produces rock-steady structure.
Term " heteroaryl " refers to aromatic heterocyclic group. Heteroaryl can be connected on the main structure in any hetero atom or carbon atom place that produces rock-steady structure.
Term " heteroaryl alkyl " refers to the direct heteroaryl ring that is connected with alkyl. Heteroaryl alkyl can be connected on the main structure in any alkyl carbon atoms place that produces rock-steady structure.
Term " heterocyclic radical " refers to as defined above heterocyclic group. Heterocyclic ring can be connected on the main structure in any hetero atom or carbon atom place that produces rock-steady structure.
Term " heterocyclic radical alkyl " refers to the direct heterocyclic ring that is connected with alkyl. The heterocyclic radical alkyl can be connected on the main structure in any alkyl carbon atoms place that produces rock-steady structure.
Term " alkyl " only refers to not contained unsaturated bond, had the straight or branched hydrocarbon chain group that singly-bound is connected with the remainder of molecule that passes through of 1 to 8 carbon by what carbon and hydrogen atom formed, for example, methyl, ethyl, n-pro-pyl, 1-Methylethyl (isopropyl), normal-butyl, n-pentyl and 1,1-dimethyl ethyl (tert-butyl group).
Term " thiazolinyl " refers to contain carbon-to-carbon double bond and can be 2 aliphatic hydrocarbyls to about 10 carbon atoms that have of straight or branched, for example, vinyl, 1-acrylic, 2-acrylic (pi-allyl), different-acrylic, 2-methyl-1-propylene base, 1-cyclobutenyl and 2-cyclobutenyl.
Term " alkynyl " refers to contain at least one carbon-to-carbon triple bond and has 2 alkyl (preferably having 2 groups to about 10 carbon atoms) to the straight or branched of about 12 carbon atoms, for example, and acetenyl, propinyl and butynyl.
Term " alkoxyl " expression is bonded to the alkyl of the remainder of molecule via oxygen. The representational example of this group is-OCH3And-OC2H
5。
Term " cycloalkyl " expression 3 is to list or the multi-loop system of the non-aromatic of about 12 carbon atoms, such as, cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl. The example of polycyclic naphthene base includes but not limited to cyclic group or the volution group of perhydro naphthyl, adamantyl and norborny, bridge joint, for example, and volution (4,4) ninth of the ten Heavenly Stems-2-base.
Term " cycloalkyl-alkyl " refers to directly to be connected with alkyl contains 3 cyclic groups to the ring of about 8 carbon atoms. Cycloalkyl-alkyl can be connected on the main structure in any alkyl carbon atoms place that produces rock-steady structure. The nonrestrictive example of this group comprises cyclopropyl methyl, cyclobutyl ethyl and cyclopenta ethyl.
Term " cycloalkyl aryl " refers to directly to be connected with cycloalkyl contains 3 cyclic groups to the ring of about 8 carbon atoms. The nonrestrictive example of this group comprises phenycyclopropyl, benzyl ring butyl and benzyl ring penta Rong.
Term " cycloalkenyl group " refers to contain 3 cyclic groups to about 8 carbon atoms that have of at least one carbon-to-carbon double bond, such as, cyclopropanyl, cyclobutane base and cyclopentenyl.
If not otherwise stated, term used herein " replacement " refers to be replaced by one of following substituting group or its any combination: hydroxyl, halogen, carbonyl, cyano group, nitro, oxo (=O), sulfo-(=S), replacement or unsubstituted alkyl, replacement or unsubstituted alkoxyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted alkynyl, replacement or unsubstituted aryl, replacement or unsubstituted aryl alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted cycloalkenyl group, replacement or unsubstituted amino, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted heterocyclic radical alkyl ring, replacement or unsubstituted heteroaryl alkyl, replacement or unsubstituted heterocyclic radical, replacement or unsubstituted guanidine ,-COORx、-C(O)R
x、-C(S)R
x、-C(O)NR
xR
y、-C(O)ONR
XR
y、
-NR
xCONR
yR
z、-N(R
x)SOR
y、-N(R
x)SO
2R
y、-(＝N-N(R
x)R
y)、-NR
xC(O)OR
y、
-NR
xR
y、-NR
xC(O)R
y、-NR
xC(S)R
y、-NR
xC(S)NR
yR
z、-SONR
xR
y、
-SO
2NR
xR
y、-OR
x、-OR
xC(O)NR
yR
z、-OR
xC(O)OR
y、-OC(O)R
x、
-OC(O)NR
xR
y、-R
xNR
yC(O)R
z、-R
xOR
y、-R
xC(O)OR
y、-R
xC(O)NR
yR
z、
-R
xC(O)R
y、-R
xOC(O)R
y、-SR
x、-SOR
x、-SO
2R
xWith-ONO2, wherein, Rx、
R
yAnd RzBe selected from independently of one another heterocyclic radical alkyl ring, replacement or the unsubstituted heteroaryl alkyl of hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted alkoxyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted alkynyl, replacement or unsubstituted aryl, replacement or unsubstituted aryl alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted cycloalkenyl group, replacement or unsubstituted amino, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement, or replacement or unsubstituted heterocyclic radical. According to an embodiment, the substituting group in aforementioned " replacement " group can not further be replaced. For example, when the substituting group on " alkyl of replacement " was " aryl of replacement ", then the substituting group on " aryl of replacement " can not be " thiazolinyl of replacement ".
Term " protecting group " or " PG " refer to block or protect particular functional group's substituting group. It is reactive that other functional group on the compound can still keep. For example, " amino protecting group " is to be connected to the substituting group that is used for blocking or protecting the amido functional group in the compound on the amino. Suitable amino protecting group includes but not limited to acetyl group, trifluoroacetyl group, tert-butoxycarbonyl (BOC), benzyl oxygen carbonyl (CBz) and 9-fluorenyl methoxy carbonyl (Fmoc). Similarly, " hydroxyl protecting group " refers to block or protect the substituting group of the hydroxyl of hydroxy functional group. Suitable hydroxyl protecting group includes but not limited to acetyl group and silylation. " carboxyl-protecting group " refers to block or protect the substituting group of the carboxyl of carboxyl functional group. Suitable carboxyl-protecting group includes but not limited to-CH2CH
2SO
2Ph, cyano ethyl, 2-(TMS) ethyl, 2-(TMS) ethoxyl methyl, 2-(ptoluene-sulfonyl) ethyl, 2-(p-nitrobenzophenone sulfenyl) ethyl, 2-(diphenylphosphino)-ethyl and nitro-ethyl. Generality about protecting group and uses thereof is described, referring to " protecting group in the organic synthesis " (Protective Groups in Organic Synthesis) of T.W. Greene, John Wiley﹠Sons, New York, 1991.
Term " Cannabined receptor " refers to the known of Cannabined receptor class or any in the unknown hypotype so far, comprises CB1 and/or CB2 acceptor, and this receptor can be combined with cannabinoid modulators compound of the present invention.
Term " conditioning agent " further refers to use compound of the present invention as activator, partial agonist, antagonist or the inverse agonist of CB (for example, CB1 and/or CB2) acceptor.
To situation, unusual or " treatment " state comprise:
(1) may suffer from or be easy to suffer from situation, unusual or state but not yet suffer or manifest prevent in the individuality of clinical or inferior clinical symptom of this situation, unusual or state or postpone this situation, clinical symptoms unusual or state occur;
(2) inhibition situation, unusual or state, that is, and the development of at least a clinical or inferior clinical symptom of stop or slowing down disease or its; Or
(3) palliate a disease, that is, cause disappearing of at least a clinical or inferior clinical symptom of situation, unusual or state or its.
Can be statistically significant or be that described individuality or doctor can discover at least to the benefit of the individuality for the treatment of.
Term " individuality " comprises mammal (particularly human) and other animal, such as, domestic animal (for example, house pet comprises cat and dog), and non-domestic animal (such as, wild animal).
" treatment effective dose " refers to when being applied to the individual amount that is enough to realize the compound of described treatment during with treatment situation, unusual or state. " treatment effective dose " can treat the age, body weight, condition of individuality and reactivity and change according to compound, disease and seriousness thereof and institute.
The acceptable salt of pharmacy that consists of a part of the present invention comprise by inorganic base (such as; Li; Na; K; Ca; Mg; Fe; Cu; Zn and Mn) salt of deriving; organic base (such as; N; N '-diacetyl ethylenediamine; grape amine; triethylamine; choline; hydroxide; dicyclohexylamine; melbine; benzyl amine; trialkylamine and thiamine) salt; chiral base (such as; alkyl phenyl amine; glycinol; and phenyl glycinol) salt; natural amino acid (such as; glycine; alanine; valine; leucine; isoleucine; leucine falls; tyrosine; cystine; cysteine; methionine; proline; hydroxy-proline; histidine; ornithine; lysine; arginine; and serine) salt; alpha-non-natural amino acid (such as; the amino acid of D-isomers or replacement) salt; the salt of guanidine; the salt of the guanidine that replaces (wherein; substituting group is selected from nitro; amino; alkyl; alkenyl or alkynyl); ammonium salt; the ammonium salt that replaces, and aluminium salt. The acceptable salt of other pharmacy comprises acid-addition salts (if the words that are fit to), such as, sulfate, nitrate, phosphate, perchlorate, borate, halogen acid salt, acetate (such as, trifluoroacetate), tartrate, maleate, citrate, fumarate, succinate, palmitate, methane sulfonates, benzoate, salicylate, benzene sulfonate, ascorbate, glycerophosphate, and ketoglutaric acid salt. The acceptable salt of other pharmacy includes but not limited to that the compounds of this invention and alkyl halide or alkyl sulfate are (such as, MeI or (Me)2SO
4) quaternary ammonium salt that forms.
The acceptable solvate of pharmacy comprises hydrate and is used for other solvent of crystallization solvate of (such as, alcohol). Compound of the present invention can form solvate by the low-molecular-weight solvent of methods known in the art and standard.
Pharmaceutical composition
Pharmaceutical composition of the present invention contains at least a compound of the present invention and pharmaceutically acceptable excipient (for example pharmaceutically acceptable carrier or diluent). Preferably, this pharmaceutical composition comprises the compound of the present invention for the treatment of effective dose. Compound of the present invention can or can be sealed with the carrier of capsule, sachet, paper or other vessel form with pharmaceutically acceptable excipient (for example carrier or diluent) associating or the dilution of employing carrier.
The example of suitable carrier includes but not limited to water, salting liquid, alcohols, polyethylene glycols, poly-hydroxyl-oxethyl castor oil, peanut oil, olive oil, gelatin, lactose, white bole, sucrose, dextrin, magnesium carbonate, sucrose, cyclodextrin, amylose, dolomol, talcum powder, gelatin, agar, pectin, Arabic gum, stearic acid or cellulosic lower alkyl ether, silicic acid, aliphatic acid, fatty acid amine, glycerine monofatty ester and two glyceride, pentaerythritol fatty ester, polyoxyethylene, CMC and polyvinylpyrrolidone.
Carrier and diluent can comprise slow-release material, for example glycerin monostearate or distearin, and they can use separately or mix use with wax.
Pharmaceutical composition also can comprise any combination of one or more pharmaceutically acceptable assistants, wetting agent, emulsifying agent, suspending agent, anticorrisive agent, the salt that affects osmotic pressure, buffer, sweetener, flavouring, colouring agent or above-mentioned auxiliary material. Can prepare pharmaceutical composition of the present invention by method as known in the art, thus with its give can provide behind the patient fast, the active component of slowly-releasing or delayed release.
Pharmaceutical composition of the present invention can prepare by routine techniques, for example existsRemington： Science and Practice of Pharmacy, the 20th edition, described in 2003 (the Lippincott Williams﹠ Wilkins). For example, reactive compound can mix with carrier, perhaps adopts the carrier dilution, perhaps can seal with the carrier of capsule, sachet, paper or other vessel form. When carrier was used as diluent, it can be as the solid of the solvent of carrier, excipient or reactive compound, semisolid or fluent material. Reactive compound can be adsorbed on the granular solids contents, for example in sachet agent.
Pharmaceutical composition can be conventionally form, for example the product of capsule, tablet, aerosol, solution, suspension or topical application.
Method of administration can be any approach that can effectively reactive compound of the present invention be transported to the site of action of suitable or expectation. That suitable method of administration includes but not limited to is oral, in nasal cavity, lung, oral cavity, subcutaneous, the corium, in outer, the rectum of transdermal, stomach and intestine, bank, subcutaneous, intravenous, the urethra, in the muscle, nose, eyes (for example ophthalmic solution) or local (for example topical ointment). The preferred oral approach.
Solid orally ingestible includes but not limited to tablet, capsule (soft or hard gelatin capsule), sugar-coat agent (active component that contains powder or piller form), lozenge and dragee. The tablet, sugar-coat agent or the capsule that contain talcum powder and/or carbohydrate carrier or adhesive etc. are specially adapted to oral application. The preferred carrier of tablet, sugar-coat agent or capsule comprises lactose, cornstarch and/or farina. If when adopting syrup or elixir, can use sweetened vehicle.
Typical tablet by conventional tabletting technology preparation can comprise: (1) label: reactive compound (free cpds or its salt), 250mg cataloid (Aerosil ), 1.5mg microcrystalline cellulose (Avicel ), 70mg modified cellulose gum (Ac-Di-Sol ) and 7.5mg dolomol; (2) coatings: HPMC, the monoglyceride of about 9mg Mywacett 9-40T and about 0.9mg acidylate.
Liquid preparation includes but not limited to syrup, emulsion, Perle and aseptic injection liquid, for example moisture or anhydrous liquid suspension or solution.
For parenteral applications, particularly suitable preparation is injection solution or suspension, preferably is dissolved in the aqueous solution of the reactive compound in the poly-hydroxylating castor oil.
Methods for the treatment of
The invention provides the disease that is used for the treatment of, improves and/or prevent to be regulated by cannboid (CB) acceptor, state and/or unusually, compound and the pharmaceutical preparation thereof of those (comprise discussed below those) of particularly being regulated by CB1 or CB2 acceptor.
The present invention further provides a kind for the treatment of is regulated by Cannabined receptor (CB) and particularly CB1 or CB2 acceptor in the individuality that needs is arranged disease, state and/or unusual method, it comprises compound of the present invention or pharmaceutical composition to described individual administering therapeutic effective dose.
Disease, the state of being regulated by the CB acceptor and/or include but not limited to unusually that abnormal food appetite, metabolic disorder, catabolism are unusual, diabetes, obesity, the obstacle relevant with social activity, mood disorder, epileptic attack, substance abuse, learning disorder, cognitive disorder, memory disorders, organ contraction, muscle cramp, respiratory disorder, locomotor activity obstacle, moving obstacle, dysimmunity (such as, autoimmunity barrier), inflammation, Growth of Cells, pain (such as, neuropathic pain), reach the syndrome relevant with nerve degeneration, unusual and disease.
Appetite correlation syndrome, unusual or disease include but not limited to obesity, overweight state, apositia, disease of eating too much at one meal, evil physique, misadjustment appetite etc. Obesity correlation syndrome, unusual or disease include but not limited to the obesity that unusually (comprised the desire to the composition of consumption sugar, carbohydrate, alcohol or medicine or any tool enjoyment value) etc. and caused by heredity, diet, food intake dose, metabolic syndrome, unusual or disease, hypothalamic unusual or disease, age, unusual cellulite distributions, unusual fatty lattice chamber distributions, mandatory eating disorder, motivation. Include but not limited to that with obesity correlation syndrome, the unusual symptom relevant with disease activity reduces.
Metabolism correlation syndrome, unusual or disease include but not limited to metabolic syndrome, dyslipidemia, hypertension, insulin sensitivity or resistance, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, arteriosclerosis, Hypertriglyceridemia, artery sclerosis, other angiocardiopathy, osteoarthritis, cutaneous diseases, sleep-disorder (sleep rhythm disorder, sleep-disorder, insomnia, sleep apnea and hypnolepsy), gall stone, hepatomegaly, steatosis, abnormal ALT level, PCO disease, inflammation etc.
Diabetes correlation syndrome, unusual or disease include but not limited to accommodation abnormality of glucose, insulin resistance, GI, hyperinsulinemia, dyslipidemia, hypertension, obesity, hyperglycaemia etc.
Catabolism correlation syndrome, unusual or disease include but not limited to rely on relevant catabolism with lung merit attitude obstacle and respirator; Cardiac function is unusual, and for example, the cardiac function relevant with valvulopathy, miocardial infarction, cardiomegaly or congestive heart failure is unusual.
Eye disease includes but not limited to glaucoma, the glaucoma correlation intraocular pressure retinitis, retinal disease, uveitis, part tissue of eye acute impaired (for example, conjunctivitis).
Social activity or mood correlation syndrome, unusual or disease include but not limited to that depression (includes but not limited to the bipolarity depression; have or do not have single or the recurrent Serious depression onset of vain hope feature, nervous feature, melancholy feature, atypical characteristics or generation onset; SAD has early onset or Delayed onset and has or do not have light strongly fragrant disease, nervous depression and the social phobia of atypical characteristics, the depression of following dementia, anxiety disorder, mental disease, the social disturbance of emotion, cognitive disorder etc.).
Substance abuse correlation syndrome, unusual or disease include but not limited to drug abuse and drug withdrawal. The material of abuse includes but not limited to alcohol, amphetamine (or amphetamine sample material), caffeine, hemp, ***e, psychedelia, inhalant, opiate, nicotine (and/or tobacco product), heroin abuse, barbiturates, Hog (or Hog sample compound), hypnotic sedative agent, benzodiazepine derivatives, or the combination of aforementioned any material. Compound and pharmaceutical composition also can be used for treating anxiety disorder or the mood disorder that withrawal symptom and material bring out.
The present invention further provides a kind of method for the treatment of nicotine dependence, habituation, give up or help to give up or reduce Tobacco using in the individuality that needs is arranged, the method comprises to the compounds of this invention of described individual administering therapeutic effective dose or pharmaceutical composition.
The study of available compounds for treating of the present invention, cognition or memory correlation syndrome, unusual or disease include but not limited to the loss of memory that causes because of age, disease, drug side-effect (adverse events) etc. or impaired. Remembering impaired is the cardinal symptom of dementia, and also can be and such as the relevant symptom of Alzheimer's disease, schizophrenia, Parkinson's disease, Hang Ting Dun Shi chorea, Pi Keshi disease, storehouse Jia Shi disease, HIV, angiocardiopathy, head trauma and the diseases such as cognitive impairment relevant with the age. Usually, dementia is the disease that comprises the loss of memory and the extra intellectual impairment except memory. Compound of the present invention and pharmaceutical composition also can be used for cognitive impaired relevant with attention deficit (such as, attention deficit disorder) for the treatment of.
Muscle cramp syndrome, unusual or disease include but not limited to multiple sclerosis, cerebral paralysis etc.
Locomotor activity and activity syndrome, unusual or disease include but not limited to apoplexy, Parkinson's disease, multiple sclerosis, epilepsy etc.
Breathe correlation syndrome, unusual or disease includes but not limited to breathing problem, COPD, pulmonary emphysema, asthma, bronchitis etc.
Can include but not limited to the kidney dysfunction nephritis of modulators for treatment of the present invention mesangium Accretive Type ephritis, kidney syndrome, hepatic insufficiency (hepatitis, cirrhosis).
Self exempt from disease or inflammation correlation syndrome, unusual or disease includes but not limited to psoriasis, lupus erythematosus, connective tissue disease, siogren's syndrome, stiff property arthritis vertebralis, rheumatoid arthritis, adjuvant arthritis, minute voltinism arthritis vertebralis, behcet disease, self exempts from disease hemolytic anemia, multiple sclerosis, ALS, albuminoid degeneration, graft rejection or affect the disease that plasma cell is; Anaphylactia: delayed or type Ⅰ hypersensitivity reaction, allergic rhinitis, contact dermatitis or allergic conjunctivitis, infectiousness parasitic disease, viral or bacteriosis (such as, AIDS and meningitis), inflammatory disease (such as, joint disease, include but not limited to arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, regional ileitis, inflammatory bowel disease (IBD) and IBS (IBS)), and osteoporosis.
Be correlated with property syndrome, unusual or disease of Growth of Cells includes but not limited to mammalian cell proliferation out of control, breast cancer cell propagation, prostate gland cancer cell propagation etc.
Pain correlation syndrome, unusual or disease include but not limited to the chronic ache, allergy, rheumatoid arthritis, dermatitis, immune deficiency, chronic inflammatory pain of pain, bone and arthralgia, antimigraine, cancer pain, toothache, the dysmenorrhoea of maincenter and the mediation of peripheral approach, antenatal throe, inflammation form, pain, chronic neuropathic pain (for example, with diabetic neuropathy, sciatica, nonspecific property back pain, fibromyalgia and the HIV correlation DPN relevant pain relevant with allergy, rheumatoid arthritis, dermatitis or immune deficiency; Postherpetic neuralgia, trigeminal neuralgia, the pain that is caused by wound, amputation, cancer, toxin or chronic inflammatory state), He Jiejinshi disease, myasthenia gravis, nephrotic syndrome, chorionitis, thyroiditis etc.
The syndrome relevant with nerve degeneration, unusual or disease includes but not limited to Parkinson's disease, multiple sclerosis, epilepsy, traumatic head or brain is impaired, encephalitis, eyes are impaired or apoplexy etc. is followed ischemic or the damage of Secondary cases biochemical.
Compound of the present invention also can be used for the treatment of disease as herein described, state with other and/or unusual forms of pharmacologically active agents is combined with. Therefore, also provide the methods for the treatment of that comprises compound of the present invention and other forms of pharmacologically active agents administering drug combinations. Can include but not limited to the suitable forms of pharmacologically active agents that the compounds of this invention is united use the medicine of anti-obesity, such as, apo-B secretion/microsomal triglyceride transfer protein (apo-B/MTP) inhibitor, 11beta-Hydroxysteroid dehydrogenase-1 (11 β-HSD1 type) inhibitor, PYY3-36Or its analog, MCR-4 activator, CCK-A (CCK-A) activator, MARI (such as, sibutramine), sympathetic transmitter releasers, β3Adrenoceptor agonists, dopamine-receptor stimulant (such as, bromine is hidden graceful), melanocyte-stimulating hormone receptor analogs, 5HT2cReceptor stimulating agent, melanin concentrating hormone antagonists, leptin (OB albumen), leptin analog, leptin receptor activator, galanin antagonist, lipase inhibitor (such as, Orlistat, namely, orlistat), anoretic (such as, the Magainin activator), neuropeptide-Y receptor antagonist, Protirelin agent, dehydrobenzene or its analog, glucocorticoid receptor agonist or antagonist, Orexins receptor antagonist, glucagon-like-peptide-1 (GLP-1) receptor stimulating agent, Protein-tyrosine-phosphatase (PTP-1B) inhibitor, DPP IV (DPP-IV) inhibitor, ciliary nerves nourish the factor (such as, AxokineTMCan derive from Regeneron Pharmaceuticals, Inc., Tarrytown, N.Y and Procter﹠Gamble Company, Cincinnati, Ohio), human agouti-related protein (AGRP) inhibitor, motilin (ghrelin) receptor antagonist, histamine 3 receptor antagonists or inverse agonist, and neuromedin U receptor stimulating agent. Other anti-obesity medicament (comprising following listed preferred agents) is known, is apparent for those of ordinary skills based on content disclosed in this invention perhaps.
Particularly preferably hidden graceful, the ephedrine of orlistat, sibutramine, bromine, leptin, PYY3-36Or the anti-obesity medicament of its analog (comprising complete PYY) and Pseudoephedrine and so on. Preferably compound of the present invention and mixed treatment are carried out administration in conjunction with motion and reasonable diet.
The anti-obesity medicament that uses in combination of the present invention, pharmaceutical composition and method can prepare with method known to persons of ordinary skill in the art, and for example, sibutramine can be according to United States Patent (USP) 4,929, and 629 description is prepared; Bromine hidden graceful can be according to United States Patent (USP) 3,752,814 and 3,752,888 description is prepared; Orlistat can be according to United States Patent (USP) 5,274, and 143,5,420,305,5,540,917 and 5,643,874 description is prepared; PYY3-36(comprising analog) can be prepared according to the description of U.S. Patent Publication No. 2002/0141985 and international publication number WO 03/027637. The list of references of all above-mentioned citations all is incorporated herein by reference.
Can comprise that with other suitable forms of pharmacologically active agents of the compounds of this invention administering drug combinations design is in order to the medicine for the treatment of tobacco abuse (for example, non-its ketone hypochlorite (the trade (brand) name Zyban of nicotine receptor partial agonist, peaceTM) and Nicotine replacement therapy), the medicine (for example, Dopaminergic Drugs is such as, apomorphine) for the treatment of erectile dysfunction, ADD/ADHD agent (for example, RitalinTM(methylphenidylacetate hydrochloride), StratteraTM(STRATTERA), ConcertaTM(methylphenidylacetate hydrochloride), and AdderallTM(aspartic acid amphetamine; Amphetamine sulfate; Sucrose acid dexamphetamine; And sulfuric acid dexamphetamine)), and the crapulent medicine for the treatment of, such as, opiate antagonist (for example, Nagqu ketone (trade name ReViaTMBe referred to as) and nalmefene), disulfiram (trade name AntabuseTM), and Acamprosate salt (trade name CampralTM)). In addition, also can be by co-administered in order to the medicine that alleviates alcohol withdrawal symptom, such as, benzodiazepine derivatives, beta blocker, clonidine, flat, the lyrica of carbodiazide, and Gabapentin (NeurontinTM). Crapulent treatment is preferably combined with behaviour therapy, comprise and for example improve motivation treatment, cognitive behavioral therapy and be routed to self-help group, comprise temperance society (AA).
Spendable other forms of pharmacologically active agents comprises antihypertensive, antidepressants (for example, fluoxetine hydrochloride (ProzacTM)); Cognitive improvement medicine (for example, donepezil hydrochloride (AirceptTM), and other acetylcholinesteraseinhibitors inhibitors); Neuroprotective agent (for example, Memantine hydrochloride); Antipsychotics (for example, Ziprasidone (GeodonTM), sharp times ketone (RisperdalTM) and Olanzapine (ZyprexaTM)); Insulin and insulin analog (for example, LysPro insulin); GLP-1 (7-37) (the short peptide of giving birth to of insulin) and GLP-1 (7-36)-NH2 Sulfonylurea and analog thereof; Chlorpropamide, glibenclamide, orinase, tolazamide, acetohexamide, Glypizide, Glimepiride, Repaglinide, meglitinide; Biguanides: melbine, Fen Famin, buformin; α 2-antagonist and imidazolines: midaglizole, Yi Gelie diindyl, Deriglidole, idazoxan, Efaroxan, Fluparoxan; Other insulin secretion stimulators: Linogliride, A-4166; Glitazone: ciglitazone, Actos(Pioglitazone), Englitazone, troglitazone, Darglitazone, Avandia(BRL49653); Fatty acid oxidation inhibitors: Clomoxir, Etomoxir; Phlorose enzyme inhibitor: acarbose, Miglitol, emiglitate, voglibose, MDL-25,637, Camiglibose, MDL-73,945; Beta-2-agonists: BRL 35135, BRL 37344, RO 16-8714, ICI D7114, CL 316,243; CD-840: L-386,398; Lipid lowering agent: benzene chlorine thunder department; Fenfluramine; Vanadate and vanadium complex (for example, Naglivan) and the peroxide vanadium complex; The amylin antagonist; Glucagon antagonists; The newborn function inhibitor of sugar; The Somat analog; Lipotropism fat distintegrant: nicotinic acid, acipimox, WAG 994, pramlintide (SymlinTM), AC 2993, Nateglinide, aldose reductase inhibitor (for example, Zopolrestat), glycogen phosphorylase inhibitors, SODH inhibitor, sodium-hydrogen exchanger 1 type (NHE-1) inhibitor and/or cholesteral biosynthesis inhibitor or cholesterol absorption inhibitor, HMG-CoA reductase inhibitor particularly, or HMG-CoA synthetase inhibitors, or HMG-COA reductase or the agent of synthase gene expression inhibiting, CETP inhibitor, cholic acid bond, the special class of shellfish, ACAT inhibitor, inhibitor for squalene synthetic enzyme, antioxidant or nicotinic acid. Compound of the present invention also can with the native compound administering drug combinations for reducing blood plasma cholesterol level. Described native compound is commonly referred to as nutritional medicine and comprises, for example, and garlic P.E, cactus plant extracts, and nicotinic acid.
Compound of the present invention (comprising pharmaceutical composition and used method) can make up the medicine of using for the preparation of being used for treatment as herein described individually or with other forms of pharmacologically active agents.
General preparation method
The compound of general formula (1) can be synthetic by flow process as follows.
Wherein W and Y are N; U, V and X are C; B is O; P is 0 or 1; And R, R1And R2The compound of defined formula (1) can synthesize shown in flow process 1 in generality is described.
In above-mentioned flow process, the compound of general formula K can oxidizedly (for example, be used SeO2(selenium dioxide) oxidation) generate the compound of Formula B, its can carry out subsequently reductive amination process (for example, under standard conditions (for example, in NH4There are the lower hydrogenation of carrying out in OAc, Pd/C)) obtain the ortho position diamines of general formula C. But Compound C coverlet acidylate (for example, is used formula pgOCH2The acyl chlorides of COCl or formula (pgOCH2) acid anhydrides (wherein, pg is pure protecting group, for example, benzyl or methoxy (MOM)) of CO) obtain single N-acyl group diamines of general formula D. The compound of general formula D can carry out intramolecular cyclization reaction and produce compd E. Compd E can by dehydrogenation (for example, use oxidant (such as, high cerium ammonium nitrate or 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ))) produce the compound of general formula F. Compound F 17-hydroxy-corticosterone is converted to compound G1 and/or G2. For example, make the compound F 17-hydroxy-corticosterone derivation that the compound of general formula G1 and/or G2 can be provided by acylation reaction, alkylated reaction or arylation reaction, it can be separated. The compound of thus obtained general formula G1 and/or G2 can be hydrolyzed and form compound H 1 and/or H2. Compound H 1 and/or H2 can with amine (for example, HNR1R
2) coupling forms the compound of formula (1). The amine that is fit to includes but not limited to N, N '-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC) and BTA-1-base oxygen base three (dimethylamino)- hexafluorophosphate (BOP) reagent.
In another embodiment, wherein X and Y are N; U, V and W are C; B is O; P is 0 or 1; R, R1And R2The compound of the formula (1) described in the generality description can synthesize shown in flow process 2.
Flow process 2
In above-mentioned flow process, the compound of general formula K can, for example, use alkali (such as, LiHMDS or LDA) go materialization, thereafter, use diethy-aceto oxalate acidylate for example to obtain the compound of general formula L. Then, the compound of general formula L can be with the hydrazine that replaces (such as, RNHNH2) process to obtain the compound of formula M and/or N. The compound of thus obtained formula M and/or N can be hydrolyzed and with amine (for example, HNR1R
2) coupling forms the compound of formula (1). The amine that is fit to includes but not limited to N, N '-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC) and BTA-1-base oxygen base three (dimethylamino)- hexafluorophosphate (BOP) reagent.
In another embodiment, wherein V and Y are nitrogen; U, W and X are carbon; B is oxygen; P is 0 or 1, and R, R1And R2Can shown in flow process 3, synthesize such as the compound in the formula (1) described in the generality description.
Flow process 3
In above-mentioned flow process, the compound of general formula O is converted to the compound of general formula P. Then, the amine coupling of Compound P and general formula Q, for example, by heating or using such as Hg (OAc)2And so on reagent catalysis carry out coupling, form the compound of general formula R. Compound R is gone to protect and condensation and form the compound of general formula S. The protective reaction of compound R and subsequently intermolecular condensation be preferable over acid (such as, p.TsOH, MsOH, TfOH or CF3COOH) carry out under the existence. The compound of general formula S can be hydrolyzed and with amine (for example, HNR1R
2) coupling forms the compound of formula (1). The amine that is fit to includes but not limited to N, N '-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC) and BTA-1-base oxygen base three (dimethylamino)- hexafluorophosphate (BOP) reagent.
Should be appreciated that all isomers of the formula of the present invention includes (I) compound and pharmacy acceptable derivates thereof, comprise all geometrical isomerisms, tautomerism and optical form, and their mixture (for example, racemic mixture). When having other chiral centre in formula (I) compound, the present invention also comprises all possible diastereoisomer, comprises its mixture. Different isomeric forms can separate or splits by conventional method, or any specific isomers can obtain by conventional synthetic method or by stereospecificity or dissymmetric synthesis. The present invention also comprises isotope-labeled compound, the Compound Phase of itself and formula I and the following stated with, but the atomic mass that has one or more atoms to be had to be different from atomic mass common in the nature or mass number or the atom of mass number substitute. Can mix the isotope that isotopic example in the compounds of this invention comprises hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine and chlorine, such as,3H、
11C、
14C、
18F、
123I, and125I。
Contain the acceptable salt of pharmacy of other isotopic the compounds of this invention of aforementioned isotope and/or other atom and compound also within the scope of the invention. Isotope-labeled the compounds of this invention (for example mixed therein radio isotope, such as,3H、
14The compound of C) can be used for the Tissue distribution analysis of medicine and/or substrate. Tritium (that is,3H) and carbon-14 (that is,14C) isotope because it is easy to preparation and determination methods particularly preferably.11C and8The F isotope is specially adapted to PET (positron emission transaxial tomography),125The I isotope is specially adapted to SPECT (single photon emission computed laminagraphy), and they all can be used for the brain video picture. In addition, with heavier isotope (such as, deuterium, that is,2H) replacement can provide some the treatment advantage that produces owing to higher metabolic stability, and for example, therefore the dosage requirement that Half-life in vivo increases or reduces, is preferred in some cases. The compounds of this invention of isotope-labeled formula I and the following stated can be by carrying out disclosed program in disclosed in the above flow process and/or the following example, by replacing nonisotopically labelled reagent to prepare with the isotope labeling reagent that is easy to get.
The compound of formula (I) can crystallization or the preparation of noncrystalline form, and if crystallization, optionally form hydrate or solvate. The present invention comprises stoichiometric hydrate or solvate in its scope, and contains the water of variable quantity and/or the compound of solvent.
By following examples embodiment of the present invention are illustrated.But, should be appreciated that embodiment of the present invention are not limited in the detail of these embodiment, their other version is known or is conspicuous for those skilled in the art based on content disclosed in this invention.
Experimental section
Abbreviation and notes show: use following abbreviation and notes to show hereinafter.M.P.: fusing point.Bop reagent: (benzotriazole-1-base oxygen base) three (dimethylamino) hexafluorophosphate.FC; Fast silica gel chromatogram.J: with Hz is the coupling constant of unit representation.THF: tetrahydrofuran (THF).Et
3N: triethylamine.BuLi: butyllithium.LiHMDS: hexamethyldisilazane base lithium.
Intermediate 1
5-(2-bromophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid step 1:2-oxo-(5-oxo three ring [4.3.1.1.
3,8] 11 carbon-4-yl) ethyl acetate
(1.27ml in ether 5.4mmol) (10.0ml) solution, and stirred 15 minutes under this temperature under-78 ℃ the hexane solution of the 1.6M of n-BuLi to be added into hexamethyldisilazane.In this mixture, add ether (27.0ml) solution of high Buddha's warrior attendant ketone [900mg, 5.4mmol,, R.M. and Gill, G.B., J.Chem.Soc. (C), 1970,671 preparations] and continue down to stir 45 minutes in-78 ℃ according to Black.(0.98ml 6.5mmol), slowly heats mixture to being up to 25 ℃ to add oxalic acid diethyl ester.After stirring is spent the night, in solution, add entry (25ml) and separate each layer.With ether (20ml) washed twice, with 1N HCl acidifying, (3 * 20ml) extractions are with organic layer Na to use ether then with water layer
2SO
4Drying is filtered and evaporation.Obtain title compound through fast silica gel chromatogram (petrol ether/ethyl acetate 97: 3), be yellow oil (589mg, 36%).
1H-NMR (δ ppm, CDCl
3, 300MHz): 15.75 (s, 1H); 4.33 (q, J=7.2,2H); 2.80 (br. t, J=6,1H); 2.75-2.70 (m, 1H); 2.13-85 (m, 8H); 1.81-1.69 (m, 4H); 1.36 (m, t, J=7.2,3H) .IR (cm
-1, pure): 3423 (br), 2982 (w), 2919 (s), 2851 (m), 1741 (s), 1599 (s, br).Step 2:5-(2-bromophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate
With intermediate 1 (2.0g, 7.56mmol), 2-bromophenyl hydrazine hydrogenchloride (1.86g, 8.32mmol) and the solution of ethanol (30ml) refluxed 1 hour.After the cooling, precipitated solid is collected and drying by filtering, obtain pure title product (2.04g, 65%).
1H-NMR(δppm，CDCl
3，300MHz)：7.67(dd，J＝7.8，1.2，1H)；7.42-7.26(m，3H)；4.40(q，J＝7.2，2H)；3.79(br?t，J＝5.4，1H)；2.54(br?t，J＝7.2，1H)；2.18(br?s，2H)；2.14-1.92(m，4H)；1.92-1.60(m，6H)；1.39(t，J＝7.2，3H)。
Step 3:5-(2-bromophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid
With 5-(2-bromophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), the ethanol of 6-diene-7-ethyl formate: (270mg 4.82mmol) refluxed 2 hours together for water (20: 1) solution and KOH.After removing ethanol, resistates is soluble in water, use 1N HCl acidified aqueous solution to pH 4.0.Throw out is filtered and drying, obtain pure intermediate 1 (715mg, 77%).
1H-NMR(δppm，CDCl
3，300MHz)：7.71(dd，J＝7.8，1.5，1H)；7.50-7.32(m，3H)；3.79(br?t，J＝5.1，1H)；2.56(br?t，J＝5.0，1H)；2.19(s，2H)；2.12-1.90(m，4H)；1.90-1.66(m，6H)。
Intermediate 2 to 11 uses 2-oxo-(5-oxo three ring [4.3.1.1. according to the step 2 and the 3 described methods of intermediate 1
3,8] 11 carbon-4-yl) phenyl that replaces of ethyl acetate, suitable (not) or pyridyl hydrazine and alkali makes.
Intermediate 2
5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid step 1:5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate
Productive rate: 54%.
1H-NMR(δppm，CDCl
3，300MHz)：7.43，7.30(AB，J＝10，4H)；4.40(q，J＝7.5，2H)；3.79(t，J＝5.1，1H)；3.0(t，J＝5.4，1H)；2.21(br.s，2H)；2.06-1.77(m，10H)；1.40(t，J＝7.5，3H)。
Step 2:5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid
Productive rate: 89%.
1H-NMR(δppm，DMSO-d
6)：7.59(d，J＝8.7，2H)；7.39(d，J＝8.7，2H)；3.76(br?s，1H)；2.97(br?s，1H)；2.14(br?s，2H)；1.67-1.98(m，10H)。
Intermediate 3
5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid step 1:5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate
Productive rate: 96%.
1H-NMR(δppm，CDCl
3，300MHz)：7.50-7.40(m，1H)；7.02-6.90(m，2H)；4.38(q，J＝7.2，2H)；3.76(br?s，1H)；2.66(br?s，1H)；2.17(br?s，2H)；2.05-1.70(m，10H)，1.37(t，J＝7.2，3H)。
Step 2:5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid
Productive rate: 95%.
1H-NMR(δppm，CDCl
3，300MHz)：12.80(br?s，1H)；7.70-7.55(m，2H)；7.30(brt，J＝7.5，1H)；3.66(br.s，1H)；2.63(br?s，1H)；2.13(s，2H)；2.00-1.71(m，10H)。
Intermediate 4
5-(4-fluorophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid step 1:5-(4-fluorophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate
Productive rate: 55%.
1H-NMR(δppm，CDCl
3，300MHz)：7.38-7.31(m，2H)；7.18-7.11(m，2H)；4.39(q，J＝7.5，2H)；3.78(br.s，1H)；2.95(br.s，1H)；2.20(br.s，2H)；2.06-1.76(m，10H)；1.39(t，J＝7.2，3H)。
Step 2:5-(4-fluorophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid
Productive rate: 81%.
1H-NMR(δppm，DMSO-d
6，300MHz)：12.60(br.s，1H)；7.47-7.35(m，4H)；3.67(br.s，1H)；2.91(br.s，1H)；2.14(br.s，2H)；1.98-1.71(m，10H)。
Intermediate 5
5-(4-aminomethyl phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid step 1:5-(4-aminomethyl phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate
Productive rate: 91%.
1H-NMR(δppm，CDCl
3，300MHz)：7.23(s，4H)；4.39(q，J＝7.2，2H)；3.79(br.t，J＝5.7，1H)；3.00(br.s，1H)；2.41(s，3H)；2.19(br.s，2H)；2.07-1.95(m，2H)；1.95-1.73(m，8H)；1.40(t，J＝7.2，3H)。
Step 2:5-(4-aminomethyl phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid
Productive rate: 99%.
1H-NMR(δppm，DMSO-d
6，300MHz)：12.60(br.s，1H)；7.34(d，J＝8.1，2H)；7.26(d，J＝8.1，2H)；3.68(br.s，1H)；2.94(br.s，1H)；2.37(s，3H)；2.12(br.s，2H)；2.05-1.62(m，10H)。
Intermediate 6
5-(4-p-methoxy-phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid step 1:5-(4-p-methoxy-phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate
Productive rate: 78%.
1H-NMR(δppm，CDCl
3，300MHz)：7.29(d，J＝9.0)；6.96(d，J＝9.0，2H)；4.39(q，J＝7.2，2H)；3.79(br.t，J＝5.0，1H)；2.96(br.s，1H)；2.19(br.s，1H)；2.08-1.96(m，2H)；1.96-1.74(m，8H)；1.39(t，J＝7.2，3H)。
Step 2:5-(4-p-methoxy-phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid
Productive rate: 95%.
1H-NMR(δppm，CDCl
3，300MHz)：7.28(d，J＝9.0，2H)；6.98(d，J＝9.0，2H)；3.86(s，3H)；3.78(t，J＝5.4，1H)；2.99(br.s，1H)；2.21(br.s，2H)；2.10-1.70(m，10H)。
Intermediate 7
5-phenyl-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid step 1:5-phenyl-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate
Productive rate: 63%.
1H-NMR(δppm，CDCl
3，300MHz)：7.50-7.32(m，5H)；4.40(q，J＝7.5，2H)；3.80(t，J＝5.4，1H)；3.02(br.t，J＝4.8，1H)；2.22(br.s，2H)；2.07-1.95(m，2H)；1.95-1.76(m，8H)；1.40(t，J＝7.5，3H)。Step 2:5-phenyl-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid
Productive rate: 91%.
1H-NMR.(δppm，CDCl
3，300MHz)：7.58-7.42(m，3H)；7.37(dd，J＝7.8，1.2，2H)；3.80(t，J＝5.4，1H)；3.06(br.s，1H)；2.22(br.s，2H)；2.10-1.75(m，10H)。
Intermediate 8
5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid step 1:5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate
Productive rate: 71%.
1H-NMR(δppm，CDCl
3，300MHz)：7.52(s，1H)；7.34(s，2H)；4.39(q，J＝6.9，2H)；3.79(br.t，J＝5.4，1H)；2.55(br.t，J＝4.6，1H)；2.19(br.s，2H)；2.10-1.60(m，10H)；1.39(t，J＝6.9，3H)。
Step 2:5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid
Productive rate: 95%.
1H-NMR(δppm，CDCl
3，300MHz)：7.57(d，J＝1.8，1H)；7.38(dd，J＝8.4，1.8，1H)；7.32(d，J＝8.4，1H)；3.78(br.t，J＝5.4，1H)；2.57(br.t，J＝4.6，1H)；2.20(br.s，2H)；2.10-2.65(m，10H)。
Intermediate 9
5-(2-chloro-phenyl-)-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid step 1:5-(2-chloro-phenyl-)-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate
Productive rate: 56%.
1H-NMR(δppm，CDCl
3，300MHz)：7.53-7.48(m，1H)；7.45-7.32(m，3H)；4.40(q，J＝7.5，2H)；3.80(t，J＝5.7，1H)；2.57(br.t，J＝5.4，1H)；2.17(m，2H)；2.08-1.65(m，10H)；1.39(t，J＝7.5，3H)。
Step 2:5-(2-chloro-phenyl-)-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid
Productive rate: 96%.
1H-NMR(δppm，DMSO-d
6，300MHz)：12.66(br.s，1H)；7.72(d，J＝8.1，1H)；7.70-7.51(m，3H)；3.68(t，J＝5.1，1H)；2.46(br.s，1H)；2.13(br.s，2H)；2.03-1.64(m，10H)。
Intermediate 10
5-(5-chloropyridine base)-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid step 1:5-(5-chloropyridine base)-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate
Productive rate: 28%.
1H-NMR(δppm，DMSO-d
6，300MHz)：8.46-8.44(d，J＝2.7，1H)；8.08(dd，J＝8.7，2.7，1H)；7.74(d，J＝8.7，1H)；4.21(q，J＝6.9，2H)；3.13-3.06(m，2H)；2.12-1.62(m，12H)；1.12(t，J＝7.2，3H)。
Step 2:5-(5-chloropyridine base)-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid
Productive rate: 78%.
1H-NMR(δppm，DMSO-d
6，300MHz)：13.25(br.s，1H)，8.44(d，J＝2.5，1H)；8.06(dd，J＝8.0，2.5，1H)；7.70(d，J＝8.1，1H)；3.22(br.s，1H)；3.05(br.s，1H)；2.12-1.64(m，12H)。
Intermediate 11
5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid step 1:5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate
Productive rate: 97%.
1H-NMR(δppm，CDCl
3)：4.36(q，J＝7.2，2H)；3.61(br.t，J＝5.4，1H)；3.10(br.s，1H)，2.16(br.s，2H)；2.08-1.95(m，4H)；1.85-1.70(m，6H)；1.38(t，J＝7.2，2H)。
Step 2:5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid
Productive rate: 79%.
1H-NMR(δppm，DMSO-d
6)：12.78(br.s，1H)；3.54(br.s，1H)；2.97(br.s，1H)；2.09(br.s，2H)；1.97-1.85(m，4H)；1.77(br.s，2H)；1.68(t，J＝12.0，4H)。
Intermediate 12a and intermediate 12b
6-methyl-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate (intermediate 12a) and 5-methyl-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate (intermediate 12b):
With 5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid (100mg, DMF 0.38mmol) (2ml) solution NaH (50% mineral oil dispersion liquid, 20mg, 0.4mmol) handle and under room temperature, stirred 45 minutes, in this mixture, add then methyl iodide (60mg, 0.026mmol).Continue to stir 1.5 hours.Mixture is poured in the water, with ethyl acetate extraction and use anhydrous sodium sulfate drying.Evaporation also separates by fast silica gel chromatogram and to obtain intermediate 12a and intermediate 12b.
Intermediate 12a:Productive rate: 36%.
1H-NMR(δppm，CDCl
3)：4.37(q，J＝7.2，2H)；3.82(s，3H)；3.71(t，J＝5.4，1H)；3.00(br.t，J＝4.8，1H)；2.18(br.s，2H)；2.10-1.80(m，4H)；1.80(br.t，J＝12.3，6H)；1.39(t，J＝7.2，3H)。
13C-NMR(δppm，CDCl
3)：161.02，158.50，132.17，127.49，60.58，39.36，36.29，35.35，34.69，32.41，28.63，27.15，14.21。
Intermediate 12b: productive rate: 36%.
1H-NMR(δppm，CDCl
3)：4.34(q，J＝7.2，2H)；4.02(s，3H)；3.54(t，J＝5.7，1H)；3.03(t，J＝5.1，1H)；2.14(br.s，2H)；2.07-1.93(m，4H)；1.84-1.67(m，6H)；1.37(t，J＝7.2，3H)。
13C-NMR(δppm，CDCl
3)：163.32，150.32，136.54，130.80，60.32，36.78，36.14，34.65，33.65，29.57，28.68，26.46，14.40。
Intermediate 13a and intermediate 13b
6-amyl group-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4,7-diene-7-formic acid (intermediate 13a) and 5-amyl group-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-formic acid (intermediate 13b)
Step 1:6-amyl group-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4,7-diene-7-ethyl formate (intermediate 13aa) and 5-amyl group-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-ethyl formate (intermediate 13bb):
Intermediate 13aa and 13bb by be similar to the described method of intermediate 12a and 12b by intermediate 11 (1.00g, 3.84mmol), (53 μ l 4.20mmol) make for DMF (3ml) and 1-bromo-Skellysolve A.
Intermediate 13aa:
1H-NMR (δ ppm, CDCl
3, 300MHz): 4.39-4.28 (m, 4H); 3.53 (t, J=5.4,1H); 3.04 (t, J=5.4,1H); 2.13 (br.s, 2H); 2.04-1.94 (m, 4H); 1.84-1.66 (m, 8H); 1.37 (t, J=6.9,3H); 1.30-1.24 (m, 4H); 0.88 (t, J=6.9,3H).
Intermediate 13bb:
1H-NMR (δ ppm, CDCl
3, 300MHz): 4.37 (q, J=6.9,2H); 4.07 (t, J=7.5,2H); 3.71 (br.s, 1H); 2.98 (br.s, 1H); 2.18 (br.s, 2H); 2.02-1.92 (m, 4H); 1.85-1.71 (m, 8H); 1.38 (t, J=6.9,3H); 1.40-1.24 (m, 4H); 0.89 (t, J=7.2,3H).
Step 2:6-amyl group-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4,7-diene-7-formic acid (intermediate 13a) and 5-amyl group-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-formic acid (intermediate 13b)
By intermediate 13aa (400mg, 1.21mmol) and intermediate 13bb (400mg, 1.21mmol), KOH (136mg, 2.42mmol), ethanol (10mmol) and H
2O (0.5ml) makes intermediate 13a (270mg, 73%) respectively,
1H-NMR (δ ppm, CDCl
3, 300MHz): 4.39 (t, J=7.8,2H); 3.64 (br.s, 1H); 3.07 (br.s, 1H); 2.14 (br.s, 2H); 2.04-1.94 (m, 4H); 1.79-1.72 (m, 8H); 1.35-1.28 (m, 4H); 0.89 (t, J=7.5,3H) and intermediate 13b (290mg, 79%).
1H-NMR(δppm，CDCl
3，300MHz)：4.06(t，J＝7.2，2H)；3.70(br.s，1H)；2.98(br.s，1H)；2.18(br.s，2H)；2.02-1.93(m，4H)；1.84-1.68(m，8H)；1.40-1.24(m，4H)；0.89(t，J＝7.2，3H)。
Phenyl hydrazine and alkali preparation that intermediate 14 to 21 uses 2-oxo-2-(3-oxo two rings [2.2.1] heptan-2-yl) ethyl acetate, suitable (not) to replace according to the step 2 of intermediate 1 and the described method of step 3.
Intermediate 14
1-phenyl-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid
Step 1:2-oxo-2-(3-oxo two ring [2.2.1] heptan-2-yl) ethyl acetate
Title product by the described method of the step 1 that is similar to intermediate 1 by hexamethyldisilazane (4.2ml, 20.0mmol), ether (91ml), the nBuLi (hexane solution of 2.3M, 11.63ml, 27.3mmol), Norcamphor (2.0g, 18.2mmol) and oxalic acid diethyl ester (2.96ml, 21.82mmol) preparation.
Productive rate: 56%.
1H-NMR(δppm，CDCl
3，300MHz)：11.41(br.s，1H)；4.35(q，J＝7.2，2H)；3.81(br.s，1H)；2.81(br.s，1H)；2.05-1.85(m，3H)；1.80(br.d，J＝10.5，1H)；1.59(br.t，J＝7.2，2H)；1.41(t，J＝7.2，3H)。
Step 2:1-phenyl-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-ethyl formate
Productive rate: 52%.
1H-NMR(δppm，CDCl
3，300MHz)：7.73(d，J＝8.7，2H)；7.47(t，J＝7.2，2H)；7.33(t，J＝7.2，1H)；4.42(q，J＝7.2，2H)；3.72(br.s，1H)；3.68(br.s，1H)；2.13(br.d，J＝8.7，1H)；2.05-1.95(m，2H)；1.72(d，J＝8.7，1H)；1.42(t，J＝7.2，3H)；1.30-1.18(m，2H)。
Step 3:1-phenyl-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid
Productive rate: 79%.
1H-NMR(δppm，CDCl
3，300MHz)：7.73(d，J＝7.8，2H)；7.50(t，J＝7.8，2H)；7.36(t，J＝7.5，1H)；3.75(s，1H)；3.72(s，1H)；2.17(br.d，J＝9.0，1H)；2.10-1.93(m，2H)；1.74(d，J＝8.7，1H)；1.38-1.08(m，2H)。
Intermediate 15
1-(2-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid
Step 1:1-(2-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-ethyl formate
Productive rate: 87%.
1H-NMR(δppm，CDCl
3，300MHz)：7.72-7.60(m，2H)；7.41-7.33(m，2H)；4.42(q，J＝7.2，2H)；3.69(s，1H)；3.40(s，1H)；2.14(br.d，J＝9.0，1H)；2.05-1.82(m，2H)；1.72(d，J＝9.3，1H)；1.30(t，J＝7.2，3H)；1.35-1.12(m，2H)。
Step 2:1-(2-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid
Productive rate: 93%.
1H-NMR(δppm，CDCl
3，300MHz)：7.59-7.50(m，2H)；7.45-7.33(m，2H)；(dt，J＝8.7，1.8，2H)；3.72(s，1H)；3.42(s，1H)；2.17(br.d，J＝8.7，1H)；2.10-1.85(m，2H)；1.74(d，J＝8.7，1H)；1.38-1.18(m，2H)。
Intermediate 16
1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid
Step 1:1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-ethyl formate
Productive rate: 72%.
1H-NMR(δppm，CDCl
3，300MHz)：7.60(d，J＝8.7，2H)；7.43(d，J＝8.7，2H)；4.42(q，J＝7.2，2H)；3.69(br.s，1H)；3.66(br.s，1H)；2.14(br.d，J＝8.7，1H)；2.10-1.95(m，2H)；1.72(br.d，J＝8.7，1H)；1.42(t，J＝7.2，3H)，1.30-1.15(m，2H)。
IR(KBr，cm
-1)：2977(m)，2871(m)，1716(s)，1502(s)，1373(s)，1230(s)，1092(s)，831(m)。
Step 2:1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid
Productive rate: 74.5%.
1H-NMR(δppm，CDCl
3，300MHz)：7.70(d，J＝6.7，2H)；7.50(d，J＝6.7，2H)；3.70(s，2H)；2.16(br.d，J＝8.7，1H)；2.10-1.94(m，2H)；1.74(br.d，J＝8.7，1H)；1.2(m，2H)。IR(KBr，cm
-1)：3460(vs)；2943(m)，2873(m)，1705(vs)，1684(vs)，1500(vs)，1357(s？)，1252(vs)，1093(vs)，835(s)。
Intermediate 17
1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid
Step 1:1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-ethyl formate
Productive rate: 51%.
1H-NMR(δppm，CDCl
3，300MHz)：7.53(d，J＝2.4，1H)；7.49(d，J＝8.4，1H)；7.36(dd，J＝8.4，2.4，1H)；4.41(q，J＝7.2，2H)；3.69(br.s，1H)；3.38(br.s，1H)；2.14(br.d，J＝9.0，1H)；2.07-1.82(m，2H)；1.70(br.d，J＝9.0，1H)；1.41(t，J＝7.2，3H)；1.29-1.13(m，2H)。
Step 2:1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid
Productive rate: 87%.
1H-NMR(δppm，CDCl
3，300MHz)：7.56(d，J＝2.1，1H)；7.48(d，J＝8.4，1H)；7.38(dd，J＝8.4，2.1，1H)；3.71(br.s，1H)；3.41(br.s，1H)；2.16(br.d，J＝8.7，1H)；2.07-1.82(m，2H)；1.72(br.d，J＝8.7，1H)；1.31-1.14(m，2H)。
Intermediate 18
1-(2-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid
Step 1:1-(2-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-ethyl formate
Productive rate: 79%.
1H-NMR(δppm，CDCl
3，300MHz)：7.69(dd，J＝7.8，1.5，1H)；7.50(dd，J＝7.8，2.1，1H)；7.44(td，J＝7.8，1.5，1H)；7.32(td，J＝7.8，2.1，1H)；4.41(q，J＝7.2，2H)；3.69(br.s，1H)；3.39(br.s，1H)；2.18(br.d，J＝9.0，1H)；2.05-1.81(m，2H)；1.70(d，J＝8.7，1H)；1.41(t，J＝7.2，3H)；1.30-1.12(m，2H)。
Step 2:1-(2-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid
Productive rate: 92%.
1H-NMR(δppm，CDCl
3，300MHz)：7.71(dd，J＝8.4，1.5，1H)；7.53-7.40(m，2H)；7.34(td，J＝7.8，2.1，1H)；3.73(br.s，1H)；3.41(br.s，1H)；2.19(br.d，J＝8.7，1H)；2.04-1.82(m，2H)；1.73(d，J＝7.2，1.5，1H)；1.32-1.15(m，2H)。
Intermediate 19
1-(4-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid
Step 1:1-(4-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-ethyl formate
Productive rate: 81%.
1H-NMR(δppm，CDCl
3，300MHz)：7.65-7.50(m，4H)；4.42(q，J＝7.2，2H)；3.69(s，2H)；3.67(s，2H)；2.13(br.d，J＝8.7，1H)；2.06-1.95(m，2H)；1.74(d，J＝8.7，1H)；1.42(t，J＝7.2，3H)；1.28-1.15(m，2H)。
Step 2:1-(4-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid
Productive rate: 83%.
1H-NMR(δppm，CDCl
3，300MHz)：7.62(s，4H)；3.71(s，2H)；2.17(br.d，J＝9.0，1H)；2.06-2.01(m，2H)；1.75(d，J＝9.0，1H)；1.30-1.17(m，2H)。
Intermediate 20
1-(4-fluorophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid
Step 1:1-(4-fluorophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-ethyl formate
Productive rate: 86%.
1H-NMR(δppm，CDCl
3，300MHz)：7.69(dd，J＝9.0，4.8，2H)；7.15(t，J＝9.0，2H)；4.42(q，J＝7.2，2H)；3.67(br.s，2H)；3.40(br.s，1H)；2.16(br.d，J＝8.7，1H)；2.03-1.85(m，2H)；1.72(br.d，J＝9.0，1H)；1.43(t，J＝7.2，3H)；1.32-1.17(m，2H)。
Step 2:1-(4-fluorophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid
Productive rate: 60%.
1H-NMR(δppm，CDCl
3，300MHz)：7.70(dd，J＝8.7，4.8，2H)；7.18(t，J＝8.7，2H)；3.70(s，2H)；2.17(br.d，J＝8.7，1H)；2.10-1.90(m，2H)；1.74(d，J＝8.7，1H)；1.35-1.18(m，2H)。
Intermediate 21
1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid
Step 1:1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-ethyl formate
Productive rate: 81%.
1H-NMR(δppm，CDCl
3，300MHz)：7.80-7.68(m，1H)；7.05-6.95(m，2H)；4.42(q，J＝7.2，2H)；3.67(br.s，1H)；3.47(br.s，1H)；2.12-2.08(br.d，J＝8.7，1H)；2.03-1.90(m，2H)；1.72-1.65(br.d，J＝8.7，1H)；1.41(t，J＝7.2，3H)；1.30-1.17(m，2H)。
Step 2:1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid
Productive rate: 78%.M.P.：153-156℃.
1H-NMR(δppm，CDCl
3，300MHz)：7.80-7.70(m，1H)；7.10-6.97(m，2H)；3.70(br.s，1H)；3.50(br.s，1H)；2.12(d，J＝7.2，1H)；2.08-1.86(m，2H)；1.72(d，J＝8.7，1H)；1.35-1.17(m，2H)。
1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid: the optical resolution of intermediate 21
Intermediate 21a
With intermediate 21 (racemizes, 15.0g 51.72mmol) (3.66ml 28.44mmol) handles with (S)-(-)-α-Jia Jibianji amine at the slurries of acetonitrile (LR grade) in (150ml), under room temperature, stirred 5-10 minute, then with mixture reflux 15 minutes.Slowly add methyl alcohol (24ml) until forming clear soln, continue heating 30 minutes, then mixture is slowly cooled to room temperature.Collect the crystallization that forms and use acetonitrile/MeOH 9: 1 (～15ml) washing by filtering.By being dissolved in CH
2Cl
2And with 1NHCl extraction by the diastereoisomeric salt recovered acid.Identical program is repeated to obtain for several times being rich in afterwards mixture (100mg) [intermediate 21a, the R of the enantiomorph of wash-out
t=38.20 minutes, CHIRALCEL AS-H post (size: 250 * 4.6mm, particle size: 5 μ), use 90: 10: 0.1 normal hexanes: Virahol: 90: 10: 0.1 mixture of trifluoroacetic acid is as elutriant, flow velocity 1ml/ minute].M.P.：114-115℃；e.e＝92％。
Intermediate 21b
With the mother liquid evaporation that the first step obtained of aforesaid method, at CH
2Cl
2And distribute layering then between the 1N HCl aqueous solution.Dry (Na
2SO
4) and evaporate mixture (the 9g) (R of two kinds of enantiomorph acid that organic layer obtains being rich in the enantiomorph of quick wash-out
t=34.65 minutes, under the condition identical with the above; E.e=34%).By replacing (S)-(-)-α-Jia Jibianji amine to make the mixture that is rich in this enantiomorph reach 91%e.e (intermediate 21b, productive rate=72mg) with (R)-(+)-α-Jia Jibianji amine in about the described method of enantiomorph of back wash-out above.M.P.：110-112℃。
Intermediate 22 and 23 uses 2-(3-hydroxyl-4,7, phenyl hydrazine and alkali preparation that 7-trimethylammonium two ring [2.2.1] hept-2-ene"-2-base-2-oxo ethyl acetate, suitable (not) replace according to the step 2 and the described method of step 3 of intermediate 1.
Intermediate 22
1-(2,4 dichloro benzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid step 1:2-(3-hydroxyl-4,7,7-trimethylammonium two ring [2.2.1] hept-2-ene"-2-base-2-oxo ethyl acetate
With DL-camphor (5g, toluene 33mmol) (25ml) solution is added into sodium hydride (60% dispersion liquid under 60 ℃, 1.34g, 56mmol) and oxalic acid diethyl ester (6.69g 49mmol) stirred 1 hour under uniform temp in the slurries in toluene (30ml) and with mixture.With reaction mixture termination reaction in ice, with 1N HCl acidifying, with ethyl acetate extraction and with organic layer Na
2SO
4Drying, vacuum are steamed to desolventize and are obtained title product (7.3g, 88%), and it is directly used in next step without being further purified.
Productive rate: 88%.
1H-NMR(δppm，CDCl
3，300MHz)：11.39(br.s，1H)；4.35(q，J＝7.2，2H)；3.29(d，J＝4.2，1H)；2.30-2.04(m，1H)；1.70-1.40(m，1H)；1.46(br.d，J＝8.7，2H)；1.38(t，J＝7.2，3H)；1.01，0.97，0.83(3s，9H)。
Step 2:1-(2,4 dichloro benzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-ethyl formate
Productive rate: 42%.
1H-NMR(δppm，CDCl
3，300MHz)：7.53(s，1H)；7.36(s，2H)；4.40(q，J＝7.2，2H)；3.16(d，J＝3.6，1H)；2.13(m，1H)；1.40(t，J＝7.2，3H)；1.26(m，2H)；0.88(s，6H)；0.83(s，3H)。
Step 3:1-(2,4 dichloro benzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid
Productive rate: 72%.
1H-NMR(δppm，DMSO-d
6，300MHz)：12.80(bt.s，1H)；7.95(d，J＝2.1，1H)；7.67(d，J＝8.7，1H)；7.63(dd，J＝8.7，2.1，1H)；3.01(d，J＝3.6，1H)；2.13-2.06(m，1H)；1.79(br.t，J＝8.7，1H)；1.32(br.t，J＝9.3，1H)；1.16-1.00(m，1H)；0.88(s，3H)；0.84(s，3H)；0.77(s，3H)。
Intermediate 23
3-(2,4 difluorobenzene base)-1,10,10-trimethylammonium-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-formic acid
Step 1:3-(2,4 difluorobenzene base)-1,10,10-trimethylammonium-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-ethyl formate
Productive rate: 42%.
1H-NMR(δppm，CDCl
3，300MHz)：7.58-7.48(m，1H)；7.03-6.80(m，2H)；4.40(q，J＝7.2，2H)；3.15(d，J＝4.2，1H)；2.20-2.08(m，1H)；1.88-1.76(m，1H)；1.40(t，J＝7.2，3H)；1.40-1.08(m，2H)；0.99，0.92，0.79(3s，9H)。
Step 2:3-(2,4 difluorobenzene base)-1,10,10-trimethylammonium-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-formic acid
Productive rate: 72%.
1H-NMR(δppm，DMSO-d
6，300MHz)：12.80(br.s，1H)；7.80-7.57(m，2H)；7.29(br.t，J＝8.4，1H)；3.01(d，J＝3.6，1H)；2.08-2.02(m，1H)；1.79(br.t，J＝9.6，1H)；1.32(br.t，J＝9.0，1H)；1.06(br.t，J＝9.01H)；0.91，0.88，0.73(3s，9H)。
Intermediate 24
10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-formic acid
Step 1:2-oxo-2-(10-oxo three ring [6.2.2.0
2,7] 12 carbon-2,4,6-triolefin-9-yl) ethyl acetate
Title product is by the described method preparation of the step 1 that is similar to intermediate 1.By three ring [6.2.2.0
2,7] 12 carbon-2,4,6-triolefin-9-ketone [be prepared by one of known method in organic synthesis field, for example, according to people such as Hales, Tetrahedron, 1995,51, the description of 7777-7790 is prepared] (2.5g, 14.53mmol), hexamethyldisilazane (4.9ml, 23.2mmol), 2.34M
N-BuLi (10ml, 23.4mmol) and oxalic acid diethyl ester (3.18ml 21.18mmol) makes required product (2.3g, 63%).
Productive rate: 63%.
1H-NMR(δppm，CDCl
3，400MHz)：12.9(s，1H)；7.20-7.15(m，4H)；4.91(s，1H)；4.31(q，J＝7.2，2H)；3.79(s，1H)；2.00-1.90(m，2H)；1.73-1.60(m，2H)；1.34(t，J＝7.2，3H)。
Step 2:10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-ethyl formate
Productive rate: 91%.
1H-NMR(δppm，CDCl
3，400MHz)：7.58(d，J＝2.2，1H)；7.45(d，J＝8.5，1H)；7.38(dd，J＝8.5，2.0，1H)；7.33(br.d，J＝7.0，1H)；7.16(br.d，J＝7.08，1H)；7.13(td，J＝7.6，1.5，1H)；7.08(td，J＝7.5，1.5，1H)；4.91(s，1H)；4，45(q，J＝7.2，2H)；4.29(s，1H)；1.81-1.72(m，4H)；1.43(t，J＝7.2，3H)。
Step 3:10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-formic acid
1H-NMR(δppm，CDCl
3，400MHz)：7.60(d，J＝2.1，1H)；7.45(d，J＝8.5，1H)；7.41(dd，J＝8.5，2.1，1H)；7.35(br.d，J＝6.8，1H)；7.17(br.d，J＝7.2，1H)；7.14(td，J＝7.5，1.3，1H)；7.09(td，J＝7.5，1.3，1H)；4.94(s，1H)；4.32(s，1H)；1.82-1.73(m，4H)。
10-(2,4 difluorobenzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-formic acid
Step 1:10-(2,4 difluorobenzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-ethyl formate
Productive rate: 71%.
1H-NMR(δppm，CDCl
3，300MHz)：7.67-7.57(m，1H)；7.34(d，J＝6.9，1H)；7.20-7.01(m，5H)；4.90(s，1H)；4.44(q，J＝6.9，2H)；4.39(br.s，1H)；1.79(s，4H)；1.45(t，J＝6.9，3H)。
Step 2:10-(2,4 difluorobenzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-formic acid
Productive rate: 86%.
1H-NMR(δppm，CDCl
3，300MHz)：7.68-7.58(m，1H)；7.35(d，J＝7.2，1H)；7.21-7.04(m，5H)；4.94(s，1H)；4.41(br.s，1H)；1.81(br.s，4H)
Intermediate 26 according to the step 2 of intermediate 1 and the described method of step 3 with in 9, in 13-2-[11-(4-chloro-phenyl-)-10,12,15-three oxygen-11-azepine Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6-triolefin-14-yl]-phenyl hydrazine and alkali preparation that 2-oxo ethyl acetate, suitable (not) replace.
Intermediate 26
In 13,14 interior-16-(4-chloro-phenyl-)-15,17-dioxo-10-(2,4 dichloro benzene base)-10,11,16-three azepine five rings [6.5.5.0
2,7.0
9,13.0
14,18] 18 carbon-2,4,6,9 (13), in 11-pentaene-12-formic acid step 1:9-, in the 13--11-(4-chloro-phenyl-)-11-azepine Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6-triolefin-10,12,14-triketone
With 11-oxa-Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6-triolefin-10,12, the 14-triketone is [according to people such as Takeda in Tetrahedron 1970,26, description among the 1435-1451 is prepared] (1.0g, 4.11mmol), (1.2g, 9.05mmol) xylene solution refluxed 6 hours the 4-chloroaniline.In reaction mixture, add entry and extract with AcOEt.With organic layer Na
2SO
4Dry and steaming desolventizes.Resistates is carried out flash chromatography (AcOEt-sherwood oil 4: 96 → 16: 84) obtain title product (930mg, 65%).
Productive rate: 65%.
1H-NMR(δppm，CDCl
3，300MHz)：7.40-7.222(m，6H)；6.47(d，J＝8.7，2H)；4.18(dd，J＝3.3，1H)；4.07-4.02(m，1H)；3.59(dd，J＝8.7，3.3，1H)；3.49(dd，J＝8.4，3.3，1H)；2.56(dd，J＝20.4，2.1，1H)；2.43(dd，J＝20.4，3.3，1H)。
In the step 2:9,13 interior-2-[11-(4-chloro-phenyl-)-10,12,15-trioxy--11-azepine Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6-triolefin-14-yl]-2-oxo ethyl acetate
Title product is by the described method preparation of the step 1 that is similar to intermediate 1.After purification by flash chromatography, in 9-, in the 13--11-(4-chloro-phenyl-)-11-azepine Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6-triolefin-10,12,14-triketone (800mg, 2.28mmol), hexamethyldisilazane (0.68ml, 3.2mmol), n-BuLi (15% hexane solution, 1.31ml, 3.1mmol) and oxalic acid diethyl ester (0.62ml, 4.6mmol) obtain pure title product (530mg, 52%).
Productive rate: 52%.
1H-NMR(δppm，CDCl
3，300MHz)：13.0(br.s，1H)；7.36-7.20(m，6H)；6.47(d，J＝7.2，2H)；5.54(br.s，1H)；4.49-4.38(m，3H)；3.54(br.s，2H)；1.45(t，J＝7.2，3H)。
In the step 3:13,14 interior-16-(4-chloro-phenyl-)-15,17-dioxo-10-(2,4 dichloro benzene base)-10,11,16-three azepine five rings [6.5.5.0
2,7.0
9,13.0
14,18] 18 carbon-2,4,6,9 (13), 11-pentaene-12-ethyl formate
Productive rate: 66%.
1H-NMR(δppm，CDCl
3，300MHz)：7.63(d，J＝2.4，1H)；7.51(d，J＝8.4，1H)；7.47-7.35(m，3H)；7.30-7.15(m，4H)；6.44(d，J＝9.0，2H)；5.44(d，J＝3.0，1H)；4.83(d，J＝2.7，1H)；4.49(q，J＝7.2，2H)；3.56(dd，J＝8.7，3.3，1H)；3.48(br.d，J＝8.7，1H)；1.46(t，J＝7.2，3H)。
In the step 4:13,14 interior-16-(4-chloro-phenyl-)-15,17-dioxo-10-(2,4 dichloro benzene base)-10,11,16-three azepine five rings [6.5.5.0
2,7.0
9,13.0
14,18] 18 carbon-2,4,6,9 (13), 11-pentaene-12-formic acid
Productive rate: 76%.
1H-NMR(δppm，CDCl
3，300MHz)：7.66(d，J＝2.4，1H)；7.54-7.40(m，3H)；7.28-7.19(m，5H)；6.45(d，J＝8.7，2H)；5.50(d，J＝3.0，1H)；4.87(d，J＝3.0，1H)；3.59(dd，J＝8.7，3.0，1H)；3.50(br.d，J＝8.7，1H)。
Intermediate 27
10-(2,4 difluorobenzene base)-10,11-diaza Fourth Ring [6.5.1.0
2,7.0
9,13] 14 carbon-2,4,6,9 (13), 11-pentaene-12-formic acid
Step 1:2-oxo-2-(10-oxo three ring [6.2.1.0
2,7] 11 carbon-2 (7), 3,5-triolefin-9-yl) ethyl acetate
Title product is by the described method preparation of the step 1 that is similar to intermediate 22.By benzo norborneol ketone (2.4g, 15.18mmol), sodium hydride (60% dispersion liquid, 619mg, 25mmol) and oxalic acid diethyl ester (3.09ml 22.7mmol) makes title product (2.6g, 52%).
1H-NMR(δppm，CDCl
3，300MHz)：10.63(br.s，1H)；7.75-7.20(m，5H)；4.81(d，J＝1.5，1H)；4.35(q，J＝7.2，2H)；3.75(d，J＝1.5，1H)；2.57(dt，J＝9.3，1.8，1H)；2.42(d，J＝8.7，1.5，1H)；1.43(t，J＝7.2，3H)。
Step 2:10-(2,4 difluorobenzene base)-10,11-diaza Fourth Ring [6.5.1.0
2,7.0
9,13] 14 carbon-2,4,6,9 (13), 11-pentaene-12-ethyl formate
Title product is by the described method preparation of the step 3 that is similar to intermediate 20.By (2Z)-hydroxyl (10-oxo three ring [6.2.1.0
2,7] 11 carbon-2,4,6-triolefin-9-pitches base) ethyl acetate (1.0g, 3.87mmol), 2,4 difluorobenzene base hydrazonium salt hydrochlorate (838mg, 4.64mmol), ethanol (13.0ml) and acetate (15.0ml) makes title product (1.21g, 85%).
1H-NMR(δppm，CDCl
3，300MHz)：7.79-7.69(m，1H)；7.35-7.26(m，2H)；7.05-6.94(m，4H)，4.52(br.s，1H)，4.41(q，J＝7.5，2H)；4.32(br.s，1H)；3.00(br.d，J＝8.1，1H)；2.85(dt，J＝8.1，1.5，1H)；1.41(t，J＝7.5，3H)。
Step 3:10-(2,4 difluorobenzene base)-10,11-diaza Fourth Ring [6.5.1.0
2,7.0
9,13] 14 carbon-2,4,6,9 (13), 11-pentaene-12-formic acid
Title product is by being similar to the described method preparation of intermediate.By 10-(2,4 difluorobenzene base)-10,11-diaza Fourth Ring [6.5.1.0
2,7.0
9,13] 14 carbon-2,4,6,9 (13), and 11-pentaene-12-ethyl formate KOH (367mg, 6.5mmol), ethanol (10.4ml) and H
2O (0.5ml) makes title product (810mg, 73%).
1H-NMR(δppm，DMSO-d
6，300MHz)：12.95(m，1H)；7.78-7.57(m，2H)；7.32-7.25(m，3H)；6.98-6.89(m，2H)；4.43(s，2H)；2.89(d，J＝8.1，1H)；2.71(d，J＝8.1，1H)。
Intermediate 28 to 30 prepares with phenyl hydrazine and the alkali that 2-hydroxyl-2-(3-oxo two ring [2.2.2] suffering-2-pitch base) ethyl acetate, suitable (not) replace according to the step 2 and the described method of step 3 of intermediate 1.
Intermediate 28
3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.2.0
2,6] 11 carbon-2 (6), 4-diene-5-formic acid step 1:2-hydroxyl-2-(3-oxo two ring [2.2.2] suffering-2-pitch base) ethyl acetate
With two ring [2.2.2] suffering-2-ketone (2.4g, 19.35mmol) toluene (20ml) solution under 60 ℃, be added into sodium hydride (60% dispersion liquid, 603mg, 25.16mmol) and oxalic acid diethyl ester (3.15ml 23.22mmol) stirred 1 hour under identical temperature in the slurries in toluene (10ml) and with mixture.With reaction mixture termination reaction in ice, also use ethyl acetate extraction with 1N HCl acidifying, with organic layer Na
2SO
4Drying, vacuum are steamed to desolventize and are obtained intermediate 28 (1.2g, 27%), and it is directly used in next step without being further purified.
1H-NMR(δppm，CDCl
3，300MHz)：13.80(br.s，1H)；4.36(q，J＝6.9，2H)；3.57(br.s，1H)；2.52(br.s，1H)；1.82-1.60(m，8H)；1.38(t，J＝6.9，3H)。
Step 2:3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.2.0
2,6] 11 carbon-2 (6), 4-diene-5-ethyl formate
Productive rate: 48%.
1H-NMR(δppm，CDCl
3，300MHz)：7.70-7.60(m，1H)；7.06-6.94(m，2H)；4.43(q，J＝7.2，2H)；3.70(br.s，1H)；3.15(br.s，1H)；1.78(d，7.8，4H)；1.45-1.36(m，7H)。
Step 3:3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.2.0
2,6] 11 carbon-2 (6), 4-diene-5-formic acid:
Productive rate: 90%.
1H-NMR(δppm，CDCl
3，300MHz)：
1H-NMR(δppm，CDCl
3，300MHz)：7.72-7.60(m，1H)；7.09-6.98(m，2H)；3.73(br.s，1H)；3.18(br.s，1H)；1.80(d，J＝6.6，4H)；1.40(d，J＝7.8，4H)。
Intermediate 29
3-(3, the 4-dichlorophenyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-formic acid step 1:3-(3, the 4-dichlorophenyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-ethyl formate
Productive rate: 69%.
1H-NMR(δppm，CDCl
3，300MHz)：7.90(d，J＝2.1，1H)；
7.59(dd，J＝7.5，2.1，1H)；7.52(d，J＝8.7，1H)；4.42(q，J＝7.5，2H)；3.71(br.s，1H)；3.66(br.s，1H)；2.14(d，J＝8.7，1H)；2.00(d，J＝8.4，2H)；1.73(d，J＝9.3，1H)；1.42(t，J＝7.5，3H)；1.20(d，J＝6.9，2H)。
Step 2:3-(3, the 4-dichlorophenyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-formic acid
Productive rate: 90%.
1H-NMR(δppm，CDCl
3，300MHz)：7.92-7.87(m，1H)；7.62-7.52(m，2H)；3.73(br.s，1H)；3.71(br.s，1H)；2.16(d，J＝6.6，1H)；2.03(d，J＝6.3，2H)；1.76(d，J＝8.7，1H)；1.23(d，J＝6.0，2H)。
Intermediate 30
3-(2-oxyethyl group-4-fluorophenyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-formic acid step 1:3-(2-oxyethyl group-4-fluorophenyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-ethyl formate
1H-NMR(δppm，CDCl
3，300MHz)：7.53(q，J＝6.3，1H)；6.78-6.66(m，2H)；4.40(q，J＝6.9，2H)；4.10-4.00(m，2H)；3.65(br.s，1H)；3.35(br.s，1H)；2.08(d，J＝8.1，1H)；2.00-1.80(m，2H)；1.66(d，J＝9.0，1H)；1.44-1.32(m，6H)；1.24(d，J＝6.0，2H)。
Step 2:3-(2-oxyethyl group-4-fluorophenyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-formic acid
Productive rate: 91%.
1H-NMR(δppm，DMSO-d
6，300MHz)：12.62(br.s，1H)；7.48(t，J＝7.8，1H)；7.18(d，J＝8.4，1H)；6.94-6.86(m，1H)；4.17(d，J＝6.6，2H)；3.49(br.s，1H)；3.34(br.s，1H)；2.00-1.88(m，3H)；1.63(d，J＝7.8，1H)；1.30(t，J＝6.6，1H)；1.09(t，J＝10.5，2H)。
Intermediate 31a and 31b, 32a and 32b are according to intermediate 12a and the described method of 12b and be hydrolyzed according to intermediate 13a and the described method of 13b subsequently, are made by 2-oxo-2 (3-oxo two rings [2.2.1] heptan-2-yl) ethyl acetate, hydrazine hydrate, 4-methyl-benzyl bromine and 4-fluoro benzyl bromide respectively.
Intermediate 31a
Step 1:4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-ethyl formate
Productive rate: 1.30g, 66%.
1H-NMR(δppm，CDCl
3)：4.36(q，J＝6.9，2H)；3.58(br.s，1H)；3.45(br.s，1H)，2.02-1.92(m，3H)；1.71(d，J＝9.0，1H)；1.38(t，J＝6.9，3H)；1.30-1.20(m，2H)。
Step 2:1-(4-methyl-benzyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-ethyl formate: (intermediate 31aa)
And
2-(4-methyl-benzyl)-4,5,6,7-tetrahydrochysene-2H-4,7-methylene radical-indazole-3-ethyl formate (intermediate 31bb) intermediate 31aa:
1H-NMR (δ ppm, CDCl
3, 300MHz): 7.15 (s, 4H); 5.28 (d, J=4.8,2H); 4.38 (q, 7.2,2H); 3.54 (br.s, 1H); 2.97 (br.s, 1H); 2.34 (s, 3H); 1.98-1.78 (m, 3H); 1.52 (d, J=8.7,1H); 1.39 (t, J=6.9,3H); 1.12-0.98 (m, 1H); 0.82-0.68 (m, 1H).
Intermediate 31bb:
1H-NMR (δ ppm, CDCl
3, 300MHz): 7.20-7.05 (m, 4H); 5.72 (d, J=15.6,1H); 5.49 (d, 14.7,1H); 4.38-4.25 (m, 2H); 3.52 (br. s, 1H); 3.41 (br. s, 1H); 2.29 (s, 3H); 2.22 (br. s, 1H); 1.99-1.80 (m, 2H); 1.66 (d, J=7.2,1H); 1.35 (t, J=6.9,3H); 1.26-1.19 (m, 2H)
Step 3a:3-(4-methyl-benzyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-formic acid:
Intermediate 31a (294mg, 82%).
1H-NMR(δppm，CDCl
3，300MHz)：7.15(s，4H)；5.27(d，J＝3.6，2H)；3.57(br.s，1H)；3.03(br.s，1H)；2.34(s，3H)；1.96-1.81(m，2H)；1.74-1.65(m，1H)；1.55(d，J＝9.0，1H)；1.12-1.02(m，1H)；0.83-0.74(m，1H)。
Step 3b:2-(4-methyl-benzyl)-4,5,6,7-tetrahydrochysene-2H-4,7-methylene radical-indazole-3-formic acid:
Intermediate 31b:(68mg, 85%).
1H-NMR (δ ppm, CDCl
3, 300MHz): 7.10 (d, J=3.3,4H); 5.72 (d, 15.0,1H); 5.49 (d, J=14.4,1H); 3.58 (br.s, 1H); 3.42 (br.s, 1H); 2.29 (s, 3H); 1.99-1.88 (m, 3H); 1.67 (d, J=8.7,1H); 1.23 (d, J=10.5,2H).
Intermediate 32a and 32b
Step 1:
1-(4-luorobenzyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-ethyl formate (intermediate 32aa) reaches
2-(4-luorobenzyl)-4,5,6,7-tetrahydrochysene-2H-4,7-methylene radical-indazole-3-ethyl formate (intermediate 32bb)
Intermediate 32aa:
1H-NMR (δ ppm, CDCl
3, 300MHz): 7.28-7.20 (m, 2H); 7.03 (t, J=8.7,2H); 5.29 (d, J=3.3,2H); 4.38 (q, 6.9,2H); 3.55 (br.s, 1H);
3.02(br.s，1H)；1.98-1.79(m，2H)；1.70-1.62(m，1H)；1.55(d，J＝9.0，1H)；1.39(t，J＝6.9，3H)；1.14-0.98(m，1H)；0.82-0.68(m，1H)。
Intermediate 32bb:
1H-NMR (δ ppm, CDCl
3, 300MHz): 7.24-7.17 (m, 2H); 6.95 (t, J=8.4,2H); 5.72 (d, J=15.6,1H); 5.48 (d, 15.0,1H); 4.29 (q, J=7.2,2H); 3.51 (br.s, 1H); 3.40 (br.s, 1H); 1.94 (d, J=6.0,3H); 1.66 (d, J=9.0,1H); 1.35 (t, J=7.2,3H), 1.28-1.18 (m, 2H).
Step 2a:1-(4-luorobenzyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid:
Intermediate 32a:(294mg, 72%).
1H-NMR(δppm，DMSO-d
6，300MHz)：12.42(br.s，1H)；7.36-7.25(m，2H)；7.20(t，J＝9.0，2H)；5.31(br.s，2H)；3.39(br.s，1H)；3.32(br.s，1H)；1.90-1.70(m，3H)；1.55(d，J＝8.7，1H)；0.99-0.80(m，1H)；0.79-0.62(m，1H)。
Step 2b:2-(4-luorobenzyl)-4,5,6,7-tetrahydrochysene-2H-4,7-methylene radical-indazole-3-formic acid:
Intermediate 32b:(55mg, 60%).
1H-NMR(δppm，CDCl
3，300MHz)：7.25-7.17(m，2H)；6.96(t，J＝8.7，2H)；5.72(d，J＝14.4，1H)；5.50(d，15.3，1H)；3.59(br.s，1H)；3.43(br.s，1H)；1.84(d，J＝6.9，3H)；1.69(d，J＝8.4，1H)；1.23(d，J＝10.2，2H)。
Embodiment 101
N (7)-piperidines-1-base-5-(2-bromophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
With the intermediate 1 among the DMF (3ml) (300mg, solution 0.78mmol) under room temperature with bop reagent (319mg, 0.72mmol) and Et
3(0.10ml 0.99mmol) handled 15 minutes N, and thereafter, (80 μ l 0.90mmol) add this mixture, and at room temperature stir 1 hour with the N-amino piperidine.Mixture is poured in the water, collected formed precipitation by filtering, dry also by the fast silica gel chromatogram purifying, obtain pure title compound (270mg, 74%).M.P.：244℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.72(d，J＝7.6，1H)；7.65(br.s，1H)；7.50-7.30(m，3H；3.97(br.s，1H)；2.85(br.s，4H)；2.51(br.s，1H)；2.16(br.s，2H)；2.10-1.50(m，14H)；1.40(br.s，2H)。IR(cm
-1，KBr)：3311(w)，2913(s)，2844(m)，2793(m)，1687(s)，1570(w)，1522(s)，1489(m)，1479(m)，1440(m)，1352(m)，1227(m)，1214(m)。MS(m/z)469.4([M+H1+]
+)。
Embodiment 102
N (7)-benzyl-5-(2-bromophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 1 (300mg, 0.78mmol), DMF (3ml), Et
3N (0.10ml, 0.99mmol), bop reagent (319mg, 0.72mmol) and benzylamine (80 μ l 0.72mmol) obtain title compound (280mg, 76%).M.P.：201℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.70(d，J＝7.5，1H)；7.44(dd，J＝7.5，1.5，1H)；7.41-7.20(m，8H)；4.63(dd，J＝14.4，6.0，1H)；4.50(dd，J＝16.5，5.4，1H)；4.00(br.t，J＝5.1，1H)；2.52(br.t，J＝5.1，1H)；2.13(br.s，2H)；2.13-1.92(m，4H)；1.92-1.65(m，6H)。IR(cm
-1，KBr)：3428(m)，2908(s)，2845(m)，1672(s)，1566(m)，1522(s)，1498(s)，1472(s)，1351(m)，1087(m)，1024(m)，1010(m)，778(m)，763(m)，726(m)，698(m)。MS(m/z)：476.4([M+H]
+)。
Embodiment 103
N (7)-morpholino-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (100mg, 0.29mmol), DMF (1.0ml), Et
3N (40 μ l, 0.29mmol), bop reagent (129mg, 0.29mmol) and the amino morpholine of N-(28 μ l 0.29mmol) obtain title compound (97mg, 78%).M.P.：220℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.75(br.s，1H)；7.47(d，J＝8.1，2H)；7.29(d，J＝8.1，2H)；3.96(br.s，1H)；3.85(t，J＝4.5，4H)；2.99(br.s，1H)；2.95(t，J＝4.5，5H)；2.20(br.s，2H)；2.10-1.76(m，10H)。IR(KBr，cm
-1)：2915(s)，2848(m)，1674(s)，1532(m)，1498(s)，1304(m)，1267(m)，1219(m)，1112(s)，1091(s)，895(m)，838(s)。MS(m/z)：427.3([M+H]
+)。
Embodiment 104
N (7)-(3-pyridylmethyl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (100mg, 0.29mmol), DMF (1.0ml), Et
3N (48 μ l, 0.34mmol), bop reagent (128mg, 0.29mmol) and the 3-aminomethyl pyridine (30 μ l 0.29mmol) obtain title compound (98mg, 78%).M.P.：180℃。
1H-NMR(δppm，DMSO-d
6，300MHz)：8.76(t，J＝6.0，1H)；8.52(br.s，1H)；8.43(dd，J＝4.8，1.5，1H)；7.70(d，J＝8.1，1H)；7.62(d，J＝8.4，2H)；7.46(d，J＝8.4，2H)；7.34(dd，J＝8.1，4.8，1H)；4.39(d，J＝6.0，2H)；3.80(br.s，1H)；2.95(br.s，1H)；2.14(br.s，2H)，2.00-1.69(m，10H)。MS(m/z)：433.2([M+H］
+)。
Embodiment 105
N (7)-(4-pyridylmethyl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (100mg, 0.29mmol), DMF (1.0ml), Et
3N (48 μ l, 0.34mmol), bop reagent (128mg, 0.29mmol) and the 4-aminomethyl pyridine (30 μ l 0.29mmol) obtain title compound (119mg, 94%).M.P.：167-168℃。
1H-NMR(δppm，DMSO-d
6，300MHz)：8.79(t，J＝6.3，1H)；8.48(d，J＝4.5，2H)；7.65(dd，J＝7.5，1.5，2H)；7.48(dd，J＝7.5，1.5，2H)；7.27(d，J＝4.5，2H)；4.39(d，J＝5.7，2H)；3.80(br.s，1H)；2.97(br.s，1H)；2.14(br.s，2H)，2.00-1.68(m，10H)。IR(cm
-1，KBr)：3212(m)，2913(s)，2850(m)，1656(s)，1529(m)，1498(s)，1419(m)，1363(m)，1232(m)，1160(m)，1084(m)，842(m)。MS(m/z)：433.1([M+H]
+)。
Embodiment 106
N (7)-cyclohexyl-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,110
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (100mg, 0.29mmol), DMF (1.0ml), Et
3N (40 μ l, 0.29mmol), bop reagent (129mg, 0.29mmol) and cyclo-hexylamine (40 μ 1 0.29mmol) obtain title compound (110mg, 89%).M.P.：162℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.47(d，J＝8.7，2H)；7.30(d，J＝8.7，2H)；6.85(d，J＝8.7，1H)；4.01(br.t，J＝5.5，1H)；4.00-3.80(m，1H)；2.99(br.t，J＝5.6，1H)；2.20(br.s，2H)；2.08-1.68(m，12H)；1.48-1.10(m，8H)。IR(cm
-1，KBr)：3336(m)，2928(s)，2909(s)，2846(m)，1649(s)，1537(s)，1498(s)，1366(m)，1231(m)，1164(m)，1088(m)，838(m)。MS(m/z)：424.1([M+H1
+)。
Embodiment 107
N (7)-(N-cyclohexyl-N-methylamino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (250mg, 0.72mmol), DMF (3ml), Et
3N (0.22.0ml, 1.60mmol), bop reagent (322mg, 0.72mmol) and 3-N-cyclohexyl-N-methyl hydrazine (140mg 1.10mmol) obtains title compound (215mg, 65%).M.P.：219℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.64(br.s，1H)；7.46(d，J＝9.0，2H)，7.31(d，J＝9.0，2.1，2H)，3.97(br.s，1H)；2.98(br.s，1H)，2.69(s，3H)，2.62(br.s，1H)；2.19(br.s，2H)；2.05-1.70(m，14H)；1.40-1.00(m，6H)。IR(cm
-1，KBr)：MS(m/z)：453.20([M+H
+)。
Embodiment 108
N (7)-cyclohexyl methyl-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (100mg, 0.29mmol), Et
3N (40 μ l, 0.29mmol), bop reagent (129mg, 0.29mmol) and the hexanaphthene methylamine (38 μ l 0.23mmol) obtain title compound (93mg, 73%).M.P.：117℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.46(d，J＝8.1，2H)；7.29(d，J＝8.1，2H)；7.03(br.s，1H)；4.01(br.s，1H)，3.22(t，J＝6.6，2H)；3.00(br.s，1H)；2.20(br.s，2H)；2.10-1.50(m，15H)；1.40-1.10(m，4H)，1.10-0.85(m，2H)。IR(cm
-1，KBr)：3441(m)，2924(s)，2849(m)，1670(s)，1528(m)，1499(s)，1477(m)，1364(m)，1214(m)，1232(m)，1162(w)，1087(m)，838(m)。MS(m/z)：438.2([M+H]
+)。
Embodiment 109
N (7)-(diamantane-1-yl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (120mg, 0.35mmol), DMF (1.0ml), Et
3N (58 μ l, 0.42mmol), bop reagent (154mg, 0.35mmol) and the 1-adamantanamines (52mg 0.35mmol) obtains title compound (117mg, 70%).M.P.：249-252℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.47(d，J＝8.7，2H)；7.29(d，J＝8.7，2H)；6.73(br.s，1H)；4.00(br.s，1H)；2.98(br.s，1H)；2.23-1.54(m，27H)。IR(cm
-1，KBr)：3389(s)，2904(s)，2849(m)，1674(s)，1561(w)，1527(s)，1499(s)，1479(m)，1455(m)，1364(m)，1356(m)，1232(m)，1219(m)，1170(w)，1090(m)，1014(w)，837(m)。MS(m/z)：476.2([M+H]
+)。
Embodiment 110
N (7)-(1S, in 2-1,3,3-trimethylammonium-two ring [2.2.1] heptan-2-yl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (120mg, 0.35mmol), DMF (1.0ml), Et
3N (58 μ l, 0.42mmol), (154mg, 0.35mmol) and 1,3,3-trimethylammonium-two ring [2.2.1] heptan-(53mg 0.80mmol) obtains title compound (135mg, 80%) to 2-base amine to bop reagent.M.P.：229℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.91(s，1H)；7.47(d，J＝8.7，2H)；7.39(d，J＝8.1，2H)；7.34-7.20(m，3H)；6.99(t，J＝8.8，1H)；3.86(br.t，J＝4.8，1H)；3.35(s，3H)；3.00(br.s，1H)；2.17(br.s，2H)；2.00-1.70(m，10H)。IR(cm
-1，KBr)：3396(s)，2909(s)，2845(m)，1685(s)，1587(m)，1563(m)，1498(s)，1475(s)，1464(s)，1438(s)，1366(m)，1223(m)，1152(m)，1092(s)，1083(m)，1014(m)，837(s)。MS(m/z)：478.3([M+H]
+)。
Embodiment 111
N (7)-(2-benzyl chloride base)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (100mg, 0.29mmol), DMF (1.0ml), Et
3N (40 μ l, 0.29mmol), bop reagent (129mg, 0.29mmol) and the 2-chlorobenzylamine (35 μ l 0.29mmol) obtain title compound (102mg, 75%).M.P.：162-164℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.50-7.18(m，9H)；4.67(d，J＝6.3，2H)；3.99(br.t，J＝4.8，1H)；3.00(br.t，J＝4.8，1H)；2.20(br.s，2H)；2.00-1.70(m，10H)。IR(KBr，cm
-1)：3422(m)，2916(s)，2845(m)，1670(s)，1564(m)，1531(s)，1497(s)，1478(s)，1442(m)，1360(m)，1249(m)，1232(m)，1163(m)，1085(s)，1047(m)，1012(m)，976(m)，835(m)。MS(m/z)：466.0([M+H]
+)。
Embodiment 112
N (7)-(4-benzyl chloride base)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (100mg, 0.29mmol), Et
3N (40 μ l, 0.29mmol), bop reagent (129mg, 0.29mmol), and the 4-chlorobenzylamine (36 μ l 0.29mmol) obtain title compound (115mg, 85%).M.P.：198℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.45(d，J＝8.7，2H)；7.40-7.20(m，7H)；4.54(d，J＝6.3，2H)，4.00(br.s，1H)；3.00(br.s，1H)；2.21(br.s，2H)；2.10-1.95(m，2H)；1.95-1.70(m，8H)。IR(cm
-1，KBr)：3317(m)，2914(s)，2847(m)，1657(s)，1538(s)，1498(s)，1365(m)，1247(m)，1087(m)，1015(m)；839(m).MS(m/z)：466.3([M+H]
+)。
Embodiment 113
N (7)-(4-luorobenzyl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (100mg, 0.29mmol), DMF (1.0ml), Et
3N (40 μ l, 0.29mmol), bop reagent (129mg, 0.29mmol) and the 4-flunamine (33 μ l 0.29mmol) obtain title compound (96mg, 73%).M.P.：201℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.44(d，J＝8.4，2H)；7.30-7.25(m，5H)；7.00(t，J＝8.4，2H)；4.54(d，J＝6.0，2H)，4.01(br.s，1H)；3.00(br.s，1H)；2.20(br.s，2H)；2.05-1.95(m，2H)；1.95-1.80(m，8H)。IR(cm
-1，KBr)：3345(m)，2921(s)，2900(m)，2850(m)，1648(s)，1542(s)，1508(s)，1364(m)，1354(m)，1258(m)，1233(m)，1217(s)，1155(m)，1087(m)，834(s)。MS(m/z)：450.0([M+H]
+)。
Embodiment 114
N (7)-(2, the 4-difluorobenzyl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (150mg, 0.43mmol), DMF (2.0ml), Et
3N (60 μ l, 0.43mmol), (193mg, 0.43mmol), and 2, (52 μ l 0.43mmol) obtain title compound (195mg, 96%) to 4-two flunamines to bop reagent.M.P.：185℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.49-7.27(m，6H)；6.90-6.75(m，2H)；4.57(d，J＝6.3，2H)，3.98(t，J＝5.7，1H)；2.99(br.t，J＝5.4，1H)，2.20(br.s，2H)，2.05-1.80(m，10H)。IR(cm
-1，KBr)：3428(s)，2920(m)，2898(m)，1673(s)，1535(s)，1500(s)，1430(s)，1229(m)，1161(m)，1064(m)，986(m)，835(m)，960(m)，861(m)。MS(m/z)：468.10([M+H]
+)。
Embodiment 115
N (7)-(2, the 6-difluorobenzyl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (150mg, 0.43mmol), DMF (2.0ml), Et
3N (60 μ l, 0.43mmol), (193mg, 0.43mmol) and 2, (52 μ l 0.43mmol) obtain title compound (178mg, 87%) to 6-difluorobenzyl amine to bop reagent.M.P.：166-167℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.44(d，J＝8.7，2H)；7.30-7.20(m，3H)；6.88(t，J＝7.8，2H)，4.68(d，J＝5.7，2H)，4.00(br.t，J＝5.4，1H)；2.98(br.s，1H)，2.19(br.s，2H)，2.05-1.60(m，10H)。IR(cm
-1，KBr)：3427(m)，2930(m)，2905(m)，1681(s)，1594(m)，1563(m)，1530(s)，1499(s)，1471(s)，1364(m)，1260(m)，1161(m)，1087(s)，994(s)，839(m)。MS(m/z)：468.10([M+H]
+)。
Embodiment 116
N (7)-(4-trifluoromethyl benzyl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (100mg, 0.29mmol), Et
3N (40 μ l, 0.29mmol), bop reagent (129mg, 0.29mmol) and 4-(trifluoromethyl) benzylamine (42 μ l 0.27mmol) obtain title compound (115mg, 79%).M.p.：228℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.57(d，J＝8.6，2H)；7.46-7.39(m，4H)；7.37(br.t，J＝5.4，1H)；7.28(d，J＝8.7，2H)；4.63(d，J＝6.0，2H)，3.99(br.t，J＝4.2，1H)；3.00(br.s，1H)；2.21(br.s，2H)；2.05-1.96(m，2H)；1.96-1.84(m，8H)。IR(cm
-1，KBr)：3350(m)，2916(s)，2850(m)，1647(s)，
1618(m)，1541(s)，1498(s)，1325(s)，1256(m)，1232(m)，1159(s)，1124(s)，1112(s)，1086(s)，1065(s)，1015(m)，978(m)，850(m)，834(m)。
Embodiment 117
N (7)-(1-phenylethyl))-and 5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (150mg, 0.43mmol), DMF (2.0ml), Et
3N (60 μ l, 0.43mmol), bop reagent (193mg, 0.43mmol) and S-(-)-phenylethylamine (58 μ 1 0.43mmol) obtain title compound (130mg, 67%).M.P.：85-86℃。
1H-NMR (δ ppm, CDCl
3, 300MHz): 7.50-7.40 (m, 5H); 736-7.20 (m, 4H); 5.27 (quintet, 7.2,1H), 4.00 (t, J=5.6,1H); 2.98 (t, J=5.6,1H), 2.19 (br.s, 2H), 2.10-1.75 (m, 10H), 1.57 (d, J=6.9,3H).IR(cm
-1，KBr)：3410(m)，2913(s)，2845(m)，1667(s)，1526(s)，1498(s)，1478(s)，1363(m)，1219(m)，1160(m)，1084(s)，1014(m)，835(m)，699(m)。MS(m/z)：446.10([M+H]
+)。
Embodiment 118
N (7)-(R-1-phenylethyl))-and 5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (100mg, 0.29mmol), DMF (1.0ml), Et
3N (46 μ l, 0.32mmol), (136mg, 0.32mmol) (39mg 0.32mmol) obtains title compound (90mg, 69%) to bop reagent with the R-1-phenylethylamine.M.P.：65-70℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.50-7.18(m，10H)；5.35-5.18(m，1H)；4.00(br.s，1H)；2.98(br.s，1H)；2.19(br.s，2H)；2.10-1.71(m，10H)；1.57(d，J＝6.9，3H)。IR(cm
-1，KBr)：3408(s)，3062(w)，3029(w)，2914(s)，2845(s)，1667(s)，1596(w)，1585(w)，1526(s)，1498(s)，1478(s)，1441(s)，1406(m)，1363(m)，1353(w)，1271(m)，1232(s)，1218(m)，1159(m)，1083(s)，1033(m)，1013(m)，933(w)，835(m)。MS(m/z)：446.3([M+H]
+)。
Embodiment 119
N (7)-(1-methyl isophthalic acid-phenylethyl))-and 5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (100mg, 0.29mmol), DMF (1.0ml), Et
3N (46 μ l, 0.32mmol), (136mg, 0.32mmo1)/and α, (48mg 0.36mmol) obtains title compound (90mg, 67%) to α-Er Jiajibianji amine to bop reagent.M.P.：181℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.47(br.d，J＝8.7，4H)；7.36-7.28(m，5H)；7.22(br.t，J＝7.2，1H)；3.92(br.s，1H)；3.35(s，3H)；2.99(br.s，1H)；2.18(br.s，2H)；2.00-1.74(m，10H)；1.79(s，6H)。IR(cm
-1，KBr)：3407(m)，3090(w)，3060(w)，3024(w)，2965(w)，2898(s)，2845(m)，1675(s)，1563(w)，1497(s)，1479(s)，1438(m)，1407(w)，1379(w)，1362(m)，1340(w)，1254(w)，1231(w)，1219(w)，1194(w)，1159(w)，1085(m)，1031(w)，1015(m)，834(m)。MS(m/z)：460.1(25，[M+H]
+)；342.3(100)。
Embodiment 120
N (7)-(2-pyridylmethyl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (100mg, 0.29mmol), DMF (1.0ml), Et
3N (48 μ l, 0.34mmol), bop reagent (128mg, 0.29mmol) and the 2-aminomethyl pyridine ((30 μ l 0.29mmol) obtain title compound (98mg, 78%).M.P.：187℃。
1H-NMR(δppm，DMSO-d
6，300MHz)：8.66(t，J＝6.0，1H)；8.49(br.d，J＝5.1，1H)；7.76(td，J＝7.6，1.8，1H)；7.64(d，J＝9.0，2H)；7.51(d，J＝9.0，2H)；7.31(d，J＝7.6，1H)；7.26(m，1H)；4.50(d，J＝6.0，2H)；3.82(br.s，1H)；2.98(br.s，1H)；2.15(br.s，2H)，2.00-1.70(m，10H)。IR(cm
-1，KBr)：2918(m)，2847(m)，1781(s)，1496(s)，1443(m)，1366(m)，1230(m)，1113(m)，1089(m)，1059(m)，835(m)。MS(m/z)：433.2([M+H]
+)
Embodiment 121
N (7)-(N ,-phenyl amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,110
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (200mg, 0.29mmol), Et
3N (80 μ l, 0.58mmol), bop reagent (258mg, 0.58mmol), and phenyl hydrazine (60 μ l 0.58mmol) obtain title compound (185mg, 73%).M.P.：103-105℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.59(s，1H)；7.48(d，J＝8.7，2H)；7.33(d，J＝8.7，2H)；7.22(t，J＝7.5，2H)；6.94(d，J＝8.7，2H)；6.88(t，J＝7.5，1H)；3.89(br.t，J＝4.7，1H)；3.03(br.s，J＝3.5，1H)；2.20(br.s，2H)；2.00-1.75(m，10H)。IR(cm
-1，KBr)：3279(m)，2912(s)，2845(m)，1678(s)，1603(m)，1497(s)，1467(m)，1353(m)，1232(m)，1090(m)，1012(m)，835(m)。MS(m/z)：433.1([M+H]
+)。
Embodiment 122
N (7)-(N '-phenyl amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,110
4,8] 14 carbon-4 (8), 6-diene-7-carboxamide hydrochloride
(100mg, solution 0.23mmol) at room temperature use the HCl saturated solution in the ether (2.0ml) to handle, and at room temperature stir 1 hour, and the solid of filtering-depositing obtains title compound (90mg, 73%) with the embodiment 121 in the exsiccant ether (20ml).M.P.：135-136℃。
1H-NMR(δppm，DMSO-d
6，300MHz)：9.95(s，1H)；7.65(d，J＝9.0，2H)；7.52(d，J＝9.0，2H)；7.13(t，J＝7.8，2H)；6.74(d，J＝7.5，2H)；6.69(t，J＝7.5，1H)；3.67(br.s，1H)；3.02(br.s，1H)；2.15(br.s，2H)；2.00-1.71(m，10H)。IR(cm
-1，KBr)：3419(br.s)，3020(m)，1642(s)，1498(m)，1216(m)，1092(w)，1014(w)，836(m)。MS(m/z)：433.3([M+H]
+)。
Embodiment 123
N (7)-(2-chloro-phenyl-amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (200mg, 0.58mmol), Et
3N (90 μ l, 0.64mmol), bop reagent (258mg, 0.58mmol) and 2-chlorophenyl hydrazine hydrogenchloride (104mg 0.58mmol) obtains title compound (168mg, 62%).M.P.：155℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.60(s，1H)；7.49(d，J＝8.7，2H)；7.38-7.20(m，3H)；7.11(t，J＝7.2，1H)；7.04(dd，J＝7.5，1.5，1H)；6.82(t，J＝7.6，1H)；6.56(br.s，1H)；3.90(br.s，1H)；3.03(br.s，1H)；2.20(br.s，2H)；2.01-1.70(m，10H)。IR(cm
-1，KBr)：3376(m)，3310(m)，2909(m)，1683(s)，1597(m)，1563(w)，1498(s)，1470(s)，1423(w)，1364(m)，1212(m)，1088(m)，1026(m)，835(m)。MS(m/z)：467.9([M+H]
+)。
Embodiment 124
N (7)-(2-chloro-phenyl-amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-carboxamide hydrochloride
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (250mg, 0.73mmol), DMF (3ml), Et
3N (0.12.0ml, 0.86mmol), bop reagent (322mg, 0.73mmol) and N-(2-chloro-phenyl-)-N-methyl hydrazine hydrochloride (220mg 0.80mmol) obtains title compound (210mg, 60%).M.P.：229℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.91(s，1H)；7.47(d，J＝8.7，2H)；7.39(d，J＝8.1，2H)；7.34-7.20(m，3H)；6.99(t，J＝8.8，1H)；3.86(br.t，J＝4.8，1H)；3.35(s，3H)；3.00(br.s，1H)；2.17(br.s，2H)；2.00-1.70(m，10H)。IR(cm
-1，KBr)：3396(s)，2909(s)，2845(m)，1685(s)，1587(m)，1563(m)，1498(s)，1475(s)，1464(s)，1438(s)，1366(m)，1223(m)，1152(m)，1092(s)，1083(m)，1014(m)，837(s)。
Embodiment 125
N (7)-[(4-chloro-phenyl-) amino]]-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,110
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (100mg, 0.29mmol), Et
3N (0.27ml, 1.94mmol), bop reagent (129mg, 0.29mmol) and 4-chlorophenyl hydrazine hydrochloride (52mg 0.29mmol) obtains title compound (105mg, 77%).M.P.：208-210℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.58(s，1H)；7.49(d，J＝8.4，2H)；7.33(d，J＝8.4，2H)；7.18(d，J＝8.7，2H)；6.88(d，J＝8.7，2H)；6.00(br.s，1H)；3.87(br.s，1H)；3.03(br.s，1H)；2.20(s，2H)；2.00-1.70(m，10H)。IR(cm
-1，KBr)：3282(m)，2912(s)，2845(m)，1670(s)，1596(m)，1498(s)，1470(s)，1253(m)，1231(m)，1091(s)，1013(m)，834(m)。MS(m/z)：467.2([M+H]
+)。
Embodiment 126
N (7)-(2,4 dichloro benzene base amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,110
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (200mg, 0.58mmol), Et
3N (90 μ l, 0.65mmol), bop reagent (258mg, 0.58mmol) and 2,4 dichloro benzene hydrazonium salt hydrochlorate (125mg 0.59mmol) obtains title compound (226mg, 77%).M.P.：214-215℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.60(s，1H)；7.49(d，J＝8.7，2H)；7.40-7.22(m，3H)；7.11(dd，J＝8.7，2.4，1H)；6.97(d，J＝8.7，1H)；6.49(br.s，1H)；3.87(br.t，J＝4.61，1H)；3.03(br.s，1H)；2.20(br.s，2H)；2.04-1.70(m，10H).IR(cm
-1，KBr)：3300(m)，2907(m)，2845(m)，1681(s)，1498(s)，1471(s)，1232(m)，1089(m)，863(m)，837(m)。
Embodiment 127
N (7)-[(2,4 dichloro benzene base-N '-methylamino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (300mg, 0.88mmol), DMF (3.0ml), Et
3N (0.15ml, 1.05mmol), bop reagent (387mg, 0.88mmol) and N-(2,4 dichloro benzene base)-N-methyl hydrazine (296mg 0.97mmol) obtains title compound (220mg, 49%).M.P.：192℃。
1H-NMR(δppm，CDCl
3，400MHz)：8.90(s，1H)；7.44(dt，J＝8.8，2.0，2H)；7.29-7.26(m，4H)；7.17(dd，J＝8.4，2.4，1H)；3.80(br.s，1H)；3.30(s，3H)；2.97(br.s，1H)；2.15(s，2H)；1.86-1.75(m，10H)。IR(cm
-1，KBr)：3396(s)，2909(s)，2845(m)，1685(s)，1587(m)，1563(m)，1498(s)，1475(s)，1464(s)，1438(s)，1366(m)，1223(m)，1152(m)，1092(s)，1083(m)，1014(m)，837(s)。MS(m/z)：514.9([M+H]
+)。
Embodiment 128
N (7)-[(2,4 dichloro benzene base-N '-methylamino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-carboxamide hydrochloride
(100mg, solution 0.19mmol) use the saturated solution (2.0ml) of HCl in ether to handle, and at room temperature keep 1 hour, and the solid of filtering-depositing obtains title compound (102mg, 95%) with the embodiment 127 in the ether (2.0ml).M.P.：203℃。
1H-NMR(δppm，CDCl
3，400MHz)：9.86(s，1H)；7.53(d，J＝7.2，2H)；7.42-7.36(m，3H)；7.33(d，J＝1.7，1H)；7.20(dd，J＝8.8，1.7，1H)；3.29(s，3H)；2.99(br.s，1H)；2.21(s，2H)；1.88(m，4H)；1.88-1.80(m，6H)。IR(cm
-1，KBr)：3386m)，3197(m)，2916(s)，2901(s)，2845(m)，1687(s)，1474(s)，1439(s)，1260(m)，1323(m)，1241(m)，1124(m)，1106(m)，1089(s)，1012(m)，938(m)，845(m)，829(m)。MS(m/z)：515.0([M-HCl+H]
+)。
Embodiment 129
N (7)-(2,4 dichloro benzene base-N '-cyclohexyl amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (200mg, 0.58mmol), Et
3N (0.26ml, 1.87mmol), bop reagent (258mg, 0.58mmol) and N-cyclohexyl-N-(2,4 dichloro benzene base) hydrazonium salt hydrochlorate (427mg 1.28mmol) obtains title compound (162mg, 48%).M.P.：95-96℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.72(s，1H)；7.47(d，J＝8.4，2H)；7.42(d，J＝8.7，1H)；7.40-7.20(m，3H)；7.17(dd，J＝8.7，2.4，1H)，3.86(br.t，J＝5.2，1H)；3.75(br.s，1H)；2.99(br.s，1H)；2.17(s，2H)，2.00-1.70(m，14H)，1.43-1.10(m，6H)。IR(cm
-1，KBr)：3400(m)，2919(s)，2850(s)，1683(s)，1564(w)，1498(s)，1474(s)，1363(m)，1233(m)，1218(m)，1100(m)，1062(m)，833(m)，753(w)。MS(m/z)：583.1([M+H]
+)。
Embodiment 130
N (7)-(4-fluorophenyl amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (200mg, 0.58mmol), Et
3N (0.16ml, 1.15mmol), bop reagent (258mg, 0.58mmol) and the 4-fluorophenyl hydrazine hydrochloride (95mg 0.58mmol) obtains title compound (218mg, 83%).M.P.：125-127℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.59(s，1H)；7.48(d，J＝8.6，2H)；7.32(d，J＝8.6，2H)；7.00-6.80(m，4H)；3.88(br.s，1H)；3.03(br.s，1H)；2.20(br.s，2H)；2.05-1.70(m，10H)。IR(cm
-1，KBr)：3263(m)，2912(s)，2847(m)，1671(s)，1508(s)，1498(s)，1475(m)，1234(m)，1219(m)，1088(m)，884(w)，831(m)。MS(m/z)：451.0([M+H]
+)。
Embodiment 131
N (7)-(4-fluorophenyl amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-carboxamide hydrochloride
With the embodiment 130 (100mg in the ether (2.0ml), 0.22mmo) solution at room temperature use the HCl saturated solution in the ether (2.0m1) to handle, and at room temperature stirred 1 hour, the solid of filtering-depositing also washs with ether, obtain title compound (106mg, 98%).M.P.：175℃。
1H-NMR(δppm，DMSO-d
6，300MHz)：9.99(s，1H)；7.64(d，J＝8.5，2H)；7.50(d，J＝8.5，2H)；6.98(t，J＝8.7，2H)；6.74(dd，J＝8.7，4.8，2H)；3.67(br.s，1H)；3.01(br.s，1H)；2.15(s，2H)；2.00-1.70(m，10H).IR(cm
-1，KBr)：3247(br.m)，2916(m)，2844(m)，1694(s)，1507(s)，1498(s)，1234(s)，1089(m)，1014(m)，990(w)，836(m)。MS(m/z)：451.0([M+H]
+)。
Embodiment 132
N (7)-(2,4 difluorobenzene base amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (200mg, 0.58mmol), Et
3N (22 μ l, 1.58mmol), bop reagent (258mg, 0.58mmol) and 2,4 difluorobenzene hydrazonium salt hydrochlorate (105mg 0.58mmol) obtains title compound (225mg, 82%).M.P.：195-196℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.56(s，1H)；7.49(d，J＝9.0，2H)；7.32(d，J＝9.0，2H)；7.01(m，1H)；6.86-6.74(m，2H)；6.24(br.s，1H)，3.87(be.t，J＝4.6，1H)；3.03(br.s，1H)；2.20(br.s，2H)；2.02-1.78(m，10H)。IR(cm
-1，KBr)：3276(w)，2912(m)，2846(w)，1683(s)，1499(s)，1467(m)，1137(m)，1114(m)，848(m)，836(m)。MS(m/z)：469.1([M+H]
+)。
Embodiment 133
N (7)-(3-fluorophenyl amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (250mg, 0.72mmol), DMF (3ml), Et
3N (0.22.0ml, 1.60mmol), bop reagent (322mg, 0.72mmol) and the 3-fluorophenyl hydrazine hydrochloride (119 μ l 0.72mmol) obtain title compound (165mg, 50%).M.P.：203℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.58(s，1H)；7.51(d，J＝9.0，2H)；7.33(d，J＝9.0，2H)，7.16(q，J＝6.6，1H)；6.72-6.53(m，3H)；3.88(br.s，1H)；3.03(br.s，1H)；2.21(br.s，2H)；2.05-1.80(m，10H)。IR(cm
-1，KBr)：3259(m)，2913(s)，1617(s)，1601(m)，1498(s)，1442(m)，1269(m)，1234(m)，1140(m)，1089(s)，1012(m)，832(m)，760(m)，679(m)。MS(m/z)：451.10([M+H]
+)。
Embodiment 134
N (7)-(3-chloro-2-pyridinylamino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (150mg, 0.44mmol), DMF (1.5ml), Et
3N (68 μ l, 0.48mmol), bop reagent (203mg, 0.46mmol) and 3-chloro-2-hydrazino pyridine (69mg 0.48mmol) obtains title compound (170mg, 83%).M.P.：200-203℃。
1H-NMR(δppm，DMSO-d
6，300MHz)：9.85(s，1H)；8.46(s，1H)；8.0(dd，J＝4.5，1.5，1H)；7.69(dd，J＝7.5，1.5，1H)；7.66(d，J＝8.7，2H)；7.51(d，J＝9.0，2H)；6.75(dd，J＝7.8，4.8，1H)；3.73(br.s，1H)；3.02(br.s，1H)；2.15(br.s，2H)；2.00-1.70(m，10H)。IR(cm
-1，KBr)：3382(m)，2902(m)，2846(m)，1683(m)，1664(m)；1589(s)，1498(s)，1455(s)，1401(m)，1229(m)，1117(m)，1089(m)，1030(m)，833(m)。MS(m/z)：468.10([M+H]
+)。
Embodiment 135
N (7)-(5-chloro-2-pyridinylamino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (150mg, 0.44mmol), DMF (1.5ml), Et
3N (68 μ l, 0.48mmol), bop reagent (203mg, 0.46mmol) and 5-chloro-2-hydrazino pyridine (70mg 0.49mmol) obtains title compound (170mg, 83%).M.P.：130-135℃。
1H-NMR(δppm，DMSO-d
6，300MHz)：10.02(s，1H)；8.62(s，1H)；8.06(d，J＝2.4，1H)；7.66(d，J＝8.5，2H)；7.60(dd，J＝8.7，2.5，1H)；7.51(d，J＝8.5，2H)；6.60(d，J＝8.7，1H)；3.69(br.s，1H)；3.01(br.s，1H)；2.15(br.s，2H)；2.00-1.70(m，10H)。IR(cm
-1，KBr)：3285(m)，2909(s)，2847(m)，1671(s)，1595(m)，1498(s)，1477(s)，1364(m)，1255(m)，1233(m)，1089(m)，1012(m)，832(m)。MS(m/z)：468.10([M+H]
+)。
Embodiment 136
N (7)-(2-phenylethyl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (100mg, 0.29mmol), Et
3N (40 μ l, 0.29mmol), bop reagent (129mg, 0.29mmol) and phenylethylamine (36 μ l 0.29mmol) obtain title compound (105mg, 81%).M.P.：148℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.46(d，J＝8.7，2H)；7.35-7.18(m，7H)；7.07(br.t，J＝7.5，1H)；3.99(br.t，J＝4.7，1H)；3.63(q，J＝7.5，2H)；3.00(br.t，J＝4.7，1H)；2.90(t，J＝7.5，2H)；2.20(br.s，2H)；2.05-1.95(m，2H)；1.94-1.75(m，8H)。IR(cm
-1，KBr)：3398(m)，2913(s)，2843(m)，1673(s)，1538(s)，1498(s)，1483(s)，1382(m)，1231(m)，1086(m)，998(m)，839(m)。MS(m/z)：446.1([M+H]
+)。
Embodiment 137
N (7)-(N ', N '-diphenyl amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,110
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (300mg, 0.88mmol), DMF (3ml), Et
3N (0.27ml, 1.94mmol), (387mg, 0.88mmol) and N, (192mg 0.87mmol) obtains title compound (370mg, 83%) to N-phenylbenzene hydrazonium salt hydrochlorate to bop reagent.M.P.：214℃。
1H-NMR(δppm，CDCl
3，300MHz)：9.04(s，1H)；7.47(d，J＝8.4，2H)；7.33(d，J＝8.4，2H)；7.28-7.20(m，8H)；7.00(t，J＝8.4，2H)；3.94(br.s，1H)；3.03(br.s，1H)；2.20(s，2H)；2.05-1.80(m，10H)。IR(cm
-1，KBr)：3384(m)，2912(m)，2900(m)，1702(s)，1591(m)，1497(s)，1466(m)，1277(w)，1235(w)，1092(m)，1012(w)。MS(m/z)：509.4([M+H]
+)。
Embodiment 138
N7-[1-(2-chloro-phenyl-) ethyl]-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 2 (100mg, 0.29mmol), DMF (1.0ml), Et
3N (48 μ l, 0.34mmol), bop reagent (141mg, 0.31mmol) and (±)-1-(2-chloro-phenyl-) ethamine (48 μ l 0.29mmol) obtain title compound (104mg, 77%).M.P.：198℃。
1H-NMR (δ ppm, CDCl
3, 300MHz): 7.48-7.18 (m, 8H); 5.27 (quintet, J=7.2,1H); 3.99 (br.s, 1H); 2.98 (br.s, 1H); 2.18 (br.s, 2H); 2.06-1.74 (m, 10H); 1.56 (d, J=7.2,3H).IR(cm
-1，KBr)：3400(m)，2915(s)，2880(s)，1666(s)，1498(s)，1528(s)，1480(s)，1362(m)，1229(m)，1085(m)，1012(w)，834(m)，696(m)。
Embodiment 139
N (7)-benzyl-5-(4 '-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide
Use intermediate 2 (100mg, 0.29mmol), DMF (1ml), triethylamine (0.04ml, 0.29mmol), bop reagent (128mg, 0.29mmol) and benzylamine (0.031ml, 0.291mmol) synthetic by being similar to embodiment 101 described methods, obtain title compound (72mg, 57%).M.P.：164-166℃。
1H-NMR(δppm，CDCl
3)：7.45(d，J＝8.4，2H)；7.39-7.21(m，7H)；4.58(d，J＝6.0，2H)；4.02(t，J＝5.4，1H)；3.00(br.t，J＝4.7，1H)；2.20(br.d，2H)；2.04-1.77(m，10H).IR(cm
-1，KBr)：3471(m)，3403(m)，2919(s)，2884(m)，1672(s)，1534(m)，1499(s)。
Embodiment 140
N (7)-piperidines-1-base-5-(4 '-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide:
Use intermediate 2 (100mg, 0.291mmol), triethylamine (0.04ml, 0.29mmol), bop reagent (128mg, 0.29mmol) and 1-amino piperidine (0.031ml, 0.291mmol) synthetic by being similar to embodiment 101 described methods, obtain title compound (85mg, 68%).M.P.：185-188℃。
1H-NMR(δppm，CDCl
3)：7.67(br.s，1H)；7.46(d，J＝8.7，2H)；7.29(d，J＝8.7，2H)；3.99(br.t，J＝5.4，1H)；2.99(br.t，1H)；2.85(br.s，4H)；2.19(br.s，2H)；2.06-1.69(m，14H)；1.44-1.38(m，2H)。IR(cm
-1，KBr)：3436(m)，3320(m)；2921(s)，2853(m)，1694(m)，1668(s)，1499(m)。
Embodiment 141
7-(4 '-chloro-phenyl-)-6,7-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-5-diene-5-base-piperidines-1-base ketone:
Use intermediate 2 (100mg, 0.291mmol), triethylamine (0.04ml, 0.29mmol), bop reagent (128mg, 0.29mmol) and piperidines (0.028ml, 0.291mmol) synthetic by being similar to embodiment 101 described methods, obtain title compound (85mg, 71%).M.p.：151-153℃。
1H-NMR(δppm，CDCl
3)：7.43(d，J＝9.0)；7.31(d，J＝9.0)；3.70(br.s，2H)；3.55(t，J＝5.1，2H)；3.00-3.10(m，2H)；2.21(br.s，2H)；2.05-1.78(m，10H)；1.75-1.50(m，18H)。IR(cm
-1，KBr)：2913(m)，1634(s)，1498(m)。
Embodiment 142
N (7)-phenyl-5-(4 '-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide:
Use intermediate 2 (100mg, 0.291mmol), triethylamine (0.04ml, 0.29mmol), bop reagent (128mg, 0.29mmol) and aniline (0.026ml, 0.29mmol) synthetic by being similar to embodiment 101 described methods, obtain title compound (95mg, 77%).M.p.：188-190℃。
1H-NMR(δppm，CDCl
3)：8.78(br.s，1H)；7.67(d，J＝8.4，2H)；7.50(d，J＝8.7，2H)；7.30-7.37(m，4H)；7.12(t，J＝8.4，1H)；4.05(t，J＝5.4，1H)；3.02(t，J＝4.8，1H)；2.22(br.s，2H)；2.10-1.75(m，10H)。IR(cm
-1，KBr)：3365(m)，2915(m)，2844(m)，1682(s)，1532(s)，1498(s)。
Embodiment 143
N (7)-piperidines-1-base-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 3 (100mg, 0.30mmol), DMF (1.0ml), Et
3N (42 μ l, 0.31mmol), bop reagent (135mg, 0.31mmol) and the N-amino piperidine (33 μ l 0.31mmol) obtain title compound (96mg, 73%).M.P.：215℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.61(br.s，1H)；7.49-7.40(m，1H)；7.05-6.95(m，2H)；3.96(br.s，1H)；2.86(br.s，4H)；2.65(br.s，1H)；2.18(br.s，2H)，2.04-1.90(m，2H)；1.85-1.62(m，12H)；1.42(br.s，2H)。IR(cm
-1，KBr)：MS(m/z)：427.20([M+H]
+)。
Embodiment 144
N (7)-(diamantane-1-yl)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 3 (150mg, 0.44mmol), DMF (1.0ml), Et
3N (72 μ l, 0.52mmol), bop reagent (192mg, 0.44mmol) and the 1-adamantanamines (65mg 0.44mmol) obtains title compound (156mg, 75%).M.P.：221-224℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.50-7.38(m，1H)；7.06-6.93(m，2H)；6.68(br.s，1H)；3.97(br.s，1H)；3.35(br.s，3H)；2.22-1.54(m，27H)。IR(cm
-1，KBr)：3394(m)，2915(s)，2850(s)，1669(s)，1611(m)，1566(m)，1520(s)，1483(m)，1440(m)，1359(m)，1353(m)，1273(m)，1225(m)，1220(m)，1140(m)，1092(m)，1082(m)，966(m)，850(m)。MS(m/z)：478.2([M+H]
+)。
Embodiment 145
N (7)-(1S, in 2-1,3,3-trimethylammonium-two ring [2.2.1] heptan-2-yl)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 3 (150mg, 0.44mmol), DMF (1.0ml), Et
3N (72 μ l, 0.52mmol), (192mg, 0.44mmol) and 2-amino-1,3, (66mg 0.44mmol) obtains title compound (176mg, 84%) to 3-trimethylammonium-two ring [2.2.1] heptane to bop reagent.M.P.：235-238℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.51-7.42(m，1H)；7.07-6.95(m，3H)；3.98(br.s，1H)；3.72(d，J＝6.0，1H)；2.67(br.s，1H)；2.18(br.s，2H)；2.06-1.54(m，13H)；1.54-1.28(m，2H)；1.28-1.14(m，2H)；1.16，1.10，0.85(3s，9H)。IR(cm
-1，KBr)：3419(s)，2927(s)，2905(s)，2870(m)，1669(s)，1567(m)，1515(s)，1480(m)，1442(m)，1366(m)，1275(m)，1226(m)，1226(m)，1097(m)，1080(m)，967(m)，858(m)，845(m)。MS(m/z)：480.3([M+H]
+)。
Embodiment 146
N (7)-(S-1-phenylethyl))-and 5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 3 (150mg, 0.46mmol), DMF (1.5ml), Et
3N (75 μ l, 0.51mmol), bop reagent (214mg, 0.53mmol) and the S-1-phenylethylamine (65 μ l 0.50mmol) obtain title compound (120mg, 58%).M.P.：123-128℃。7.50-7.13 (m, 7H); 7.06-6.94 (m, 2H); 5.27 (quintet, J=7.2,1H); 3.97 (br.s, 1H); 2.65 (br.s, 1H); 2.17 (b r.s, 2H); 2.06-1.74 (m, 10H); 1.56 (d, J=7.2,3H).IR(cm
-1，KBr)：3404(m)，2911(s)，2846(m)，1668(s)，1519(s)，1480(m)，1439(m)，1367(w)，1352(w)，1275(m)，1227(m)，1145(m)，1081(m)，966(w)，854(m)。MS(m/z)：448.2([M+H]
+)。
Embodiment 147
N (7)-(R-1-phenylethyl)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 3 (150mg, 0.46mmol), DMF (1.5ml), Et
3N (75 μ l, 0.51mmol), (214mg, 0.53mmol) (65 μ l 0.50mmol) obtain title compound (125mg, 61%) to bop reagent with the R-1-phenylethylamine.M.P.：123-128℃。
1H-NMR (δ ppm, CDCl
3, 300MHz): 7.50-7.12 (m, 7H); 7.06-6.94 (m, 2H); 5.27 (quintet, J=7.5,1H); 3.97 (br.s, 1H); 2.65 (br.s, 1H); 2.17 (br.s, 2H); 2.07-1.70 (m, 10H); 1.56 (d, J=7.5,3H).IR(cm
-1，KBr)：3404(m)，2911(s)，2846(m)，1669(s)，1519(s)，1480(m)，1439(m)，1367(w)，1352(w)，1275(m)，1227(m)，1145(m)，1081(w)，966(m)，853(m)。MS(m/z)：448.2([M+H]
+)。
Embodiment 148
N (7)-(1-methyl isophthalic acid-phenylethyl)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 3 (150mg, 0.46mmol), DMF (1.5ml), Et
3N (75 μ l, 0.51mmo1), (214mg, 0.53mmol) and α, (68mg 0.51mmol) obtains title compound (70mg, 33%) to the alpha-alpha-dimethyl benzylamine to bop reagent.M.P.：150-152℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.60-7.41(m，3H)；7.33(t，J＝7.2，2H)；7.22(t，J＝7.2，1H)；7.05-6.95(m，2H)；3.89(br.s，1H)；2.65(br.s，1H)；2.16(br.s，2H)；2.00-1.54(m，10H)；1.78(s，6H)。IR(cm
-1，KBr)：3419(m)，2906(m)，1678(s)，1519(s)，1276(m)，1261(m)，1134(m)，968(m)，848(m)。MS(m/z)：462.2(100，[M+H]
+)，344.1(90)。
Embodiment 149
N (7)-(2-benzyl chloride base)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 3 (100mg, 0.29mmol), DMF (1.0ml), Et
3N (48 μ l, 0.34mmol), bop reagent (128mg, 0.29mmol) and the 2-chlorobenzylamine ((55 μ l 0.46mmol) obtain title compound (152mg, 71%).M.P.：136℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.51-7.39(m，3H)；7.35(dd，J＝7.5，2.4，1H)；7.24-7.18(m，2H)；7.05-6.95(m，2H)；4.67(d，J＝6.0，2H)；3.98(t，J＝5.4，1H)；2.67(br.s，1H)；2.19(br.s，2H)，2.10-1.95(m，2H)；1.95-1.65(m，10H).IR(cm
-1，KBr)：3329(m)，2918(s)，2849(m)，1648(s)，1537(m)，1515(m)，1442(m)，1220(m)，1083(m)，1051(m)，750(m)。MS(m/z)：468.0([M+H]
+)。
Embodiment 150
N (7)-(2,4 dichloro benzene base amino)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] ten carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 3 (150mg, 0.46mmol), DMF (2.0ml), Et
3N (63 μ l, 0.46mmol), bop reagent (203mg, 0.46mmol) and 2,4 dichloro benzene hydrazonium salt hydrochlorate (98mg 0.46mmol) obtains title compound (107mg, 47%).M.P.：162℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.70(br.s，1H)；7.48(m，1H)；7.30(d，J＝1.2，1H)；7.16-6.96(m，H)；3.87(br.s，1H)；2.71(br.s，1H)；2.19(br.s，2H)，2.05-1.70(m，10H)。IR(cm
-1，KBr)：3394(br.s，s)，2916(s)，1683(s)，1519(m)，1274(m)，1216(m)，1145(s)，1118(s)，1099(m)，967(m)，850(m)，817(m)。MS(m/z)：503.0([M+H]
+)。
Embodiment 151
N (7)-[1-(2-chloro-phenyl-) ethyl]-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 3 (100mg, 0.29mmol), DMF (1.0ml), Et
3N (48 μ l, 0.34mmol), bop reagent (141mg, 0.31mmol) and (±)-1-(2-chloro-phenyl-) ethylamine (48 μ l 0.29mmol) obtain title compound (60mg, 41%).M.P.：143-146℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.46-7.14(m，5H)；7.04-6.94(m，2H)；5.26(quintet，J＝7.2，1H)；3.97(br.s，1H)；2.65(br.s，1H)；2.17(br.s，2H)；2.04-1.70(m，10H)；1.56(d，J＝7.2，3H)。IR(cm
-1，KBr)：3419(m)，2915(s)，2847(m)，1666(s)，1612(m)，1519(s0，1481(m)，1442(m)，1368(w)，1353(w)，1273(m)，1219(m)，1144(m)，1082(m)，967(m)，852(m)。
Embodiment 152
N (7)-[(S)-and the 1-phenyl propyl] 5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 3 (100mg, 0.29mmol), DMF (1.0ml), Et
3N (48 μ l, 0.34mmol), bop reagent (141mg, 0.31mmol) and (s)-(41 μ l 0.29mmol) obtain title compound (84mg, 63%) to the 1-phenylpropylamine.M.P.：127-129℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.50-7.10(m，1H)；7.34-7.15(m，6H)；7.05-6.90(m，2H)；4.99(q，J＝7.5，1H)；3.96(t.J＝6.2，1H)；2.64(br.s，1H)；2.16(br.s，2H)；2.04-1.70(m，12H)；0.94(t，J＝7.2，3H)。IR(cm
-1，KBr)：3410(m)，3325(m)，2916(s)，2848(m)，1666(s)，1612(m)，1519(s)，1481(m)，1442(m)，1367(w)，1353(w)，1273(m)，1226(m)，1217(m)，1144(m)，1083(m)，1030(w)，966(w)，966(m)，852(w)，756(s)，700(m)。MS(m/z)：462.1([M+H]
+)。
Embodiment 153
N7-[1-(2-chloro-phenyl-)-1-methylethyl]-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1
3,11.0
4.8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 3 (100mg, 0.29mmol), DMF (1.0ml), Et
3N (45 μ l, 0.31mmol), bop reagent (141mg, 0.31mmol) and 2-(2-chloro-phenyl-)-(73mg 0.43mmol) obtains title compound (95mg, 66%) to third-2-base amine.M.P.：145-147℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.57(dd，J＝7.5，1.2，1H)；7.52-7.39(m，2H)；7.32(dd，J＝7.8，1.5，1H)；7.26-7.20(m，1H)；7.16(td，J＝7.8，1.5，1H)，7.08-6.94(m，2H)；3.82(br.t.J＝6.2，1H)；2.64(br.s，1H)；2.14(br.s，2H)；1.95-1.74(m，10H)；1.88(s，6H)。IR(cm
-1，KBr)：3419(m)，2919(m)，2892(m)，2841(m)，1674(s)，1515(s)，1441(m)，1384(w)，1362(w)，1274(m)，1249(m)，1226(m)，1139(m)，1083(m)，1039(m)，967(m)，843(m)，727(m)。MS(m/z)：496.2([M+H]
+)。
Embodiment 154
(2R)-and 2-[7-(2,4 difluorobenzene base)-6,7-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 5-diene-5-base formamido group]-2-phenylacetic acid methyl esters
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 3 (200mg, 0.58mmol), DMF (2.0ml), Et
3N (193 μ l, 1.39mmol), bop reagent (282mg, 0.64mmol) and (R)-(+)-(117mg 0.58mmol) obtains title compound (140mg, 57%) to 2-phenyl glycine methyl ester hydrochloride.M.P.：138-141℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.78(d，J＝7.2，1H)；7.49-7.30(m，6H)；7.10-6.90(m，2H)；5.72(d，J＝7.5，1H)；3.91(t.J＝6.1，1H)；3.74(s，3H)；2.66(br.s，1H)；2.16(br.s，2H)；2.00-1.70(m，10H)。IR(cm
-1，KBr)：3411(m)，2915(s)，2848(m)，1744(s)，1671(s)，1613(m)，1570(m)，1519(m)，1478(m)，1478(m)，1441(m)，1352(w)，1367(w)，1352(w)，1322(m)，1273(m)，1209(m)，1081(m)，967(w)，851(w)，754(m)，698(m)。MS(m/z)：492.1([M+H]
+)。
Embodiment 155
(2S)-and 2-[7-(2,4 difluorobenzene base)-6,7-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 5-diene-5-base formamido group]-2-phenylacetic acid methyl esters
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 3 (500mg, 1.45mmol), DMF (4.0ml), Et
3N (480 μ l, 3.48mmol), (706mg, 1.59mmol) and (S)-(+) (293mg 1.45mmol) obtains title compound (525mg, 73%) to 2-phenyl glycine methyl ester hydrochloride to bop reagent.M.P.：132-135℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.78(d，J＝6.9，1H)；7.52-7.25(m，6H)；7.05-6.90(m，2H)；5.71(d，J＝7.2，1H)；3.90(t.J＝6.2，1H)；3.74(s，3H)；2.66(br.s，1H)；2.16(br.s，2H)；2.04-1.70(m，10H)。IR(cm
-1，KBr)：3432(m)，3413(m)，2919(s)，2849(m)，1755(s)，1740(s)，1672(s)，1614(m)，1570(m)，1522(s)，1479(m)，1439(m)，1223(m)，1308(m)，1326(m)，1274(m)，1259(m)，1207(m)，1161(m)，1143(m)，1082(m)，1029(w)，967(m)，845(m)，697.MS(m/z)：492.1([M+H]
+)。
Embodiment 156
N7-(3-hydroxyadamantane-1-yl)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 3 (200mg, 0.58mmol), DMF (2.0ml), Et
3N (88 μ l, 0.63mmol), bop reagent (282mg, 0.63mmol) and 3-amino-1-adamantanol (97mg 0.58mmol) obtains title compound (143mg, 51%).M.P.：240-243℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.48-7.38(m，1H)；7.05-6.94(m，2H)；6.74(br.s，1H)；3.94(br.s，1H)；2.64(br.s，1H)，2.28(br.s，2H)；2.17(br.s，2H)；2.11(br.s，2H)；2.04-1.56(m，21H)。IR(cm
-1，KBr)：3385(m)，2911(s)，2849(m)，1657(s)，1610(w)，1560(w)，1520(m)，1482(m)，1441(w)，1441(w)，1362(w)，1352(w)，1273(w)，1253(w)，1227(m)，1150(m)，1132(m)，1101(w)，1084(w)，1048(w)，1025(w)，966(m)，872(m)。MS(m/z)：494.0([M+H]
+)。
Embodiment 157
N (7)-(1-methyl isophthalic acid-phenylethyl)-5-(4-fluorophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 4 (100mg, 0.30mmol), DMF (1.5ml), Et
3N (50 μ l, 0.36mmol), (148mg, 0.33mmol) and α, (49mg 0.36mmol) obtains title compound (92mg, 68%) to the alpha-alpha-dimethyl benzylamine to bop reagent.M.P.：180-182℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.47(d，J＝7.8，2H)；7.38-7.14(m，8H)；3.91(br.s，1H)；2.95(br.s，1H)；2.17(br.s，2H)；1.97-1.76(m，16H)。IR(cm
-1，KBr)：3412(m)，3064(w)，2981(w)，2916(s)，2846(m)，1672(s)，1565(w)，1512(s)，1482(m)，1439(m)，1382(w)，1363(w)，1257(m)，1215(s)，1155(m)，1084(m)，844(m)。MS(m/z)：443.9(100％)，444.9([M+H]
+)。
Embodiment 158
N (7)-(diamantane-1-yl)-5-(4-fluorophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 4 (150mg, 0.46mmol), DMF (1.5ml), Et
3N (76 μ l, 0.55mmol), bop reagent (223mg, 0.50mmol) and the 1-adamantanamines (69mg 0.46mmol) obtains title compound (150mg, 71%).M.P.：214-216℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.36-7.26(m，2H)；7.20-7.12(m，2H)；6.73(br.s，1H)；3.99(br.s，1H)；2.94(br.s，1H)，2.19-1.55(m，27H)。IR(cm
-1，KBr)：3392(m)，2905(s)，2847(m)，1671(s)，1560(w)，1529(m)，1512(s)，1481(m)，1454(w)，1441(w)，1357(m)，1219(m)，1092(m)，841(m)。MS(m/z)：460.3([M+H]
+)。
Embodiment 158a
N7-(diamantane-2-yl)-5-(4-fluorophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,110
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 4 (100mg, 0.36mmol), DMF (1.0ml), Et
3N (124 μ l, 0.88mmol), bop reagent (170mg, 0.38mmol) and 2-adamantyl amine hydrochlorate (103mg 0.55mmol) obtains title compound (120mg, 80%).M.P.：196-198℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.69-7.63(m，2H)；7.17(t，J＝8.1，2H)；4.23(d，J＝8.4，1H)；3.75(br.s，1H)；3.65(br.s，1H)，2.14-1.87(m，14H)，1.78-1.54(m，4H)，1.26-1.21(m，2H)。IR(cm
-1，KBr)：3414(s)，2979(w)，2901(s)，2851(s)，1663(s)，1542(s)，1517(s)，1488(s)，1454(m)，1445(m)，1347(w)，1255(w)，1224(m)，1213(s)，1159(m)，1126(m)，1091(m)，953(w)，833(m)。MS(m/z)：406.2([M+H]
+)。
Embodiment 159
N7-(1,3,3-trimethylammonium two ring [2.2.1] heptan-2-yl)-5-(4-fluorophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,110
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 4 (100mg, 0.30mmol), DMF (1.5ml), Et
3N (103 μ l, 0.73mmoD, bop reagent (142mg, 0.32mmol) and 1S, 2 interior-amino-1,3, (86mg 0.46mmol) obtains title compound (101mg, 71%) to 3-trimethylammonium-two ring [2.2.1] heptane.M.P.：139-141℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.38-7.31(m，2H)；7.21-7.04(m，3H)；4.00(br.s，1H)；3.73(d，J＝9.6，1H)；2.98(br.s，1H)，2.19(br.s，1H)，2.05-1.66(m，14H)，1.51-1.39(m，2H)，1.25-1.08(m，1H)，1.21，1.01，0.85(3s，9H)。IR(cm
-1，KBr)：3418(s)，2927(s)，2904(s)，2870(m)，1670(s)，1607(w)，1560(m)，1510(s)，1525(s)，1479(m)，1440(m)，1375(w)，1355(w)，1365(w)，1220(m)，1159(m)，1151(m)，1089(m)，1029(m)，838(m)。MS(m/z)：462.3([M+H]
+)。
Embodiment 160
N (7)-piperidines-1-base-5-(4-aminomethyl phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 5 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (46 μ l, 0.33mmol), bop reagent (137mg, 0.31mmol) and the 1-amino piperidine (35 μ l 0.33mmol) obtain title compound (70mg, 56%).M.p.：228-232℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.70(br.s，1H)；7.28(d，J＝9.0，2H)；7.23(d，J＝9.0，2H)；3.99(br.t，J＝4.83，1H)；2.99(br.s，1H)；2.85(br.s，4H)；2.42(s，3H)；2.18(br.s，2H)；2.04-1.95(m，2H)；1.95-1.65(m，12H)；1.41(br.s，2H)。IR(cm
-1，KBr)：3306(m)，2949(s)，2937(s)，2911(s)，2849(s)，2790(m)，1690(s)，1563(w)，1518(s)，1488(m)，1462(m)，1349(m)，1216(m)，1127(m)，1108(m)，987(m)，830(m)。MS(m/z)：405.20([M+H]
+)。
Embodiment 161
N (7)-(2,4 dichloro benzene base amino)-5-(4-aminomethyl phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 5 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (46 μ l, 0.33mmol), bop reagent (137mg, 0.31mmol) and 2,4 dichloro benzene hydrazonium salt hydrochlorate (70mg 0.32mmol) obtains title compound (110mg, 73%).M.P.：208-215℃。
1H-NMR(δppm，CDCl
3，300MHz)：9.42(br.s，1H)；7.38-7.20(m，7H)；7.14-7.00(m，1H)；3.96(br.s，1H)；3.04(br.s，1H)；2.45(s，3H)；2.40-1.80(m，12H)。IR(cm
-1，KBr)：3314(m)，3247(m)，2914(s)，2846(m)，1674(s)，1661(s)，1515(s)，1477(s)，1478(s)，1390(m)，1363(m)，1254(m)，1235(m)，1216(m)，1089(m)，1079(m)，862(m)，825(s)。MS(m/z)：481.10([M+H]
+)。
Embodiment 162
N (7)-(2-benzyl chloride base)-5-(4-aminomethyl phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 5 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (46 μ l, 0.33mmol), bop reagent (137mg, 0.31mmol) and the 2-chlorobenzylamine (40 μ l 0.36mmol) obtain title compound (80mg, 58%).M.P.：127-130℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.70(br.s，1H)；7.48(br.d，J＝6.9，1H)；7.38-7.16(m，7H)；4.68(d，J＝6.0，2H)；4.02(br.t，J＝4.6，1H)；3.00(br.s，1H)；2.42(s，3H)；2.20(br.s，2H)；2.10-1.70(m，10H)。IR(cm
-1，KBr)：3410(m)，2915(s)，2904(s)，2842(m)，1663(s)，1526(s)，1517(s)，1478(s)，1465(s)，1439(s)，1365(m)，1352(m)，1232(m)，1215(m)，1085(m)，829(m)，756(m)。MS(m/z)：446.10([M+H]
+)。
Embodiment 163
N (7)-piperidines-1-base-5-(4-p-methoxy-phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 6 (100mg, 0.27mmol), DMF (2.0ml), Et
3N (44 μ l, 0.32mmol), bop reagent (129mg, 0.32mmol) and the 1-amino piperidine (29 μ l 0.29mmol) obtain title compound (65mg, 58%).M.P.:156 ℃ (fusion).
1H-NMR(δppm，CDCl
3，300MHz)：7.22(d，J＝6.9，3H)；6.98(d，J＝6.9，2H)；3.86(br.s，3H)；3.74(br.s，1H)；3.01(br.s，1H)，2.38-1.70(m，20H)。IR(cm
-1，KBr)：3284(m)，2917(s)，2849(s)，1655(s)，1609(m)，1519(s)，1471(s)，1440(s)，1353(m)，1298(m)，1256(s)，1231(s)，1147(m)，1071(m)，1010(m)，891(m)，814(s)。MS(m/z)：421.20([M+H]
+)。
Embodiment 164
N7-(2-benzyl chloride base)-5-(4-p-methoxy-phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 6 (100mg, 0.27mmol), DMF (1.0ml), Et
3N (44 μ l, 0.32mmol), bop reagent (129mg, 0.32mmol) and the 2-chlorobenzylamine (32 μ l 0.27mmol) obtain title compound (85mg, 69%).M.P.：178℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.50-7.45(m，2H)；7.37-7.10(m，5H)；6.98(br.d，J＝7.5，2H)；4.67(br.s，2H)；4.00(br.s，1H)；3.86(br.s，3H)；2.96(br.s，1H)；2.19(br.s，2H)，2.10-1.40(m，10H)。IR(cm
-1，KBr)：3395(s)，2904(m)，2848(m)，1667(s)，1531(s)，1515(s)，1444(s)，1353(s)，1242(s)，1230(s)，1222(s)，1231(s)，1162(m)，985(m)，839(m)。MS(m/z)：462.10([M+H]
+)。
Embodiment 165
N (7)-(2,4 dichloro benzene base amino)-5-(4-p-methoxy-phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 6 (100mg, 0.36mmol), DMF (1.0ml), Et
3N (44 μ l, 0.32mmol), bop reagent (125mg, 0.28mmol) and 2,4 dichloro benzene hydrazonium salt hydrochlorate (57mg 0.27mmol) obtains title compound (78mg, 56%).M.P.：199℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.75(br.s，1H)；7.36-7.27(m，3H)；7.10(dd，J＝9.0，1.8，1H)；7.06-6.94(d，J＝9.0，1H)；6.97(br.s，1H)；6.50(br.s，1H)；3.87(br.s，4H)；3.00(br.s，1H)；2.19(br.s，2H)，2.02-1.80(m，10H)。IR(cm
-1，KBr)：3359(s)，3020(w)，2912(s)，2844(m)，1678(s)，1517(s)，1473(s)，1247(s)，1229(s)，1075(m)，1020(m)，837(s)。MS(m/z)：497.10([M+H]
+)。
Embodiment 166
N (7)-piperidines-1-base-5-[(2-chloro-phenyl-) phenyl]-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
With the embodiment 101 in the two alkane (4.0ml) (170mg, 0.36mmol) solution with the 4-chlorophenylboronic acid (62mg, 0.33mmol), Pd (PPh
3)
2Cl
2(6mg, 0.009ml) and yellow soda ash (115mg 1.08mmol) handles, and refluxed 7 hours.Evaporating solvent also is dissolved in AcOEt with resistates, washes with water.With organic layer Na
2SO
4Drying is filtered, and removes and desolvate.Resistates obtains the product of about 70% (analyzing by HPLC) purity through the FC purifying, and it is further purified by preparation type TLC and obtains title compound (70mg, 39%).HPLC-purity: 99.8%.M.P.：206℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.59-7.38(m，4H)；7.27(d，J＝8.4，2H)；6.99(d，J＝8.4，2H)；3.84(br.s，1H)；3.35(s，3H)；2.89(br.s，4H)；2.35(br.s，1H)；2.00-1.70(m，18H)。MS(m/z)：501.2([M+H]
+)。
Embodiment 167
N (7)-[(2,4 dichloro benzene base) amino]-5-phenyl-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Use intermediate 7 (100mg, 0.33mmol), DMF (1.0ml), Et
3N (50 μ l, 0.36mmol), bop reagent (151mg, 0.34mmol) and 2,4 dichloro benzene hydrazonium salt hydrochlorate (77mg, 0.36mmol) synthetic by being similar to embodiment 101 described methods, obtain title compound (110mg, 71%).M.P.：166-170℃。
1H-NMR?(δppm，CDCl
3，300MHz)：8.60(s，1H)；7.56-7.42(m，3H)；7.39(dd，J＝7.5，2.1，2H)；7.29(d，J＝2.2，2H)；7.12(dd，J＝9.0，2.2，1H)；6.80(d，J＝9.0，1H)；6.55(br.s，1H)；3.90(t，J＝6.0，1H)，3.15(br.s，1H)；2.20(s，2H)；2.04-1.74(m，10H)。IR(cm
-1，KBr)：3371(s)，3307(m)，2910(s)，2848(m)，1683(s)，1596(m)，1564(m)，1501(m)，1463(s)，1450(s)，1393(m)，1361(m)，1231(m)，1214(m)，1075(m)，1018(m)，872(m)。MS(m/z)：467.1([M+H]
+)。
Embodiment 168
N (7)-phenyl-5-phenyl-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide:
Use intermediate 7 (100mg, 0.32mmol), DMF (2ml), triethylamine (0.05ml, 0.35mmol), bop reagent (151mg, 0.34mmol) and aniline (33 μ l, 0.35mmol) synthetic by being similar to embodiment 101 described methods, obtain title compound (70mg, 56%).M.P.：178-181℃。
1H-NMR(δppm，CDCl
3)：8.82(br.s，1H)；7.67(d，J＝7.8，2H)；7.56-7.29(m，7H)；7.09(t，J＝7.5)；4.06(br.t，J＝5，1H)；3.07(br.t，J＝4.3，1H)；2.22(br.s，2H)；2.09-1.98(m，2H)；1.98-1.76(m，8H).IR(cm
-1，KBr)：3449(br.，m)，3384(m)，2922(m)，2904(m)，2844(m)，1689(s)，1601(m)，1591(m)，1528(s)，1502(s)。
Embodiment 169
N (7)-piperidines-1-base-5-phenyl-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide:
Use intermediate 7 (155mg, 0.5mmol), DMF (2ml), triethylamine (77 μ l, 0.55mmol), bop reagent (235mg, 0.53mmol) and 1-amino piperidine (60 μ l, 0.55mmol) synthetic by being similar to embodiment 101 described methods, obtain title compound (120mg, 61%).
1H-NMR(δppm，CDCl
3)：7.69(br.s，1H)；7.53-7.32(m，5H)；4.00(br.t，J＝5.5，1H)；3.02(br.t，J＝4.6，1H)；2.84(br.t，J＝4.8，4H)；2.19(br.s，2H)；2.05-1.68(m，14H)；1.44-1.36(m，2H).IR(cm
-1，KBr)：3345(m)，3306(m)，2941(s)，2920(s)，2906(s)，1687(s)，1525(m)，1500(m)。
Embodiment 170
N (7)-benzyl-5-phenyl-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide:
Use intermediate 7 (100mg, 0.32mmol), DMF (2ml), triethylamine (0.05ml, 0.35mmol), bop reagent (151mg, 0.34mmol) and benzylamine (39 μ l, 0.35mmol) synthetic by being similar to embodiment 101 described methods, obtain title compound (70mg, 55%).M.P.：137-139℃。
1H-NMR(δppm，CDCl
3)：7.51-7.21(m，11H)；4.58(d，J＝5.7，2H)；4.03(br.t，JK＝5，1H)；3.03(br.，J＝4.3，1H)；2.20(br.s，2H)；2.08-1.98(m，2H)；1.98-1.76(m，8H)。IR(cm
-1，KBr)：3405(m)，3361(m)，2916(s)，2900(s)，2844(m)，1659(s)，1541(s)，1504(m)。
Embodiment 171
N (7)-phenyl-6,7-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-5-diene-5-base-piperidines-1-base ketone
Use intermediate 7 (100mg, 0.32mmol), DMF (2ml), triethylamine (0.05ml, 0.35mmol), bop reagent (151mg, 0.34mmol) and piperidines (36 μ l, 0.35mmol) synthetic by being similar to embodiment 101 described methods, obtain title compound (50mg, 50%).M.P.：123-125℃。
1H-NMR(δppm，CDCl
3)：7.49-7.35(m，5H)；3.71(br.s，2H)；3.57(t，J＝5.4，2H)；3.11(br.s，1H)；3.05(br.s，1H)；2.21(br.s，2H)；2.04-1.74(m，10H)；1.70-1.51(m，8H).IR(cm
-1，KBr)：2916(s)，2845(m)，1630(s)，1597(m)，1500(m)。
Embodiment 172
N (7)-(4-luorobenzyl)-5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 8 (100mg, 0.28mmol), DMF (1.0ml), Et
3N (41 μ l, 0.29mmol), bop reagent (123mg, 0.28mmol) and the 4-flunamine (37mg, 33 μ l 0.29mmol) obtain .M.P.:68-70 ℃ of title compound (95mg, 74%).
1H-NMR(δppm，CDCl
3，300MHz)：7.54(d，J＝2.4，1H)；7.38-7.15(m，5H)；7.00(t，J＝8.4，2H)；4.53(dd，J＝14.1，5.7，2H))；3.98(br.s，1H)，2.53(br.s，1H)；2.18(br.s，2H)；2.00-1.61(m，10H)。IR(cm
-1，KBr)：3415(m)，3307(m)，2913(s)，2846(m)，1667(s)，1537(s)，1509(s)，1498(s)，1441(m)，1352(m)，1220(s)，1156(m)，1088(m)，1071(m)，824(s)。MS(m/z)：484.1([M+H]
+)。
Embodiment 173
N (7)-phenyl amino-5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 8 (100mg, 0.28mmol), DMF (1.0ml), Et
3N (41 μ l, 0.29mmol), bop reagent (123mg, 0.29mmol) and phenylhydrazine (29 μ l 0.29mmol) obtain title compound (80mg, 65%).M.P.：162-163℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.53(s，1H)；7.59(d，J＝2.4，1H)；7.42(dd，J＝8.4，2.1，1H)；7.35(d，J＝8.4，1H)；7.22(t，J＝8.4，2H)；6.95(d，J＝8.4，2H)；6.89(t，J＝7.2，1H)；3.87(br.s，1H)，2.57(br.s，1H)；2.18(br.s，2H)；2.00-1.67(m，10H)。IR(cm
-1，KBr)：3292(m)，2911(s)，2845(m)，1670(s)，1603(m)，1566(m)，1525(m)，1496(s)，1477(m)，1441(m)，1351(m)，1232(m)，1219(m)，1133(m)，1121(m)，1104(m)，1086(m)，887(m)825(m)。MS(m/z)467.8([M+H]
+)。
Embodiment 174
N (7)-(2-chloro-phenyl-amino)-5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 8 (100mg, 0.27mmol), DMF (1.0ml), Et
3N (94 μ l, 0.66mmol), bop reagent (129mg, 0.29mmol) and 2-chlorophenyl hydrazine hydrochloride (52mg 0.29mmol) obtains title compound (88mg, 66%).M.P.：110℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.54(s，1H)；7.59(d，J＝2.1，1H)；7.42(dd，J＝8.4，2.4，1H)；7.34(d，J＝8.4，1H)；7.28(dd，J＝8.1，1.6，1H)；7.15(td，J＝8.1，1.6，1H)；7.04(dd，J＝8.1，1.5，1H)；6.82(td，J＝8.1，1.5，1H)；6.55(br.s，1H)；3.87(br.t，J＝5.1，1H)；2.58(br.t，J＝5.1，1H)；2.18(br.s，2H)；2.05-1.63(m，8H)；1.35-1.20(m，2H)。IR(cm
-1，KBr)：3217(m)，2916(s)，2847(m)，1678(s)，1668(s)，1595(m)，1498(s)，1475(s)，1441(s)，1361(m)，1232(m)，1218(m)，1133(m)，1106(m)，1084(m)，1063(m)，937(w)，826(m)。MS(m/z)501.0([M+H]
+)。
Embodiment 175
N (7)-(2,4 dichloro benzene base amino)-5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 8 (100mg, 0.27mmol), DMF (1.0ml), Et
3N (82 μ l, 0.59mmol), bop reagent (123mg, 0.28mmol) and 2,4 dichloro benzene hydrazonium salt hydrochlorate (62mg 0.29mmol) obtains title compound (95mg, 67%).M.P：153-156℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.52(br.s，1H)；7.59(d，J＝1.8，1H)；7.42(dd，J＝8.1，1.8，1H)；7.36-7.24(m，2H)；7.12(dd，J＝8.7，2.4，1H)；6.97(d，J＝8.7，1H)；6.48(br.s，1H)；3.85(br.s，1H)；2.57(br.s，1H)；2.18(br.s，2H)；2.00-1.60(m，10H)。IR(cm
-1，KBr)：3307(m)，2920(s)，2905(s)；2848(m)，1682(s)，1495(s)，1469(s)，1388(m)，1353(m)，890(m)，864(m)。MS(m/z)：535.1([M+H]
+)。
Embodiment 176
N (7)-(2-bromophenyl amino)-5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 8 (100mg, 0.27mmol), DMF (1.0ml), Et
3N (82 μ l, 0.59mmol), bop reagent (123mg, 0.28mmol) and the 2 bromo phenyl hydrazine hydrochloride (62mg 0.29mmol) obtains title compound (70mg, 48%).M.P.：196-199℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.56(br.s，1H)；7.59(d，J＝1.8，1H)；7.45(br.t，J＝8.1，2H)；7.41(d，J＝8.1，1H)；7.19(t，J＝7.8，1H)；7.02(d，J＝7.8，1H)；6.75(t，J＝7.8，1H)；6.52(br.s，1H)；3.87(br.s，1H)；2.57(br.s，1H)；2.18(br.s，2H)；2.00-1.60(m，8H)；1.30-1.26(m，2H)。IR(cm
-1，KBr)：3216(m)，2915(s)，2847(m)，1685(s)，1595(m)，1566(m)，1497(s)，1441(m)，1387(m)，1352(m)，1263(m)，1232(m)，1218(m)，1129(m)，1105(m)，1085(m)，1062(m)，1019(m)，936(w)，889(w)，866(w)，825(m)。MS(m/z)：545.1([M+H]
+)。
Embodiment 177
N (7)-(N ', N '-diphenyl amino)-5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 8 (100mg, 0.27mmol), DMF (1.0ml), Et
3N (74 μ l, 0.53mmol), (123mg, 0.28mmol) and N, (141mg 0.64mmol) obtains title compound (85mg, 59%) to N-phenylbenzene hydrazonium salt hydrochlorate to bop reagent.M.p.：176-180℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.96(s，1H)；7.57(d，J＝2.1，1H)；7.40(dd，J＝8.4，2.1，1H)；7.35-7.21(m，9H)；7.01(br.t，J＝8.4，2H)；3.91(br.s，1H)，2.57(br.s，1H)；2.18(br.s，2H)；2.00-1.73(m，10H)。IR(cm
-1，KBr)：3392(m)，2915(m)，2881(m)，2845(m)，1686(s)，1590(m)，1493(s)，1462(m)，1386(m)，1354(m)，1340(m)，1311(m)，1292(m)，1273(m)，1204(m)，1150(m)，1102(m)，1088(m)，1076(w)，1028(w)，866(w)，822(w)。MS(m/z)：543.3([M+H]
+)。
Embodiment 178
N (7)-(2-phenylethyl)-5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 8 (100mg, 0.28mmol), DMF (1.0ml), Et
3N (41 μ l, 0.29mmol), bop reagent (123mg, 0.29mmol) and phenylethylamine (37 μ l 0.29mmol) obtain title compound (90mg, 71%).M.P.：63-66℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.56(d，J＝2.1，1H)；7.38(dd，J＝8.4，2.1，1H)；7.40-7.18(m，6H)；7.02(t，J＝7.2，1H)；3.97(br.s，1H)；3.61(q，J＝7.2，2H)；2.90(t，J＝8.1，2H)；2.54(br.s，1H)；2.18(br.s，2H)；2.00-1.65(m，10H)。IR(cm
-1，KBr)：3413(m)，2912(s)，2845(m)，1667(s)，1535(s)，1497(s)，1478(s)，1352(m)，1233(m)，1219(m)，1162(m)，1103(m)，1088(m)，996(m)，866(w)，699(m)。MS(m/z)：480.1([M+H]
+)。
Embodiment 179
N (7)-benzyl-5-(2 ', 4 '-dichlorophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide
With the intermediate 8 among the DMF (2ml) (100mg, solution 0.27mmol) at room temperature use bop reagent (123mg, 0.28mmol) and triethylamine (41 μ l, 0.29mmol) handled 15 minutes, (32 μ l 0.29mmol) add this mixture, and at room temperature stir 1 hour with benzylamine subsequently.Mixture is poured in the water, collected the precipitation that forms by filtering, dry also by the fast silica gel chromatogram purifying, obtain pure title compound (90mg, 73%).M.P.：65-66℃。
1H-NMR(δppm，CDCl
3)：7.54(d，J＝2.4，1H)；7.40-7.18(m，8H)；4.62(dd，J＝14.7，6.0，1H)；4.52(dd，J＝14.7，6.0，1H)；4.0(t，J＝5.4，1H)；2.53(br.s，1H)；2.18(br.s，2H)；1.05-2.10(m，10H)。IR(cm
-1，KBr)：3413(m)，2914(s)，2846(m)，1664(s)，1534(s)。
Embodiment 180
N (7)-piperidines-1-base-5-(2 ', 4 '-dichlorophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Use intermediate 8 (160mg, 0.42mmol), DMF (2ml), triethylamine (0.06ml, 0.41mmol), bop reagent (187mg, 0.42mmol) and 1-amino piperidine (0.05ml, 0.46mmol) synthetic by being similar to embodiment 101 described methods, obtain title compound (106mg, 52%).M.P.：101-104℃。
1H-NRM(δppm，CDCl
3)：7.58(br.s，1H)；7.56(d，J＝2.1，1H)；7.38(dd，J＝8.7，2.4，1H)；7.31(d，J＝8.7，1H)；3.96(br.t，J＝5.4，1H)；2.84(br.s，4H)；2.53(br.s，1H)；2.17(br.s，2H)；1.05-2.10(m，14H)；1.72-1.9(m，2H)。IR(cm
-1，KBr)：3413(m)，2914(s)，2846(m)，1664(s)，1534(s)。
Embodiment 181
N (7)-(2,4 dichloro benzene base amino)-5-(2-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 9 (100mg, 0.29mmol), DMF (1.0ml), Et
3N (45 μ l, 0.32mmol), bop reagent (136mg, 0.31mmol) and 2,4 dichloro benzene hydrazonium salt hydrochlorate (69mg 0.32mmol) obtains title compound (95mg, 65%).M.P：233-240℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.60(s，1H)；7.57(dd，J＝7.6，1.6，2H)；7.48(td，J＝8.8，2.4，1H)；7.47-7.37(m，2H)；7.29(d，J＝2.4，1H)；7.11(dd，J＝8.8，2.4，1H)；6.98(d，J＝8.8，1H)；3.87(br.t，J＝5.6，1H)；2.60(br.t，J＝5.6，1H)；2.20(br.s，2H)；2.10-1.60(m，10H)。IR(cm
-1，KBr)：3386(m)，3343(m)，2907(m)，2870(m)，2847(m)，1694(s)，1497(m)，1469(m)，1349(m)，1277(m)，1259(m)，1232(m)，1216(m)，1087(m)，1058(m)，1014(m)，859(m)。MS(m/z)：501.1([M+H]
+)。
Embodiment 182
N (7)-benzyl-5-(2-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide
Use intermediate 9 (100mg, 0.29mmol), DMF (2m1), triethylamine (46 μ l, 0.32mmol), bop reagent (136mg, 0.32mmol) and benzylamine (36 μ l, 0.32mmol) synthetic by being similar to embodiment 101 described methods, obtain title compound (83mg, 65%).M.P.：159-161℃。
1H-NMR(δppm，CDCl
3)：7.52(d，J＝7.5，1H)；7.47-7.24(m，8H)；4.62(dd，J＝15.0，6.0，1H)；4.51(dd，J＝15.0，6.0，1H)；4.01(br.s，1H)；2.55(br.s，1H)；2.18(br.s，2H)；210-1.54(m，10H)。IR(cm
-1，KBr)：3412(m)，3427(m)，2909(s)，2845(m)，1672(s)，1567(m)，1524(s)，1498(s)，1474(s)；1455(s)。
Embodiment 183
N (7)-cyclohexyl-5-(2-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide
Use intermediate 9 (100mg, 0.29mmol), DMF (2ml), triethylamine (45 μ l, 0.32mmol), bop reagent (136mg, 0.32mmol) and cyclo-hexylamine (37 μ l, 0.32mmol) synthetic by being similar to embodiment 101 described methods, obtain title compound (95mg, 77%).M.P.：218-220℃。
1H-NMR(δppm，CDCl
3)：7.55-7.52(m，1H)；7.42-7.35(m，3H)；6.80(br.d，J＝8.1，1H)；4.00(br.t，J＝5.4，1H)；3.97-3.83(m，1H)；2.54(br.s，1H)；2.17(br.s，2H)；1.99(br.s，6H)；1.92-1.52(m，8H)；1.55-1.05(m，6H)。IR(cm
-1，KBr)：3409(m)，2921(s)，2904(s)，2849(m)，1667(s)，1567(m)，1527(s)，1494(s)，1479(s)。
Embodiment 184
N (7)-piperidines-1-base-5-(2 '-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide
Use intermediate 9 (100mg, 0.29mmol), DMF (2ml), triethylamine (45 μ l, 0.32mmol), bop reagent (136mg, 0.32mmol) and 1-amino piperidine (35 μ l, 0.32mmol) synthetic by being similar to embodiment 101 described methods, obtain title compound (90mg, 72%).M.P.：251-254℃。
1H-NMR(δppm，CDCl
3)：7.62(br.s，1H)；7.54(d，J＝8.7，1H)；7.53-7.35(m，3H)；3.98(br.s，1H)；2.84(t，J＝4.8，4H)；2.54(br.s，1H)，2.17(br.s，2H)；1.98(t，J＝12.6，4H)；1.93-1.50(m，10H)；1.44-1.34(m，2H)。IR(cm
-1，KBr)：3314(m)，2905(s)，2844(m)，2804(m)，1686(s)，1567(m)，1525(s)，1492(s)，1480(s)。
Embodiment 185
N7-(2-benzyl chloride base)-5-(5-chloro-2-pyridyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 10 (100mg, 0.29mmol), DMF (1.0ml), Et
3N (40 μ l, 0.29mmol), bop reagent (128mg, 0.29mmol) and 2-chloro-benzylamine (31mg 0.29mmol) obtains title compound (64mg, 49%).M.P.：187-189℃。
1H-NMR(δppm，DMSO-d
6，300MHz)：8.81(t，J＝6.3，1H)，8.60(d，J＝2.6，1H)；8.19(dd，J＝8.6，2.6，1H)；7.96(d，8.6，1H)；7.46-7.42(m，1H)；7.38-7.27(m，3H)；4.48(d，J＝6.0，2H)；4.04(s，1H)；3.78(m，1H)；2.14(br.s，2H)；1.95-1.68(m，10H)。
Embodiment 186
N (7)-benzyl-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide:
Use intermediate 11 (100mg, 0.43mmol), DMF (1ml), triethylamine (0.06ml, 0.43mmol), bop reagent (190mg, 0.43mmol) and benzylamine (0.05ml, 0.43mmol) synthetic by being similar to embodiment 101 described methods, obtain title compound (96mg, 69%).M.P.：218-219℃。
1H-NMR(δppm，DMSO-d
6)：12.70(br.s，1H)；8.44(br.s，1H)；7.30(m，5H)；4.36(br.s，2H)；3.71(br.s，1H)；2.97(br.s，1H)；2.10(br.s，2H)；1.91(br.s，4H)；1.77(br.s，2H)；1.65(t，J＝13.2，10H)。IR(cm
-1，KBr)：3434(s)，2924(s)，2854(m)，1634(m)。
Embodiment 187
N (7)-piperidines-1-base-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide
With the intermediate 11 (160mg among the DMF (3ml), 0.68mmol) solution at room temperature use EPCI (198mg, 1.02mmol), HOBt (93mg, 0.68mmol), triethylamine (0.19ml, 1.36mmol), (0.081ml 0.68mmol) handled 16 hours for DMAP (8mg) and 1-amino piperidine.This mixture of dilute with water is used ethyl acetate extraction, passes through Na
2SO
4Drying, evaporation also obtains title compound (134mg, 63%) by the fast silica gel chromatogram purifying.M.P.：295-297℃。
1H-NMR(δppm，DMSO-d
6)：12.61(br.s，1H)；8.61(br.s，1H)；3.65(br.s，1H)；3.00(br.s，1H)；2.10(br.s，2H)；1.99-1.51(m，14H)；1.33(br.s，2H)。IR(cm
-1，KBr)：3314(m)，3199(s)，3155(m)；3085(m)，3003(m)，2907(s)，2843(s)，2805(m)，1653(s)，1590(m)，1543(m)，1509(m)。
Embodiment 188
6,7-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-5-diene-5-base-piperidines-1-base ketone
Use intermediate 11 (100mg, 0.43mmol), DMF (1ml), triethylamine (0.06ml, 0.43mmol), bop reagent (190mg, 0.43mmo1) and piperidines (43 μ l, 0.43mmol) synthetic by being similar to embodiment 101 described methods, obtain title compound (84mg, 66%).M.P.：263-264℃。
1H-NMR(δppm，CDCl
3)：3.57(br.s，4H)；3.05(br.s，1H)；2.92(br.s，1H)；2.17(br.s，2H)；2.10-1.50(m，16H)。IR(cm
-1，KBr)：3436(m)，3198(s)，3155(m)；2924(s)，2905(s)，2888(s)，1607(s)，1598(s)，1583(s)。
Embodiment 189a
N (7)-piperidines-1-base-6-methyl-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide
With ethanol: the KOH solution of the 0.27M in the water 4: 3 (3.5ml) joins intermediate 12a, and (123mg in solution 0.45mmol), and refluxed 3 hours.Mixture being concentrated into its initial volume approximately after half, with the HCl acidified aqueous solution of 1N, the solid of filtering-depositing, the dry DMF (3ml) that also is dissolved in.With solution at room temperature use DMAP (5mg), EPCI (100mg, 0.5mmol), HOBt (47mg, 0.35mmol), the 1-amino piperidine (39mg, 0.35mmol) and triethylamine (0.08ml 0.56mmol) handles 15 hours.The dilute with water mixture is used ethyl acetate extraction, passes through Na
2SO
4Dry and obtain title compound (48mg, 33%) by the fast silica gel chromatogram purifying.M.P.：188.9℃。
1H-NMR(δppm，DMSO-d
6)：6.27(br.s，1H)；3.88(s，3H)；3.06-2.92(m，2H)；2.87(t，J＝5.4，4H)；2.15(br.s，2H)；2.10-1.91(m，4H)；1.90-1.70(10H)；1.55-1.40(m，2H)。IR(cm
-1，KBr)：3440(br.，m)；3227(m)，2918(s)，2844(s)，1636(s)，1557(m)，1532(m)。
Embodiment 189b
N (7)-piperidines-1-base-5-methyl-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide
Use intermediate 12b (173mg, 0.63mmol), KOH solution, DMF (3ml), DMAP (8mg), the EPCI (167mg of ethanol (2ml), the 0.27M in alcohol-water 4: 3 (3.5ml), 0.87mmol), HOBt (78mg, 0.58mmol), 1-amino piperidine (58mg, 0.35mmol) and triethylamine (0.13ml, 0.93mmol) synthetic by the described method of embodiment 189a, produce pure title compound (148mg, 72%).M.P.：218.7℃。
1H-NMR(δppm，DMSO-d
6)：7.56(br.s，1H)；3.89(t，J＝5.4，1H)；3.74(s，3H)；2.97(t，J＝5.1，1H)；2.85(t，J＝5.1，4H)；2.162.00-1.88(m，4H)；1.90-1.66(10H)；1.47-1.36(m，2H)。
Embodiment 190a
N (7)-(1-methyl isophthalic acid-phenylethyl)-6-amyl group-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4,7-diene-7-methane amide
Title compound is synthetic by being similar to the described method of embodiment 189a.Use intermediate 13a (100mg, 0.33mmol), DMF (1.0ml), Et
3N (52 μ l, 0.36mmol), (160mg, 0.36mmol) and α, (53mg 0.39mmol) obtains title compound (100mg, 72%) to the alpha-alpha-dimethyl benzylamine to bop reagent.M.P.：66-69℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.46-7.40(m，2H)；7.58(t，J＝7.2，2H)；7.30-7.20(m，2H)；5.83(br.s，1H)；4.14(t，J＝7.8，2H)；3.11(br.t，J＝5.2，1H)；3.03(br.t，J＝5.2，1H)；2.15(br.s，1H)；2.08-1.94(m，4H)；1.79(s，6H)；1.80-1.70(m，6H)；1.32-1.20(m，4H)；0.87(t，J＝7.5，3H)。
Embodiment 190b
N (7)-(1-methyl isophthalic acid-phenylethyl)-5-amyl group-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide
Title compound is synthetic by being similar to the described method of embodiment 189b.Use intermediate 13b (100mg, 0.33mmol), DMF (1.0ml), Et
3N (52 μ l, 0.36mmol), (160mg, 0.36mmol) and α, (53mg 0.39mmol) obtains title compound (95mg, 68%) to the alpha-alpha-dimethyl benzylamine to bop reagent.M.p.：99-102℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.50-7.44(m，2H)；7.32(t，J＝7.2，2H)；7.24-7.16(m，2H)；3.97(t，J＝7.5，2H)；3.82(br.s，1H)；2.94(br.s，1H)；2.13(br.s，2H)；2.00-1.84(m，4H)；1.78(s，6H)；1.80-1.68(m，6H)；1.40-1.24(m，4H)；0.91(t，J＝7.2，3H)。
Embodiment 191
N (7)-[(1R)-2-hydroxyl-1-phenylethyl]-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
With LiBH
4(32mg, (290mg in solution 0662mmol), and refluxes mixture and spends the night 1.52mmol) to join embodiment 154 in THF (3ml).Behind the evaporating solvent,, and, use ethyl acetate extraction with 1N HCl acidifying with the oily residue diluted with water, with the organic layer that merges with the salt water washing and use Na
2SO
4Dry.Through FC (3:7AcOEt/ stone; Oil ether) purifying obtains title compound (150mg, 61%).M.P.：161-162℃。
1H-NMR(δppm，DMSO-d
6，300MHz)：8.24(d，J＝7.5，1H)；7.76-7.58(m，2H)；7.38-7.20(m，6H)；5.02-4.92(m，2H)，3.77(br.s，1H)；3.70-3.64(m，2H)；2.62(br.s，1H)；2.12(br.s，2H)；1.98-1.68(m，10H)。IR(cm
-1，KBr)：3403(m)，3007(w)，2916(s)，2848(m)，1656(s)，1612(w)，1519(s)，1483(m)，1443(m)，1368(m)，1353(m)，1273(m)，1225(m)1144(m)，1082(m)，966(m)，851(m)。MS(m/z)：452.17(M+H
+)。
Embodiment 192
N (7)-[(1S)-2-hydroxyl-1-phenylethyl]-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 191 described methods.Use embodiment 155 product (400mg, 0.81mmol), THF (5ml) and LiBH
4(35mg 1.62mmol) obtains title compound (130mg, 34%).M.P.：158-159℃。
1H-NMR(δppm，DMSO-d
6，300MHz)：8.24(d，J＝8.1，1H)；7.71(q，8.4，1H)；7.61(t，J＝8.4，1H)；7.38-7.20(m，6H)；5.00-4.94(m，2H)，3.78(br.s，1H)；3.72-3.64(m，2H)；2.62(br.s，1H)；2.11(br.s，2H)；2.00-1.65(m，10H)。MS(m/z)：452.17(M+H
+)。
Embodiment 201
N (3)-piperidines-1-base-1-phenyl-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 14 (100mg, 0.39mmol), DMF (1.0ml), Et
3N (66 μ l, 0.47mmol), bop reagent (191mg, 0.43mmol) and the 1-amino piperidine (42 μ l 0.39mmol) obtain title compound (45mg, 34%).M.P.：144℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.68(d，J＝7.8，2H)；7.68(br.s，1H)；7.48(t，J＝7.8，1H)；7.32(t，J＝7.8，1H)；3.75(br.s，1H)；3.70(br.s，1H)；2.91(br.s，4H)；2.11(br.d，J＝8.1，1H)；1.98(br.d，J＝9.3，2H)；1.80-1.50(m，5H)；1.45(br.s，2H)；1.24(br.d，J＝8.1，2H)。IR(KBr,cm
-1)：3302(m)，2987(m)，2940(s)，2856(m)，2790(m)，1686(s)，1597(m)，1537(s)，1513(s)，1489(s)，1444(m)，1339(m)，1270(m)，1225(m)，1140(m)，1127(m)，1075(w)，1036(w)，918(m)，893(m)，832(w)。MS(m/z)：337.1([M+H]
+)。
Embodiment 202
N (3)-cyclohexyl-1-phenyl-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 14 (100mg, 0.39mmol), DMF (1.0ml), Et
3N (66 μ l, 0.48mmol), bop reagent (191mg, 0.43mmol) and hexahydroaniline (45 μ l 0.39mmol) obtain title compound (99mg, 75%).M.P.：107℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.68(d，J＝8.1，2H)；7.48(t，J＝8.1，2H)；7.33(t，J＝7.8，1H)；6.80(br.d，J＝8.4，1H)；3.97-3.95(m，1H)；3.75(br.s，1H)；3.69(br.s，1H)；2.12(br.d，J＝8.7，1H)；2.11-1.90(m，4H)；1.79-1.65(m，4H)；1.48-1.15(m，7H)。IR(KBr，cm
-1)：3327(m)，2936(m)，2856(m)，1655(s)，1595(m)，1549(s)，1508(s)，1490(s)，1462(s)，1448(m)，1352(s)，1272(m)，1249(m)，1226(m)，1164(m)，1140(m)，1121(m)。MS(m/z)：336.1([M+H]
+)。
Embodiment 203
N (3)-benzyl-1-phenyl-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 14 (100mg, 0.39mmol), DMF (1.0ml), Et
3N (66 μ l, 0.48mmol), bop reagent (191mg, 0.43mmol) and benzyl amine (45 μ l 0.39mmol) obtain title compound (87mg, 65%).M.p.：115℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.66(d，J＝7.5，2H)；7.47(t，J＝7.8，2H)；7.40-7.26(m，7H)；4.64(d，J＝5.4，2H)，3.78(br.s，1H)；3.71(br.s，1H)；2.15(br.d，J＝8.4，1H)；2.00(br.d，J＝8.7，2H)；1.73(br.d，J＝8.4，1H)；1.30-1.14(m，2H)。IR(KBr,cm
-1)：3376(m)，2995(m)，2966(m)，2948(m)，2863(m)，1652(s)，1595(s)，1552(s)，1354(s)，1277(m)，1256(m)，1235(s)，1157(m)，1122(m)，1070(m)，988(m)。MS(m/z)：344.1([M+H]
+)。
Embodiment 204
N (3)-phenyl amino-1-phenyl-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 14 (100mg, 0.39mmol), DMF (1.0ml), Et
3N (66 μ l, 0.48mmol), bop reagent (191mg, 0.43mmol) and phenylhydrazine (38 μ 1 0.39mmol) obtain title compound (111mg, 82%).M.P.：189℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.59(br.s，1H)；7.71(d，J＝8.1，2H)；7.50(t，J＝8.1，2H)；7.35(t，J＝8.1，1H)；7.24(t，J＝7.8，2H)；6.96(d，J＝7.8，2H)；6.90(t，J＝7.8，1H)；3.73(br.s，2H)；2.14(br.d，J＝8.7，1H)；1.90-2.10(m，2H)；1.73(d，J＝8.4，1H)；1.31-1.14(m，2H)。IR(KBr，cm
-1)：3413(m)，3393(m)，3273(s)，2970(m)，2955(m)，2868(w)，1682(s)，1599(m)，1541(m)，1506(s)，1493(s)，1476(s)，1458(s)，1349(m)，1273(m)，1226(m)，1157(m)，1132(m)，1085(m)，1066(m)，895(m)。MS(m/z)：345.1([M+H]
+)。
Embodiment 205
N (3)-piperidines-1-base-1-(2-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 15 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (58 μ l, 0.42mmol), bop reagent (169mg, 0.38mmol) and the 1-amino piperidine (38 μ l 0.35mmol) obtain title compound (100mg, 78%).M.P.：232℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.60-7.47(m，3H)；7.42-7.35(m，2H)；3.76(br.s，1H)；3.37(br.s，1H)；2.80(br.s，4H)；2.13(br.d，J＝9.3，1H)；2.11-1.86(m，2H)；1.75-1.62(m，5H)；1.42-1.18(m，4H).IR(KBr,cm
-1)：3314(w)，2999(w)，2938(s)，2867(w)，2781(m)，1682(s)，1540(s)，1511(s)，1484(s)，1450(m)，1342(m)，1276(w)，1257(w)，1227(m)，1123(m)，1083(m)，1035(m)，987(m)，893(w)。MS(m/z)：371.1([M+H]
+)。
Embodiment 206
N (3)-cyclohexyl-1-(2-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 15 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (58 μ l, 0.42mmol), bop reagent (169mg, 0.38mmol) and hexahydroaniline (40 μ l 0.39mmol) obtain title compound (92mg, 72%).M.P.：171℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.50-7.45(m，2H)；7.45-7.35(m，2H)；6.73(br.d，J＝7.2，1H)；3.95-3.82(m，1H)；3.77(br.s，1H)；3.37(br.s，1H)；2.13(br.d，J＝9.3，1H)；2.11-1.86(m，4H)；1.70-1.66(m，4H)；1.42-1.18(m，7H)。IR(KBr,cm
-1)：3407(m)，3393(m)，2996(m)，2934(s)，2850(s)，1662(s)，1549(s)，1513(s)，1506(s)，1483(s)，1447(s)，1342(s)，1223(s)，1125(s)，1085(m)，965(m)，950(m)。MS(m/z)：370.1([M+H]
+)。
Embodiment 207
N (3)-benzyl-1-(2-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 15 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (58 μ l, 0.42mmol), bop reagent (169mg, 0.38mmol) and benzylamine (37 μ l 0.34mmol) obtain title compound (60mg, 46%).
1H-NMR(δppm，CDCl
3，300MHz)：7.55-7.15(m，10H)；4.60(br.s，2H)；3.79(br.s，1H)；3.38(br.s，1H)；2.16(br.d，J＝7.8，1H)；1.99-1.88(m，2H)；1.70(d，J＝8.7，1H)；1.31-1.20(m，2H)。IR(Neat，cm
-1)：3414(m)，2994(m)，2968(m)，2949(m)，1664(s)，1550(s)，1513(s)，1485(s)，1455(s)，1347(m)，1275(m)，1251(m)，1235(m)，1161(m)，1141(m)，1121(m)。MS(m/z)：378.1([M+H]
+)。
Embodiment 208
N (3)-phenyl amino-1-(2-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 15 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (58 μ l, 0.42mmol), bop reagent (169mg, 0.38mmol) and phenylhydrazine (34 μ l 0.34mmol) obtain title compound (105mg, 80%).M.P.：205℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.51(s，1H)；7.60-7.51(m，2H)；7.52-7.40(m，2H)；7.23(t，J＝7.8，2H)；6.95(d，J＝7.8，2H)；6.90(t，J＝7.5，1H)；3.74(br.s，1H)；3.41(br.s，1H)；2.15(br.d，J＝8.7，1H)；2.00-1.85(m，2H)；1.70(br.d，J＝8.7，1H)；1.32-1.20(m，2H)。IR(KBr，cm
-1)：3283(s)，2993(m)，2958(m)，1675(s)，1591(m)，1603(m)，1542(m)，1513(s)，1497(s)，1439(m)，1348(m)，1281(m)，1238(m)，1137(m)，1123(m)，1082(m)，1062(m)，889(m)。MS(m/z)：379.0([M+H]
+)。
Embodiment 209
N (3)-piperidines-1-base-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (48 μ l, 0.35mmol), bop reagent (152mg, 0.35mmol) and the 1-amino piperidine (37 μ l 0.35mmol) obtain title compound (68mg, 53%).MP：78-81℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.63(d，J＝8.7，2H)；7.44(d，J＝8.7，2H)；3.75(s，1H)；3.67(s，1H)；2.91(br.s，4H)；2.11(br.d，J＝8.7，1H)；2.00(br.d，J＝9.6，2H)；1.80-1.65(m，5H)；1.45(m，2H)；1.20(m，2H).IR(KBr,cm
-1)：3408(m)，2931(m)，2871(m)，2779(m)，1692(s)，1540(m)，1506(s)，1489(s)，1347(m)，1268(m)，1227(m)，1085(m)。MS(m/z)：371.2([M+H]
+)。
Embodiment 210
1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-phenylpiperidines-1-base ketone
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (54 μ l, 0.39mmol), bop reagent (160mg, 0.36mmol) and piperidines (38 μ l 0.38mmol) obtain title compound (80mg, 65%).M.P.：96-98℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.63(d，J＝8.7，2H)；7.41(d，J＝8.7，2H)；3.92-3.75(m，4H)，3.69(br.s，1H)，3.57(s，1H)，2.13(d，J＝6.9，1H)，1.97(d，J＝9.0，2H)，1.80-1.60(m，7H)，1.24(d，J＝8.7，2H)。IR(cm
-1，KBr)：2932(s)，2861(m)，1613(s)，1503(s)，1467(m)，1422(m)，1371(m)，1352(m)，1271(m)，1246(m)，1156(w)，1132(m)，1088(m)，825(m)。MS(m/z)：356.0([M+H]
+)。
Embodiment 211
N (3)-cyclohexyl-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (48 μ l, 0.35mmol), bop reagent (152mg, 0.35mmol) and hexahydroaniline (39 μ l 0.35mmol) obtain title compound (98mg, 77%).M.P.：155-158℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.64(d，J＝8.7，2H)；7.43(d，J＝8.7，2H)；6.76(br.d，J＝8.7，1H)；4.02-3.87(m，1H)；3.75(s，1H)；3.67(s，1H)；2.12(br.d，J＝8.1，1H)；2.10-1.90(m，4H)；1.80-1.57(m，4H)；1.48-1.18(m，7H)。IR(KBr，cm
-1)：3411(m)，2926(s)，2848(m)，1666(s)，1598(w)，1545(s)，1505(s)，1486(s)，1349(m)，1248(w)，1223(m)，1159(m)，1122(m)，1086(m)，829(m)，506(m)。MS(m/z)：370.3([M+H]
+)。
Embodiment 212
N (3)-cyclopentyl-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (54 μ l, 0.39mmol), bop reagent (160mg, 0.36mmol) and cyclopentyl amine (38 μ l 0.38mmol) obtain title compound (95mg, 77%).M.P.：176-178℃。
1H-NMR (δ ppm, CDCl
3, 300MHz): 7.63 (d, J=8.7,2H); 7.43 (d, J=8.7,2H); 6.81 (d, J=7.5,1H); 4.38 (sextet, J=7.5,1H); 3.76 (s, 1H), 3.66 (s, 1H), 2.20-1.90 (d, J=8.7,5H); 1.8-1.40 (m, 7H); 1.28-1.20 (m, 2H).IR(cm
-1，KBr)：3288(m)，2964(s)，2868(m)，1643(s)，1552(s)，1505(s)，1489(s)，1442(m)，1406(m)，1364(m)，1347(m)，1275(m)，1252(m)，1243(m)，1158(m)，1129(m)，1089(m)，1008(m)，836(m)。MS(m/z)：356.0([M+H]
+)。
Embodiment 213
N (3)-[(N-cyclohexyl-N-methyl) amino]-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (300mg, 1.039mmol), DMF (3ml), Et
3N (173 μ l, 1.25mmol), bop reagent (459mg, 1.039mmol) and N-methyl-N-cyclohexyl hydrazine (132mg 1.04mmol) obtains title compound (285mg, 69%).MP：62℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.63(d，J＝8.7，2H)；7.62(br.s，1H)；7.44(d，J＝9.0，2H)；3.77(s，1H)；3.67(s，1H)；2.73(br.s，3H)；2.13(br.d，J＝8.7，1H)；2.10-1.90(m，4H)；1.72(br.d，J＝8.7，1H)；1.80-1.15(m，11H)。IR(KBr，cm
-1)3258(m)，2930(s)，2854(s)，1678(s)，1596(m)，1544(s)，1501(s)，1447(s)，1350(s)，1274(m)，1233(m)，1159(m)，1121(m)，1090(s)，1051(m)，1006(m)，915(m)，866(m)，831(s)。MS(m/z)：399.1([M+H]
+)。
Embodiment 214
N (3)-phenyl-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (48 μ l, 0.35mmol), bop reagent (152mg, 0.35mmol) and aniline (31 μ l 0.35mmol) obtain title compound (80mg, 64%).M.P.：137-140℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.70(s，1H)；7.69(t，J＝9.9，4H)；7.48(d，J＝9.0，2H)；7.36(t，J＝7.9，2H)；7.12(t，J＝7.4，1H)；3.80(s，1H)；3.71(s，1H)；2.17(br.d，J＝9.0，1H)；2.10-1.95(m，2H)；1.76(br.d，J＝9.0，1H)；1.38-1.19(m，2H)。IR(KBr,cm
-1)：3283(m)，2933(w)，2865(w)，1663(s)，1597(s)，1542(s)，1500(s)，1433(m)，1350(m)，1240(m)，1089(m)，833(m)，759(m)，507(w)。MS(m/z)：364.3([M+H]
+)。
Embodiment 215
N (3)-(3-chloro-phenyl-)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (54 μ l, 0.38mmol), bop reagent (162mg, 0.37mmol) and the 3-chloroaniline (49mg 0.38mmol) obtains title compound (110mg, 78%).M.P.：158-161℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.71(br.s，1H)；7.87(t，J＝1.8，1H)；7.67(d，J＝8.7，2H)；7.54(br.d，J＝8.1，1H)；7.48(d，J＝8.7，2H)；7.28(t，J＝8.1，1H)；7.09(br.d，J＝8.1，1H)；3.80(br.s，1H)；3.71(br.s，1H)；2.17(br.d，J＝9.0，1H)；2.12-1.97(m，2H)；1.76(d，J＝8.7，1H)；1.32-1.20(m，2H)。IR(cm
-1，KBr)：3295(s)，3187(w)，3059(w)，2987(m)，2960(m)，2984(m)，2866(m)，1677(s)，1593(s)，1551(m)，1497(s)，1484(s)，1410(m)，1400(m)，1355(m)，1308(m)，1297(w)，1234(m)，1220(m)，1157(w)，1141(m)，1091(m)，1077(w)，1048(w)，1008(m)，997(m)875(m)，825(m)。MS(m/z)：398.2([M+H]
+)。
Embodiment 216
N (3)-(4-chloro-phenyl-)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (54 μ l, 0.39mmol), bop reagent (160mg, 0.36mmol) and the 4-chloroaniline (49mg 0.39mmol) obtains title compound (80mg, 58%).M.P.：182-184℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.69(s，1H)；7.67(d，J＝8.7，4H)；7.47(d，J＝8.7，2H)；7.32(d，J＝8.7，2H)；3.80(s，1H)，3.71(s，1H)，2.16(d，J＝8.7，1H)；2.03(d，J＝7.2，2H)；1.76(d，J＝8.7，1H)；1.26(d，J＝7.5，2H)。IR(cm
-1，KBr)：3306(m)，2989(w)，2971(w)，2945(m)，2868(w)，1673(s)，1660(s)，1594(s)，1545(s)，1498(s)，1407(s)，1397(m)，1310(m)，1284(m)，1240(m)，1089(s)，1008(m)，828(s)。MS(m/z)：398.0([M+H]
+)。
Embodiment 217
N (3)-(3-bromophenyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (54 μ l, 0.39mmol), bop reagent (160mg, 0.36mmol) and the 3-bromaniline (42 μ l 0.38mmol) obtain title compound (90mg, 59%).M.P.：176-178℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.69(s，1H)；8.00(d，J＝2.1，1H)；7.66(d，J＝7.5，2H)；7.61(br.d，J＝7.5，1H)；7.47(d，J＝7.5，2H)；7.25-7.17(m，2H)；3.80(s，1H)，3.71(s，1H)，2.16(d，J＝8.7，1H)；2.03(d，J＝7.8，2H)；1.76(d，J＝8.7，1H)；1.26(d，J＝7.2，2H)。IR(cm
-1，KBr)：3292(m)，2987(w)，2865(w)，1675(s)，1587(s)，1497(s)，1481(s)，1409(m)，1397(m)，1355(m)，1306(m)，1233(m)，1157(m)，1091(m)，874(w)，825。
Embodiment 218
N (3)-(2-p-methoxy-phenyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (48 μ l, 0.35mmol), bop reagent (153mg, 0.35mmol) and neighbour-methyl oxyaniline (39 μ l 0.35mmol) obtain title compound (100mg, 74%).M.P.：149-151℃。
1H-NMR(δppm，CDCl
3，300MHz)：9.32(br.s，1H)；8.54(dd，J＝8.1，2.1，1H)；7.69(d，J＝9.0，2H)；7.47(d，J＝9.0，2H)；7.10-7.02(m，2H)；6.92(dd，J＝7.8，1.5，1H)；3.94(s，3H)；3.81(br.s，1H)；3.71(br.s，1H)；2.17(d，J＝7.8，1H)；2.02(br.d，J＝8.4，2H)；1.76(d，J＝8.7，1H)；1.40-1.18(m，2H)。IR(KBr，cm
-1)：3380(m)，2873(w)，1684(s)，1601(m)，1541(s)，1499(s)，1479(s)，1461(s)，1349(m)，1247(m)，1219(m)，1118(m)，1089(m)，1044(m)，1027(m)，838(m)。MS(m/z)：394.2([M+H]
+)。
Embodiment 219
N (3)-(4-tert-butyl-phenyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (54 μ l, 0.39mmol), bop reagent (160mg, 0.36mmol) and 4-tertiary butyl aniline (62 μ l 0.38mmol) obtain title compound (100mg, 69%).M.P.：76-78℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.65(s，1H)；7.67(d，J＝8.7，2H)；7.63(d，J＝8.7，2H)；7.47(d，J＝8.7，2H)；7.37(d，J＝9.0，2H)；3.81(s，1H)，3.70(s，1H)，2.16(d，J＝9.0，1H)；2.02(d，J＝8.4，2H)；1.75(d，J＝9.0，1H)；1.33(s，9H)；1.40-1.20(m，2H)。IR(cm
-1，KBr)：2962(m)，2868(m)，1685(s)，1589(m)，1537(s)，1519(s)，1492(s)，1407(m)，1349(m)，1243(m)，1219(m)，1134(w)，1121(w)，1091(s)，1047(w)，1009(w)，830(s)。MS(m/z)：420.1([M+H]
+)。
Embodiment 220
N (3)-benzyl-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate
16 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (48 μ l, 0.35mmol), bop reagent (152mg, 0.35mmol) and benzylamine (37 μ l 0.35mmol) obtain title compound (67mg, 51%).MP：112-115℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.61(d，J＝9.0，2H)；7.45-7.20(m，8H)；4.63(br.d，J＝5.7，2H)；3.78(s，1H)；3.68(s，1H)；2.14(br.d，J＝8.5，1H)；2.05-1.90(m，2H)；1.73(bt.?d，J＝8.5，1H)；1.35-1.17(m，2H)。IR(KBr，cm
-1)：3318(m)，2995(m)，2930(m)，1652(s)，1548(s)，1501(s)，1352(m)，1275(m)，1239(m)，1120(m)，1089(m)，830(m)，701(w)，508(w)。MS(m/z)：378.3([M+H]
+)。
Embodiment 221
N (3)-(2-benzyl chloride base)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (48 μ l, 0.35mmol), bop reagent (152mg, 0.35mmol) and the 2-chlorobenzylamine (41 μ l 0.35mmol) obtain title compound (91mg, 64%).M.P.：119-122℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.63(d，J＝9.0，2H)；7.43(d，J＝9.0，2H)；7.51-7.20(m，5H)；4.72(d，J＝6.3，2H)；3.76(s，1H)；3.67(s，1H)；2.12(br?d，J＝8.6，1H)；2.10-1.90(m，2H)；1.73(br.d，J＝8.6，1H)；1.35-1.19(m，2H)。IR(KBr，cm
-1)：3319(m)，2955(m)，2868(m)，1651(s)，1595(m)，1547(m)，1490(s)，1442(m)，1352(m)，1277(m)，1237(m)，1160(m)，1123(m)，1091(m)，1007(m)，993(m)，835(m)。MS(m/z)：412.0([M+H]
+)。
Embodiment 222
N (3)-(4-benzyl chloride base)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (48 μ l, 0.35mmo1), bop reagent (152mg, 0.35mmol) and the 4-chlorobenzylamine (42 μ l 0.35mmol) obtain title compound (104mg, 73%).M.P.：157-160℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.61(d，J＝8.7，2H)；7.42(d，J＝8.7，2H)；7.31(s，4H)；7.23(br.s，1H)；4.59(d，J＝5.6，2H)；3.77(s，1H)；3.68(s，1H)；2.14(br.d，J＝8.6，1H)；2.10-1.90(m，2H)；1.73(br.d，J＝8.6，1H)；1.35-1.18(m，2H)。IR(KBr，cm
-1)：3324(m)，2979(m)，2951(m)，2875(m)，1649(s)，1560(s)，1513(s)，1444(m)，1406(m)，1354(m)，1244(m)，1160(m)，1144(m)，1092(s)，1007(m)，980(m)，946(m)，835(s)，626(m)，509(w)。MS(m/z)：412.0([M+H]
+)。
Embodiment 223
N (3)-(2, the 4-dichloro benzyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (48 μ l, 0.35mmol), (152mg, 0.35mmol) and 2, (46 μ l 0.35mmol) obtain title compound (104mg, 67%) to the 4-dichloro-benzylamine to bop reagent.MP：108-111℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.62(d，J＝8.7，2H)；7.50-7.30(m，4H)；7.34(br.s，1H)；4.70(d，J＝6.3，2H)；3.75(s，1H)；3.68(s，1H)；2.13(br.d，J＝9.0，1H)；2.10-1.90(m，2H)；1.73(br?d，J＝9.0，1H)；1.40-1.18(m，2H)。IR(KBr，cm
-1)：3294(m)，2988(w)，2949(w)，1652(s)，1554(m)，1502(s)，1491(s)，1356(m)，1252(m)，1092(m)，831(s)。MS(m/z)：447.9([M+H]
+)。
Embodiment 224
N (3)-(2-bromobenzyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (0.10ml, 0.69mmol), bop reagent (0.153g, 0.35mmol) and 2-bretylium hydrochloride (77mg 0.35mmol) obtains title compound (105mg, 67%).M.P.：141-142℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.60-7.50(m，3H)；7.50-7.22(m，5H)；7.14(td，J＝7.8，1.5，1H)；4.70(d，J＝6.3，2H)；3.80(s，1H)；3.70(s，1H)；2.14(br.d，J＝8.7，1H)；2.10-1.80(m，2H)；1.70(br.d，J＝8.7，1H)；1.35-1.15(m，2H)。IR(KBr，cm
-1)：3322(m)，2954(w)，2867(w)，1651(s)，1548(m)，1503(s)，1350(m)，1277(w)，1236(w)，1091(s)，835(m)。MS(m/z)：458.1([M+H]
+)。
Embodiment 225
N (3)-(4-bromobenzyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (0.096ml, 0.69mmol), bop reagent (0.153 the gram, 0.35mmol) and 4-bretylium hydrochloride (77mg 0.35mmol) obtains title compound (118mg, 64%).M.P.：181-183℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.60(d，J＝6.9，2H)；7.50-7.40(m，4H)；7.30-7.20(m，2H)；4.60(br.d，J＝5.1，2H)；3.80(s，1H)；3.70(s，1H)；2.14(br.d，J＝9.0，1H)；2.07-1.92(m，2H)；1.70(br.d，J＝9.0，1H)；1.30-1.15(m，2H)。IR(KBr,cm
-1)：3325(m)，2979(m)，2950(m)，1648(s)，1558(m)，1505(s)，1489(s)，1353(m)，1253(m)，1092(m)，835(s)。MS(m/z)：458.0([M+H]
+)。
Embodiment 226
N (3)-(4-luorobenzyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (48 μ l, 0.35mmol), bop reagent (152mg, 0.35mmol) and the 4-flunamine (39 μ l 0.35mmol) obtain title compound (95mg, 69%).M.P.：104-107℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.61(d，J＝9.0，2H)；7.42(d，J＝9.0，2H)；7.35(dd，J＝8.6，5.7，2H)；7.21(br.s，1H)；7.02(t，J＝8.6，2H)；4.59(d，J＝6.0，2H)；3.77(s，1H)；3.68(s，1H)；2.13(br.d，J＝8.7，1H)；2.10-1.90(m，2H)；1.73(br.d，J＝9.0，1H)；1.40-1.18(m，2H)。IR(KBr.cm
-1)：3314(m)，2968(m)，2940(m)，2872(w)，1647(s)，1554(m)，1509(s)，1357(m)，1218(m)，1091(s)，832(s)，626(w)，564(w)。MS(m/z)：396.1([M+H]
+)。
Embodiment 227
N (3)-(4-trifluoromethyl benzyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (48 μ l, 0.35mmol), bop reagent (152mg, 0.35mmol) and the 4-trifluoromethyl benzylamine (49 μ l 0.35mmol) obtain title compound (104mg, 68%).M.P.：165-168℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.67-7.57(m，4H)；7.48(d，J＝8.7，2H)；7.43(d，J＝8.7，2H)；7.30(br.t，J＝6.0，1H)；4.68(d，J＝5.7，2H)；3.77(s，1H)；3.69(s，1H)；2.13(br.d，J＝8.4，1H)；2.10-1.90(m，2H)；1.73(br.d，J＝7.2，1H)；1.30-1.18(m，2H)。IR(KBr，cm
-1)：3323(m)，2969(m)，2953(m)，2874(w)，1648(s)，1557(m)，1504(s)，1439(m)，1406(m)，1417(m)，1325(s)，1282(m)，1245(m)，1161(s)，1122(s)，1110(s)，1092(s)，1064(s)，847(m)，832(m)，625(w)，509(w)。MS(m/z)：446.0([M+H]
+)。
Embodiment 228
N (3)-phenyl amino-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (48 μ l, 0.35mmol), bop reagent (152mg, 0.35mmol) and phenylhydrazine (34 μ l 0.35mmo1) obtain title compound (92mg, 70%).MP：138-141℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.55(s，1H)；7.67(d，J＝8.5，2H)；7.46(d，J＝8.5，2H)；7.24(t，J＝7.5，2H)；6.95(d，J＝8.4，2H)；6.90(t，J＝7.5)；3.71(br.s，2H)；2.13(br.d，J＝8.1，1H)；2.10-1.95(m，2H)；1.73(br.d，J＝8.7，1H)；1.40-1.18(m，2H)。IR(KBr,cm
-1)：3258(m)，2951(m)，1660(s)，1603(s)，1500(s)，1358(m)，1306(m)，1277(m)，1127(m)，1092(s)，892(w)，828(m)，749(m)，691(m)，510(m)。MS(m/z)：379.0([M+H]
+)。
Embodiment 229
N (3)-[(4-chloro-phenyl-) amino]-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (48 μ l, 0.35mmol), bop reagent (152mg, 0.35mmol) and 4-chlorophenyl hydrazine hydrochloride (61mg 0.35mmol) obtains title compound (98mg, 69%).M.P.：202-205℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.60(s，1H)；7.66(d，J＝9.0，2H)；7.47(d，J＝9.0，2H)；7.18(d，J＝8.6，2H)；6.87(d，J＝8.6，2H)；3.71(s，2H)；2.13(br.d，J＝8.7，1H)；2.10-1.90(m，2H)；1.73(br.d，J＝9.0，1H)；1.38-1.18(m，2H)。IR(KBr，cm
-1)：3256(m)，2995(m)，2950(m)，2870(m)，1661(s)，1595(m)，1500(s)，1357(m)，1278(m)，1236(m)，1128(m)，1092(s)，894(w)，826(m)，658(w)，610(w)，503(w)。MS(m/z)：413.0([M+H]
+)。
Embodiment 230
N (3)-[(2,4 dichloro benzene base) amino]-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (100mg, 0.35mmol), DMF (1.0ml), Et
3N (57 μ l, 0.42mmol), bop reagent (152mg, 0.35mmol) and 2,4 dichloro benzene hydrazonium salt hydrochlorate (73mg 0.35mmol) obtains title compound (53mg, 34%).M.P.＝180-182℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.54(d，J＝3.0，1H)；7.66(d，J＝8.7，2H)；7.47(d，J＝8.7，2H)；7.31(d，J＝2.1，1H)；7.11(dd，J＝8.7，2.1，1H)；6.96(d，J＝8.7，1H)；6.51(d，J＝3.0，1H)；3.71(br.s，2H)；2.13(br.d，J＝7.8，1H)；2.0(m，2H)；1.74(br.d，J＝9.0，1H)；1.232-1.25(m，2H)。IR(KBr,cm
-1)：3301(m)，2993(m)，2873(m)，1674(s)，1595(w)，1542(m)，1499(s)，1352(m)，1304(m)，1232(m)，1021(m)，1049(m)，814(m)。
Embodiment 231
N (3)-[(3, the 4-dichlorophenyl) amino]-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (200mg, 0.69mmol), DMF (2.0ml), Et
3N (0.193ml, 1.38mmol), (306mg, 0.69mmol) and 3, (148mg 0.69mmol) obtains title compound (222mg, 64.5%) to the 4-dichloride phenyl hydrazine hydrochloric acid salt to bop reagent.M.P.：235-237℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.50(s，1H)；7.67(d，J＝9.0，2H)；7.48(d，J＝9.0，2H)；7.28(d，J＝8.4，1H)；7.05(d，J＝2.4，1H)；6.79(dd，J＝8.4，2.4，1H)；6.19(br.s，1H)；3.70(s，2H)；2.14(br.d，J＝8.5，1H)；2.10-1.90(m，2H)；1.7(br.d，J＝8.5，1H)；1.30-1.18(m，2H)。IR(KBr，cm
-1)：3250(m)，2995(w)，2968(w)，2946(w)，2869(m)，1667(s)，1650(s)，1598(m)，1500(s)，1475(s)，1353(m)，1277(m)，1092(m)，828(m)，610(w)。MS(m/z)：449.0([M+H]
+)。
Embodiment 232
N (3)-[(2-fluorophenyl) amino]-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (200mg, 0.69mmol), DMF (2.0ml), Et
3N (0.193ml, 1.38mmol), bop reagent (306mg, 0.69mmol) and the 2-fluorophenyl hydrazine hydrochloride (113mg 0.69mmol) obtains title compound (240mg, 87%).M.P.：91℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.50(s，1H)；7.65(d，J＝7.2，2H)；7.46(d，J＝7.2，2H)；6.95-7.10(m，3H)；6.80-6.90(m，1H)；6.40(br.s，1H)；3.70(br.s，2H)；2.14(br.d，J＝9.0，1H)；2.05-1.90(m，2H)；1.70(br.d，J＝9.0，1H)；1.30-1.17(m，2H)。IR(KBr，cm
-1)：3292(m)，2925(m)，2870(m)，1676(s)，1502(s)，1351(m)，1276(m)，1194(m)，1091(s)，831(s)。MS(m/z)：397.0([M+H]
+)。
Embodiment 233
N (3)-[(3-fluorophenyl) amino]-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (200mg, 0.69mmol), DMF (2.0ml), Et
3N (0.193ml, 1.38mmol), bop reagent (306mg, 0.69mmol) and the 3-fluorophenyl hydrazine hydrochloride (113mg 0.69mmol) obtains title compound (158mg, 58%).M.P.：199℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.50(s，1H)，7.70(d，J＝9.0，2H)；7.50(d，J＝9.0，2H)；7.30-7.10(m，1H)；6.70-6.50(m，3H)；6.20(br.s，1H)；3.70(s，2H)；2.14(br.d，J＝9.0，1H)；2.10-1.90(m，2H)；1.73(br.d，J＝9.0，1H)；1.35-1.18(m，2H)。IR(KBr,cm
-1)：3257(m)，2952(w)，2872(w)，1663(s)，1619(m)，1597(m)，1501(s)，1358(m)，1266(m)，1092(m)，827(m)。MS(m/z)：397.1([M+H]
+)。
Embodiment 234
N (3)-[(4-fluorophenyl) amino]-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (200mg, 0.69mmol), DMF (2.0ml), Et
3N (0.193ml, 1.38mmol), bop reagent (306mg, 0.69mmol) and the 4-fluorophenyl hydrazine hydrochloride (113mg 0.69mmol) obtains title compound (179mg, 65%).M.P.：212℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.50(s，1H)；7.70(d，J＝9.0，2H)；7.50(d，J＝9.0，2H)；7.00-6.80(m，4H)；3.70(s，2H)；2.14(br.d，J＝9.0，1H)；2.07-1.90(m，2H)；1.73(br.d，J＝9.0，1H)；1.35-1.18(m，2H)。IR(KBr，cm
-1)：3268(m)，2986(w)，2950(w)，1663(m)，1502(s)，1359(m)，1214(w)，1092(m)，827(m)，504(w)。MS(m/z)：397.0([M+H]
+)。
Embodiment 235
N (3)-[(2,4 difluorobenzene base) amino]-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (200mg, 0.69mmol), DMF (2.0ml), Et
3N (0.19ml, 1.38mmol), (306mg, 0.69mmol) and 2, (113mg 0.69mmol) obtains title compound (160mg, 56%) to 4--difluorophenyl hydrazine hydrochloride to bop reagent.M.P.：118-120℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.50(br.s，1H)；7.70(d，J＝8.7，2H)；7.50(d，J＝8.7，2H)；7.10-6.70(m，3H)；6.25(br.s，1H)；3.70(s，2H)；2.14(br.d，J＝8.7，1H)；2.08-1.95(m，2H)；1.70(br.d，J＝8.7，1H)；1.35-1.20(m，2H)。IR(KBr，cm
-1)：3422(m)，3286(m)，2925(m)，2871(w)，1666(m)，1501(s)，1093(m)，961(m)，831(m)。MS(m/z)：417.1([M+H]
+)。
Embodiment 236
N (3)-(N ', N '-diphenyl amino-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (200mg, 0.69mm ol), DMF (2.0ml), Et
3N (0.19ml, 1.38mmol), (306mg, 0.69mmol) and N, (113mg 0.69mmol) obtains title compound (250mg, 79.4%) to N-phenylbenzene hydrazonium salt hydrochlorate to bop reagent.M.P.：193-195℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.98(s，1H)；7.66(d，J＝9.0，2H)；7.45(d，J＝9.0，2H)；7.40-7.20(m，8H)；7.00(m，2H)；3.74(br.s，1H)；3.71(br.s，1H)；2.14(br.d，J＝8.7，1H)；2.05-1.95(m，2H)；1.70(br.d，J＝8.7，1H)；1.30-1.18(m，2H)。IR(KBr，cm
-1)：3232(w)，2924(m)，1664(m)，1590(m)，1497(s)，1357(m)，1223(m)，1092(m)，828(w)。MS(m/z)：455.0([M+H]
+)。
Embodiment 237
N (3)-cyclohexyl-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (43 μ l, 0.31mmol), bop reagent (136mg, 0.31mmol) and hexahydroaniline (33 μ l 0.31mmol) obtain title compound (104mg, 83%).M.P.：157-160℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.55(s，1H)；7.46(d，J＝8.0，1H)；7.37(d，J＝8.0，1H)；6.70(br.d，J＝8.1，1H)；4.05-3.85(m，1H)；3.75(br.s，1H)；3.36(br.s，1H)；2.13(d，J＝8.1，1H)；2.00-1.85(m，4H)；1.70-1.58(m，4H)；1.46-1.15(m，7H)。IR(KBr,cm
-1)：3398(m)，2923(m)，2850(m)，1658(s)，1543(s)，1520(s)，1485(m)，1343(m)，1249(m)，1122(m)，1105(m)，836(m)。
Embodiment 238
N (3)-cyclohexyl methyl-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (51 μ l, 0.37mmol), bop reagent (136mg, 0.31mmol) and the hexanaphthene methylamine (40 μ l 0.31mmol) obtain title compound (90mg, 69%).M.P.：111-113℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.56(br.s，1H)；7.45(d，J＝8.7，1H)；7.39(br.d，J＝8.7，1H)；6.88(br.t，J＝6.3，1H)：3.77(br.s，1H)；3.36(br.s，1H)；3.32-3.18(m，2H)；2.13(br.d，J＝8.6，1H)；2.00-1.50(m，9H)；1.25-1.11(m，5H)；1.00-0.80(m，2H)。IR(KBr，cm
-1)：3291(m)，2922(s)，2948(m)，1643(s)，1553(m)，1501(s)，1486(s)，1445(m)，1351(m)，1274(m)，1241(m)，1107(m)，1074(m)，869(m)，831(m)，800(m)，623(m)。MS(m/z)：418.1([M+H]
+)。
Embodiment 239
N (3)-(N, N-dicyclohexyl amino)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (51 μ l, 0.37mmol), (136mg, 0.31mmol) and N, (121mg 0.31mmol) obtains title compound (70mg, 45%) to N-dicyclohexyl hydrazine to bop reagent.M.P.：127-130℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.56(d，J＝2.1，1H)；7.48(d，J＝8.7，1H)；7.35(dd，J＝8.7，2.1，1H)；7.33(br.s，1H)；3.78(s，1H)；3.37(s，1H)；2.84(br.s，2H)；2.12(br.d，J＝8.4，1H)；1.97-1.80(m，6H)；1.80-1.58(m，6H)；1.40-1.00(m，13H)。IR(KBr,cm
-1)：3328(m)，2932(s)，2854(s)，1693(s)，1537(m)，1501(m)，1482(m)，1345(m)，1229(m)，1102(m)，1079(m)，867(m)，837(m)。MS(m/z)：501.50([M+H]
+)。
Embodiment 240
N (3)-(4H-1,2,4-triazole-4-yl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (42 μ l, 0.31mmol), (136mg, 0.31mmol) and 4-amino-1,2, (26mg 0.31mmol) obtains title compound (38mg, 32%) to the 4-triazole to bop reagent.M.P.：231-233℃。
1H-NMR(δppm，DMSO-d
6，300MHz)：11.95(s，1H)；8.72(s，2H)；8.0(d，J＝2.1，1H)；7.71(d，J＝8.4，1H)；7.67(dd，J＝8.4，2.1，1H)；3.58(br.s，1H)；3.41(s，1H)；2.05(br.d，J＝8.7，1H)；1.98-1.90(m，2H)；1.71(d，J＝8.7，1H)；1.24-1.08(m，2H)。IR(KBr,cm
-1)：3125(w)，3090(m)，2997(m)，2876(m)，1699(s)，1506(s)，1350(m)，1129(m)，1065(s)，923(w)，826(w)。MS(m/z)：389.3([M+H]
+)。
Embodiment 241
N (3)-(1,3,3-trimethylammonium two ring [2.2.1] heptan-2-yl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (51 μ l, 0.37mmol), bop reagent (136mg, 0.31mmol) and (1S)-2 interior-amino-1,3,3-trimethylammonium two ring [2.2.1] heptane [according to people such as Suchocki at J.Med.Chem.1991,34, be prepared (46mg described in the 1003-1010,0.34mmol)] obtain title compound (76mg, 54%).M.P.：156-159℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.56(d，J＝2.1，1H)；7.47(d，J＝8.4，1H)；7.38(dd，J＝8.4，2.1，1H)；6.91(br.d，J＝8.4，1H)；3.76(br.s，2H)；3.38(br.s，1H)；2.12(br.d，J＝7.5，1H)；2.00-1.84(m，2H)；1.80-1.58(m，4H)；1.02(m，12H)；0.85(s，3H)。IR(KBr，cm
-1)：3420(m)，2954(s)，2869(m)，1677(s)，1538(s)，1483(s)，1386(m)，1229(m)，1161(m)，1113(m)，1078(s)，823(w)，798(w)。MS(m/z)：458.10([M+H]
+)。
Embodiment 242
N (3)-(diamantane-1-yl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (0.51 μ l, 0.37mmol), bop reagent (136mg, 0.31mmol) and the 1-adamantanamines (46mg 0.31mmol) obtains title compound (108mg, 76%).M.P.：201-204℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.55(d，J＝1.8，1H)；7.45(d，J＝8.4，2H)；7.37(dd，J＝8.4，1.8，1H)；6.60(br.s，1H)；3.75(br.s，1H)；3.35(br.s，1H)；2.13(br.s，10H)；2.02-1.80(m，2H)；1.70(br.s，7H)；1.40-1.13(m，2H)。IR(cm
-1，KBr)：3400(s)，2907(s)，2851(m)，1667(s)，1542(s)，1516(s)，1483(s)，1452(m)，1359(m)，1289(w)，1230(m)，1105(m)，862(w)，832(m)。MS(m/z)：456.3([M+H]
+)。
Embodiment 243
N (3)-phenyl-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (42 μ 1,0.30mmol), bop reagent (121mg, 0.31mmol) and aniline (28 μ l 0.31mmol) obtain title compound (90mg, 71%).M.P.：66-68℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.63(br.s，1H)；7.68(d，J＝8.1，2H)；7.59(d，J＝2.1，1H)；7.49(d，J＝8.4，1H)；7.41(dd，J＝8.4，2.1，1H)；7.34(t，J＝8.1，2H)；7.11(t，J＝7.5，1H)；3.81(br.s，1H)；3.39(br.s，1H)；2.16(br.d，J＝9.0，1H)；2.05-1.86(m，2H)；1.73(d，J＝8.7，1H)；1.35-1.15(m，2H)。IR(KBr，cm
-1)：3382(m)，2948(m)，2869(m)，1681(s)，1596(s)，1542(s)，1500(s)，1434(s)，1380(m)，1347(m)，1321(m)，1282(m)，1237(m)，1218(m)，1159(m)，1096(m)，1077(m)，810(m)。MS(m/z)：398.1([M+H]
+)。
Embodiment 244
N (3)-(2,4 difluorobenzene base)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (57 μ l, 0.37mmol), bop reagent (136mg, 0.31mmol) and 2,4 difluorobenzene amine (31 μ l 0.31mmol) obtain title compound (62mg, 46%).M.P.：152-155℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.79(br.s，1H)；8.50-8.40(m，1H)；7.59(d，J＝2.1，1H)；7.48(d，J＝8.4，1H)；7.41(dd，J＝8.4，2.1，1H)；6.95-6.82(m，2H)；3.79(br.s，1H)；3.40(br.s，1H)；2.17(br.d，J＝8.7，1H)；2.10-1.90(m，2H)；1.73(d，J＝8.7，1H)；1.35-1.15(m，2H)。IR(KBr,cm
-1)：3389(s)，2993(m)，2874(m)，1685(s)，1543(s)，1505(s)，1428(m)，1345(m)，1123(m)，1102(m)，1085(m)，961(w)，852(w)，619(w)。MS(m/z)：434.0([M+H]
+)。
Embodiment 245
N (3)-(2-luorobenzyl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (51 μ l, 0.37mmol), bop reagent (136mg, 0.31mmol) and the 2-flunamine (35 μ l 0.31mmol) obtain title compound (55mg, 41%).M.P.:54 ℃ (fusion).
1H-NMR(δppm，CDCl
3，300MHz)：7.55(br.s，1H)；7.50-7.30(m，3H)；7.28-7.20(m，2H)；7.15-7.00(m，2H)；4.65(br.d，J＝5.1，2H)；3.77(br.s，1H)；3.37(br.s，1H)；2.12(br.d，J＝7.5，1H)；1.99-1.84(m，2H)；1.69(br.d，J＝8.4，1H)；1.28-1.15(m，2H)。IR(KBr，cm
-1)：3419(m)，2950(m)，2874(m)，1668(s)，1548(s)，1487(s)，1455(s)，1346(m)，1275(m)，1229(s)，1107(s)，832(m)。MS(m/z)：430.10([M+H]
+)。
Embodiment 246
N (3)-(4-luorobenzyl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (43 μ l, 0.31mmol), bop reagent (136mg, 0.31mmol) and the 4-flunamine (35 μ l 0.31mmol) obtain title compound (90mg, 68%).M.P.：106-108℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.55(d，J＝2.1，1H)；7.41(d，J＝8.4，1H)；7.39-7.25(m，3H)；7.15(br.t，J＝6.6，1H)；7.00(t，J＝8.7，2H)；4.54(dd，J＝17.0，6.6，1H)；4.59(dd，J＝17.0，6.6，1H)；3.77(br.s，1H)；3.36(br.s，1H)；2.12(br.d，J＝9.0，1H)；2.10-1.82(m，2H)；1.70(br.d，J＝9.0，1H)；1.32-1.10(m，2H)。IR(KBr,cm
-1)：3277(m)，2951(m)，2979(m)，2871(m)，1648(s)，1551(m)，1510(s)，1350(m)，1273(m)，1223(s)，1108(m)，1076(w)，833(m)。MS(m/z)：432.1([M+H]
+)。
Embodiment 247
N (3)-(2, the 4-difluorobenzyl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (51 μ l, 0.37mmol), (136mg, 0.31mmol) and 2, (36 μ l 0.31mmol) obtain title compound (93mg, 67%) to 4-two flunamines to bop reagent.M.P.：73-76℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.55(d，J＝1.8，1H)；7.40(m，3H)；7.20(br.s，1H)；6.90-6.75(m，2H)；4.50-4.70(m，2H)；3.77(br.s，1H)；3.36(br.s，1H)；2.12(br.d，J＝8.7，1H)；2.02-1.86(m，2H)；1.69(d，J＝8.7，1H)；1.14(br.d，J＝9.0，2H)。IR(KBr，cm
-1)：3421(w)，3283(m)，2996(m)，2926(w)，1648(s)，1552(m)，1505(s)，1487(s)，1455(s)，1280(m)，1138(m)，1117(m)，1098(m)，832(m)，964(w)，851(w)，832(w)。MS(m/z)：448.10([M+H]
+)。
Embodiment 248
N (3)-(2, the 6-difluorobenzyl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (0.51 μ l, 0.37mmol), (136mg, 0.31mmol) and 2, (36mg 0.31mmol) obtains title compound (74mg, 53%) to 6-two flunamines to bop reagent.M.P.：130-133℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.50-7.33(m，2H)；7.29-7.06(m，2H)；6.94-6.82(m，2H)；4.78-4.61(m，2H)；3.78(br.s，1H)；3.35(br.s，1H)；2.10(br.d，J＝8.7，1H)；2.04-1.81(m，2H)；1.68(d，J＝8.7，1H)；1.38-1.10(m，2H)。IR(cm
-1，KBr)：3305(m)，2988(w)，2971(w)，2945(w)，2868(w)，1672(s)，1660(s)，1593(s)，1545(s)，1498(s)，1406(m)，1397(m)，1355(m)，1310(w)，1240(m)，1218(w)，1120(w)，1189(s)，1048(w)，1008(w)，829(s)。MS(m/z)：448.1([M+H]
+)。
Embodiment 249
N (3)-(2-benzyl chloride base)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate
17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (43 μ l, 0.31mmol), bop reagent (136mg, 0.31mmol) and the 2-chlorobenzylamine (37 μ l 0.31mmol) obtain title compound (102mg, 74%).M.P.：117-120℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.55(d，J＝2.4，1H)；7.50-7.30(m，4H)；7.30-7.16(m，3H)；4.67(dd，J＝17，6.3，1H)；4.72(dd，J＝17.0，6.3，1H)；3.77(br.s，1H)；3.36(br.s，1H)；2.12(br.d，J＝8.6，1H)；2.00-1.86(m，2H)；1.68(br.d，J＝8.6，1H)；1.31-1.13(m，2H)。IR(KBr，cm
-1)：3309(m)，2998(m)，2968(m)，2951(m)，2925(m)，2869(m)，1640(s)，1564(s)，1504(s)，1487(s)，1442(m)，1346(m)，1281(m)，1241(m)，1110(m)，1056(m)，870(m)，832(m)。MS(m/z)：448.1([M+H]
+)。
Embodiment 250
N (3)-(4-benzyl chloride base)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (43 μ l, 0.31mmol), bop reagent (136mg, 0.31mmol) and the 4-chlorobenzylamine (37 μ l 0.31mmol) obtain title compound (108mg, 78%).M.P.：139-142℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.56(d，J＝2.2，1H)；7.42(d，8.4，1H)；7.36(dd，J＝8.4，2.2，1H)；7.29(s，4H)；7.16(br.t，J＝5.1，1H)；4.65-4.47(m，2H)；3.77(br.s，1H)；3.36(br.s，1H)；2.12(br.d，J＝8.6，1H)；2.0-1.85(m，2H)；1.70(br.d，J＝8.6，1H)；1.32-1.15(m，2H)。IR(KBr,cm
-1)：3290(m)，2934(m)，2869(m)，1652(s)，1553(s)，1489(s)，1436(m)，1351(m)，1276(m)，1249(m)，1142(m)，1076(m)，851(m)，799(m)，707(m)，654(m)，623(m)。MS(m/z)：448.2([M+H]
+)。
Embodiment 251
N (3)-(2, the 4-dichloro benzyl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (43 μ l, 0.31mmol), (136mg, 0.31mmol) and 2, (41 μ l 0.31mmol) obtain title compound (118mg, 79%) to the 4-dichloro-benzylamine to bop reagent.M.P.：57-59℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.56(s，1H)；7.45-7.37(m，4H)；7.27-7.20(m，3H)；4.60(br.d，J＝4.8，2H)；3.76(s，1H)；3.37(s，1H)；2.12(br.d，J＝8.4，1H)；2.05-1.86(m，2H)；1.71-1.65(br.d，J＝8.4，1H)；1.26-1.13(m，2H)。IR(KBr，cm
-1)：3337(m)，2948(m)，2870(m)，1737(m)，1666(s)，1545(s)，1483(s)，1381(m)，1347(m)，1236(s)，1104(s)，1078(m)，1046(m)，865(m)，832(s)。MS(m/z)：482.3([M+H]
+)。
Embodiment 252
N (3)-[S-(1-phenylethyl)]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (51 μ 1,0.37mmol), bop reagent (136mg, 0.31mmol) and S-(-)-1-phenyl ethyl amine (39 μ l 0.31mmol) obtain title compound (74mg, 66%).M.P.：91-94℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.56(d，J＝2.1，1H)；7.47-7.20(m，7H)；7.08(d，J＝7.5，1H)；5.38-5.22(m，1H)；3.75(br.s，1H)；3.35(br.s，1H)；2.11(br.t，J＝8.7，1H)；2.00-1.80(m，2H)；1.69(br.s，1H)，1.58(d，J＝6.9，3H)；1.40-1.08(m，1H)。MS(m/z)：426.10([M+H]
+)。
Embodiment 253
N (3)-[R-(1-phenylethyl)]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (51 μ l, 0.37mmol), bop reagent (136mg, 0.31mmol) and R-(+)-1-styroyl amine (33 μ l 0.31mmol) obtain title compound (66mg, 50%).M.P.：89-92℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.55(d，J＝2.1，1H)；7.50-7.20(m，7H)；7.08(d，J＝7.8，1H)；5.30(m，1H)；3.75(br.s，1H)；3.35(br.s，1H)；2.10(t，J＝9.0，1H)；2.00-1.80(m，2H)；169(br.s，1H)；1.58(d，J＝6.9，3H)；1.40-1.10(m，2H)。IR(KBr,cm
-1)：3411(m)，3247(m)，2972(m)，2952(m)，2870(m)，1638(s)，1545(m)，1502(s)，1483(s)，1448(m)，1378(m)，1359(m)，1239(m)，1262(m)，1138(m)，1101(m)，1076(m)，815(w)，699(m)。MS(m/z)：426.0([M+H]
+)。
Embodiment 254
N (3)-(2-phenylethyl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (43 μ l, 0.31mmol), bop reagent (136mg, 0.31mmol) and styroyl amine (38 μ l 0.31mmol) obtain the title compound (70mg, 53%) of waxy solid.
1H-NMR(δppm，CDCl
3，300MHz)：7.55(d，J＝1.8，1H)；7.43(d，J＝8.4，1H)；7.36(dd，J＝8.4，1.8，1H)；7.35-7.19(m，5H)；6.91(br.s，1H)；3.75(br.s，1H)；3.70-3.60(m，2H)；3.36(br.s，1H)；2.90(t，J＝7.2，2H)；2.12(br.d，J＝8.6，1H)；2.01-1.84(m，2H)；1.69(br.d，J＝8.6，1H)；1.31-1.13(m，2H)。
Embodiment 255
N (3)-[2-(4-fluorophenyl) ethyl]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (43 μ l, 0.31mmol), bop reagent (136mg, 0.31mmol) and 4-fluorobenzene ethylamine (40 μ l 0.31mmol) obtain the title compound (100mg, 73%) of glassy thickener.
1H-NMR(δppm，CDCl
3，300MHz)：7.56(d，J＝2.1，1H)；7.41(d，J＝8.4，1H)；7.37(d，J＝8.4，2.1，1H)；7.19(dd，J＝8.4，5.4，2H)；6.98(t，J＝8.7，2H)；6.90(br.t，J＝4.6，1H)；3.75(br.s，1H)；3.71-3.57(m，2H)；3.36(br.s，1H)；2.90(t，J＝7.5，2H)；2.12(br.d，J＝8.7，1H)；2.02-1.86(m，2H)；1.69(br.d，J＝8.7，1H)；1.31-1.13(m，2H)。
Embodiment 256
N (3)-phenyl amino-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (51 μ l, 0.37mmol), bop reagent (136mg, 0.31mmol) and phenylhydrazine hydrochloride (30 μ l 0.31mmol) obtain title compound (84mg, 66%).M.P.：182-185℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.48(br.s，1H)；7.58(d，J＝1.8，1H)；7.48(d，J＝8.5，1H)；7.40(dd，J＝8.5，1.8，1H)；7.26-7.20(m，3H)；7.00-6.82(m，3H)；3.73(br.s，1H)；3.40(br.s，1H)；2.13(br.d，J＝8.1，1H)；1.97-1.90(m，2H)；1.71(br.d，J＝9.0，1H)；1.30-1.15(m，2H)。IR(KBr，cm
-1)：3251(s)，2996(m)，2947(m)，2870(m)，1663(s)，1604(m)，1542(m)，1498(s)，1483(s)，1352(m)，1279(m)，1230(m)，1231(m)，1111(m)，1083(m)，1060(m)，937(m)，899(m)，889(m)，867(m)。MS(m/z)：413.0([M+H]
+)。
Embodiment 257
N (3)-[(2-chloro-phenyl-) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (107 μ 1,0.77mmo1), bop reagent (136mg, 0.31mmol) and 2-chlorophenyl hydrazine hydrochloride (55mg 0.31mmol) obtains title compound (78mg, 57%).M.P.：180-183℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.49(br.s，1H)；7.59(d，J＝2.4，1H)；7.48(d，J＝8.4，1H)；7.41(dd，J＝8.4，2.4，1H)；7.29(d，J＝8.0，1H)；7.14(t，J＝7.8，1H)；7.03(d，J＝8.1，1H)；6.83(t，J＝8.0，1H)；6.55(br.s，1H)；3.73(br.s，1H)；3.40(br.s，1H)；2.13(br.d，J＝9.0，1H)；2.01-1.87(m，2H)；1.70(br.d，J＝9.0，1H)；1.30-1.16(m，2H)。IR(KBr，cm
-1)：3255(br.，m)，2959(w)，2874(w)，1667(s)，1508(s)，1346(m)，1279(m)，1110(m)，1079(m)，1066(m)，862(w)。MS(m/z)：448.9([M+H]
+)。
Embodiment 258
N (3)-[N-(2-chloro-phenyl-)-N-methylamino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (0.51 μ l, 0.37mmol), bop reagent (136mg, 0.31mmol) and N-(2-chloro-phenyl-)-N-methyl hydrazine hydrochloride (59mg 0.31mmol) obtains title compound (104mg, 70%).M.P.：121-124℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.82(br.s，1H)；7.56(d，J＝2.1，2H)；7.45(d，J＝8.4，1H)；7.42(dd，J＝8.1，1.5，1H)；7.38(dd，J＝8.4，2.1，1H)；7.31(dd，J＝8.1，1.5，1H)；7.24(td，J＝8.1，1.5，1H)；6.99(td，J＝8.1，1.51H)；3.70(br.s，1H)；3.37(br.s，4H)；2.09(br.d，J＝8.4，1H)；2.00-1.82(m，2H)；1.67(br.d，J＝8.7，1H)；1.30-1.10(m，2H)。IR(cm
-1，KBr)：3404(s)，3253(m)，2951(w)，2868(w)，1654(s)，1587(w)，1545(w)，1500(s)，1484(s)，1475(s)，1443(m)，1348(w)，1276(m)，1236(m)，1122(m)，1107(m)，1052(m)，832(s)。MS(m/z)：461.0([M+H]
+)。
Embodiment 259
N (3)-[(4-chloro-phenyl-) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (200mg, 0.62mmol), DMF (2.0ml), Et
3N (189 μ l, 1.36mmol), bop reagent (273mg, 0.62mmol) and 4-chlorophenyl hydrazine hydrochloride (110mg 0.62mmol) obtains title compound (195mg, 70%).M.P.：141-144℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.47(s，1H)；7.59(d，J＝1.8，1H)；7.48(d，J＝8.3，1H)；7.40(dd，J＝8.3，1.8，1H)；7.18(d，J＝8.7，2H)；6.87(d，J＝8.7，2H)；6.17(br.s，1H)；3.72(s，1H)；3.40(s，1H)；2.15(br.d，J＝8.7，1H)；1.99-1.88(m，2H)；1.70(br.d，J＝8.7，1H)；1.26-1.19(m，2H)。IR(KBr，cm
-1)：3271(s)，2991(m)，1667(m)，1596(m)，1505(m)，1491(m)，1348(m)，1276(m)，1230(m)，1080(m)，1065(m)，889(m)，824(s)。MS(m/z)：447.0([M+H]
+)。
Embodiment 260
N (3)-[(2,4 dichloro benzene base) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (200mg, 0.62mmol), DMF (2.0ml), Et
3N (189 μ l, 1.36mmo1), bop reagent (273mg, 0.62mmol) and 2,4 dichloro benzene hydrazonium salt hydrochlorate (132mg 0.62mmol) obtains title compound (205mg, 69%).M.P.：187-190℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.47(d，J＝3.0，1H)；7.59(d，J＝2.1，1H)；7.47(d，J＝8.6，1H)；7.40(dd，J＝8.6，2.1，1H)；7.30(d，J＝2.4，1H)；7.11(dd，J＝8.7，1H)；6.95(d，J＝9.0，1H)；6.49(d，J＝3.0，1H)；3.71(s，1H)；3.39(s，1H)；2.12(br.d，J＝9.3，1H)；1.97-1.90(m，2H)；1.70(br.d，J＝9.3，1H)；1.25-1.15(m，2H)。IR(KBr，cm
-1)：3348(m)，3191(m)，2984(m)，2968(m)，2873(w)，1661(s)，1588(m)，1557(m)，1495(s)，1343(m)，1279(m)，1108(m)，1078(m)，1068(m)，861(m)。
Embodiment 261
N (3)-[(2,4 dichloro benzene base)-N-methylamino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (0.51 μ l, 0.37mmol), bop reagent (136mg, 0.31mmol) and N-(2,4 dichloro benzene base)-N-methyl hydrazine (59mg 0.31mmol) obtains title compound (97mg, 63%).M.P.：135-138℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.81(br.s，1H)；7.57(d，J＝1.8，1H)；7.42(d，J＝8.3，1H)；7.40(dd，J＝8.3，1.8，1H)；7.35(d，J＝8.3，1H)；7.31(d，J＝2.4，1H)；7.21(dd，J＝8.3，2.4，1H)；3.69(br.s，1H)；3.35(br.s，4H)；2.09(br.d，J＝9.0，1H)；2.00-1.80(m，2H)；1.67(br.d，J＝9.0，1H)；1.35-1.20(m，2H)。IR(cm
-1，KBr)：3348(s)，3081(w)，2963(m)，2871(w)，1683(s)，1586(w)，1565(w)，1533(m)，1505(s)，1482(s)，1470(s)，1438(m)，1345(m)，1122(m)，1105(m)，1085(m)，1464(s)，1049(m)，814(m)。MS(m/z)：495.0([M+H]
+)。
Embodiment 262
N (3)-[(3, the 4-dichlorophenyl) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (200mg, 0.619mmol), DMF (2.0ml), Et
3N (189 μ l, 1.361mmol), (273mg, 0.619mmol) and 3, (132mg 0.619mmol) obtains title compound (205mg, 69%) to the 4-dichloride phenyl hydrazine hydrochloric acid salt to bop reagent.M.P.：176-179℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.48(s，1H)；7.59(d，J＝2.1，1H)；7.48(d，J＝8.4，1H)；7.40(dd，J＝8.4，2.1，1H)；7.26(d，J＝8.7，1H)；7.03(d，J＝2.7，1H)；6.77(dd，J＝8.7，2.7，1H)；6.22(br.s，1H)；3.72(br.s，1H)；3.40(br.s，1H)；2.13(br.d，J＝9.0，1H)；2.03-1.88(m，2H)；1.70(br?d，J＝9.0，1H)；1.30-1.16(m，2H)。IR(KBr，cm
-1)：3314(m)，2951(m)，2870(m)，1678(s)，1602(m)，1511(s)，1475(s)，1384(m)，1339(m)，1253(m)，1225(m)，1126(s)，1062(s)，863(m)，819(s)。MS(m/z)：481.0([M+H]
+)。
Embodiment 263
N (3)-[(2-bromophenyl) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (103 μ l, 0.74mmol), bop reagent (136mg, 0.31mmol) and the 2 bromo phenyl hydrazine hydrochloride (69mg 0.31mmol) obtains title compound (115mg, 76%).M.P：159℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.50(d，J＝3.3，1H)；7.59(d，J＝2.4，1H)；7.50-7.39(m，3H)；7.20(t，J＝7.7，1H)；7.01(d，J＝6.9，1H)；6.77(t，J＝7.5，1H)；6.52(d，J＝3.3，1H)；3.73(s，1H)；3.40(s，1H)；2.14(br.d，J＝8.7，1H)；2.02-1.91(m，2H)；1.70(br?d，J＝8.7，1H)；1.30-1.19(m，2H)。IR(KBr，cm
-1)：3256(m)，2925(m)，2859(m)，1666(s)，1505(s)，1344(m)，1278(m)，1232(m)，1110(m)，1079(m)，1064(m)，742(m)。MS(m/z)：491.0([M+H]
+)。
Embodiment 264
N (3)-[(2-fluorophenyl) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (200mg, 0.62mmol), DMF (2.0ml), Et
3N (0.2.0ml, 1.49mmol), bop reagent (273mg, 0.62mmol) and the 2-fluorophenyl hydrazine hydrochloride (100mg 0.62mmol) obtains title compound (96mg, 72%).M.P.：131-134℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.51(br.s，1H)；7.59(d，J＝2.1，1H)；7.48(d，J＝8.6，1H)；7.40(dd，J＝8.6，2.1，1H)；7.10-6.95(m，3H)；6.90-6.80(m，1H)；3.73(br.s，1H)；3.40(br.s，1H)；2.14(br.d，J＝9.0，1H)；2.02-1.85(m，2H)；1.70(d，J＝9.0，1H)；1.30-1.15(m，2H)。IR(KBr,cm
-1)：3256(br.s)，2989(m)，2959(m)，2873(w)，1666(s)，1618(m)，1508(s)，1456(m)，1345(m)，1279(m)，1243(m)，1194(m)，1099(s)，1063(m)，863(m)。
Embodiment 265
N (3)-[(2,4 difluorobenzene base) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (150mg, 0.46mmol), DMF (2.0ml), Et
3N (154 μ l, 1.11mmol), bop reagent (205mg, 0.46mmol) and 2,4 difluorobenzene hydrazonium salt hydrochlorate (83mg 0.46mmol) obtains title compound (143mg, 69%).M.P.：157-160℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.50(br.s，1H)；7.59(d，J＝1.8，1H)；7.47(d，J＝8.4，1H)；7.39(dd，J＝8.4，1.8，1H)；7.00(dt，J＝9.0，5.4，1H)；6.82(td，J＝8.4，2.7，1H)；6.72(br.t，J＝8.1，1H)；3.72(br.s，1H)；3.40(br.s，1H)；2.13(br.d，J＝8.4，1H)；2.05-1.85(m，2H)；1.70(d，J＝8.4，1H)；1.30-1.15(m，2H)。IR(KBr，cm
-1)：3358(m)，3198(m)，3061(m)，2989(m)，2874(m)，1664(s)，1565(m)，1520(s)，1468(m)，1382(m)，1320(m)，1281(m)，1262(m)，1207(m)，1123(m)，1108(m)，1077(m)，959(m)，798(m)。MS(m/z)：449.0([M+H]
+)。
Embodiment 266
N (3)-[(3-fluorophenyl) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (103 μ l, 0.74mmol), bop reagent (136mg, 0.31mmol) and the 3-fluorophenyl hydrazine hydrochloride (50mg 0.31mmol) obtains title compound (98mg, 74%).M.P.：190℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.46(s，1H)；7.59(d，J＝2.4，1H)；7.49(d，J＝8.4，1H)；7.40(dd，J＝8.7，2.4，1H)；7.21-7.13(m，1H)；6.77-6.47(m，3H)；6.20(br.s，1H)；3.73(s，1H)；3.40(s，1H)；2.14(br.d，J＝8.6，1H)；2.02-1.88(m，2H)；1.70(br.d，J＝8.6，1H)；1.31-1.16(m，2H)。IR(KBr，cm
-1)：3411(s)，3277(s)，2986(m)，2940(m)，2870(m)，1670(s)，1615(s)，1544(s)，1504(s)，1469(s)，1444(s)，1475(s)，1341(m)，1273(m)，1237(m)，1105(m)，1081(m)，835(m)。MS(m/z)：431.1([M+H]
+)。
Embodiment 267
N (3)-[(3-chloropyridine-2-yl) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.30mmol), DMF (1.0ml), Et
3N (51 μ l, 0.32mmol), bop reagent (129mg, 0.32mmol) and 3-chloro-2-hydrazino pyridine (44mg 0.31mmol) obtains title compound (50mg, 36%).M.P.:95 ℃ (fusion).
1H-NMR(δppm，CDCl
3，300MHz)：9.40(br.s，1H)；8.10(br.d，J＝4.8，1H)；7.60(br.d，J＝7.8，2H)；7.58-7.50(m，1H)；7.39(br.d，J＝8.1，2H)；6.78(dt，J＝7.5，2.4，1H)；3.72(br.s，1H)；3.41(br.s，1H)；2.15(t，J＝8.7，1H)，2.00-1.85(m，2H)；1.69(br.d，J＝8.7，1H)；1.20-1.10(m，2H)。IR(cm
-1，KBr)：3368(br.m)，2954(m)，2870(m)，1677(s)，1591(s)，1537(m)，1498(s)，1470(s)，1406(m)，1252(m)，1227(m)，1125(s)，1080(m)，1033(m)，866(w)，832(m)。MS(m/z)：448.0([M+H]
+)。
Embodiment 268
N (5)-piperidines-1-base-3-(2 ', 4 ,-dichlorophenyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide:
Use intermediate 17 (100mg, 0.31mmol), DMF (1ml), triethylamine (0.04ml, 0.31mmol), bop reagent (136mg, 0.31mmol) and 1-amino piperidine (0.033ml, 0.31mmol) synthetic by being similar to embodiment 101 described methods, obtain title compound (62mg, 50%).
1H-NMR(δppm，CDCl
3)：7.56(d，J＝2.1，1H)；7.45(d，J＝8.4，1H)；7.37(dd，J＝8.4，2.1，1H)；3.76(br.s，1H)；3.36(br.s，1H)；2.91(br.s，4H)；2.12(br.d，J＝10.2，1H)；2.04-1.82(m，2H)；1.81-1.56(m，5H)；1.50-1.38(m，2H)；1.34-1.10(m，2H)。
Embodiment 269
N (5)-benzyl-3-(2 ', 4 '-dichlorophenyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide
Use intermediate 17 (100mg, 0.31mmol), DMF (1ml), triethylamine (0.04ml, 0.31mmol), bop reagent (136mg, 0.31mmol) and benzylamine (0.033ml, 0.31mmol) synthetic by being similar to embodiment 101 described methods, obtain title compound (94mg, 74%).
1H-NMR(δppm，CDCl
3)：7.55(d，J＝2.1，1H)；7.42(d，J＝8.4，1H)；7.37-7.23(m，6H)；7.15(br.s，1H)；4.63(dd，J＝11.0，5.0，1H)；4.57(dd，J＝11.0，5.0，1H)；3.78(br.s，1H)；3.36(br.s，1H)；2.13(br.d，J＝8.4，1H)；2.04-1.82(m，2H)；1.70(br.d，J＝8.4，1H)；1.35-1.11(m，2H)。
Embodiment 270
N (3)-piperidines-1-base-1-(2-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 18 (100mg, 0.30mmol), DMF (1.0ml), Et
3N (50 μ l, 0.36mmol), bop reagent (146mg, 0.33mmol) and the 1-amino piperidine (32 μ l 0.30mmol) obtain title compound (52mg, 42%).M.P.：236℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.73(d，J＝8.4，1H)；7.58(br.s，1H)；7.39-7.46(m，2H)；7.36-7.30(m，1H)；3.77(br.s，1H)；3.35(br.s，1H)；2.85(br.s，4H)；2.15(br.d，J＝7.8，1H)；2.00-1.71(m，6H)；1.44-1.16(m，5H)。IR(KBr.cm
-1)：3308(m)，3000(m)，2940(s)，2864(m)，2793(m)，1685(s)，1540(s)，1511(s)，1484(s)，1449(m)，1340(w)，1229(m)，1133(m)，1123(m)，1036(m)，986(m)，904(m)，832(w)。MS(m/z)：415.1([M+H]
+)。
Embodiment 271
N (3)-cyclohexyl-1-(2-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 18 (100mg, 0.30mmol), DMF (1.0ml), Et
3N (50 μ l, 0.36mmol), bop reagent (146mg, 0.33mmol) and hexahydroaniline (39 μ l 0.34mmol) obtain title compound (100mg, 80%).M.P.：178℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.26(d，J＝8.1，1H)；7.51-7.40(m，2H)；7.33(br.t，J＝8.1，1H)；6.73(br.d，J＝8.4，1H)；3.85-4.05(m，1H)；3.77(br.s，1H)；3.35(br.s，1H)；2.15(br.d，J＝7.2，1H)；2.00-1.85(m，4H)；1.80-1.65(m，4H)；1.50-1.14(m，7H)。IR(KBr.cm
-1)：3413(m)，2938(s)，2854(m)，1662(s)，1541(s)，1512(s)，1480(s)，1450(s)，1341(m)，1299(m)，1222(m)，1159(m)，1125(m)。MS(m/z)：414.0([M+H]
+)。
Embodiment 272
N (3)-benzyl-1-(2-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 18 (100mg, 0.30mmol), DMF (1.0ml), Et
3N (50 μ l, 0.36mmol), bop reagent (146mg, 0.33mmol) and benzylamine (32 μ l 0.30mmol) obtain title compound (60mg, 47%).M.P.：110℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.70(d，J＝8.4，1H)；7.45-7.16(m，9H)；4.61(m，2H)；3.79(br.s，1H)；3.56(br.s，1H)；2.16(br.d，J＝8.7，1H)；2.05-1.80(m，2H)；1.70(br.d，J＝8.7，1H)；1.35-1.15(m，2H)。IR(KBr，cm
-1)：3419(w)，3020(s)，2401(w)，1661(w)，1549(w)，1516(w)，1484(w)，1427(w)，1343(w)，1216(s)。MS(m/z)：422.0([M+H]
+)。
Embodiment 273
N (3)-phenyl amino-1-(2-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 18 (100mg, 0.30mmol), DMF (1.0ml), Et
3N (50 μ l, 0.36mmol), bop reagent (146mg, 0.33mmol) and phenylhydrazine (30 μ l 0.30mmol) obtain title compound (101mg, 80%).M.P.：219℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.51(br.s，1H)；7.50(d，J＝7.8，1H)；7.60-7.41(m，2H)；7.36(br.t，J＝8.4，1H)；7.34(t，J＝7.8，2H)；6.95(d，J＝7.8，2H)；6.89(t，J＝7.5，1H)；3.73(br.s，1H)；3.39(br.s，1H)；2.16(br.d，J＝7.2，1H)；2.00-1.85(m，2H)；7.70(d，J＝8.7，1H)；1.28-1.20(m，2H)。IR(KBr，cm
-1)：3283(m)，2992(m)，2959(m)，2863(w)，1675(s)，1603(m)，1542(m)，1511(s)，1497(s)，1438(m)，1348(m)，1281(m)，1240(m)，1136(m)，1123(m)，1084(m)，1029(m)，888(m)。MS(m/z)：423.0([M+H]
+)。
Embodiment 274
N (3)-piperidines-1-base-1-(4-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 19 (100mg, 0.30mmol), DMF (1.0ml), Et
3N (50 μ l, 0.36mmol), bop reagent (146mg, 0.33mmol) and the 1-amino piperidine (33 μ l 0.30mmol) obtain title compound (124mg, 99%).M.P.：173℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.60(br.s，4H)；3.70(br.s，1H)；3.65(br.s，1H)；2.90(br.s，4H)；2.20(br.d，J＝7.14，1H)；2.00(br.d，J＝8.6，2H)；1.90-1.60(m，6H)；1.30-1.20(m，3H)。IR(KBr，cm
-1)：3408(w)，3308(w)，2929(s)，2859(m)，2780(m)，1692(s)，1591(m)，1541(s)，1503(s)，1489(s)，1440(m)，1401(m)，1348(s)，1268(m)，1226(s)，1154(m)，1122(s)，1064(m)，1006(m)，827(s)。MS(m/z)：415.1([M+H]
+)。
Embodiment 275
N (3)-cyclohexyl-1-(4-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 19 (100mg, 0.30mmol), DMF (1.0ml), Et
3N (50 μ l, 0.36mmol), bop reagent (146mg, 0.33mmol) and hexahydroaniline (34 μ l 0.30mmol) obtain title compound (91mg, 73%).M.P.：164℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.58(s，4H)；6.75(br.d，J＝8.1，1H)；3.93(m，1H)；3.75(br.s，1H)；3.67(br.s，1H)；2.12(br.d，J＝8.4，1H)；2.10-1.90(m，4H)；1.80-1.70(m，3H)；1.60-1.20(m，8H)。IR(KBr,cm
-1)：3410(m)，2922(m)，2848(m)，1667(s)，1591(w)，1546(s)，1504(s)，1486(s)，1450(m)，1349(m)，1224(m)，1160(m)，1122(m)，1065(m)，1006(m)，827(m)。MS(m/z)：414.1([M+H]
+)。
Embodiment 276
N (3)-benzyl-1-(4-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 19 (100mg, 0.30mmol), DMF (1.0ml), Et
3N (50 μ l, 0.36mmol), bop reagent (146mg, 0.33mmol) and benzylamine (33 μ l 0.30mmol) obtain title compound (107mg, 85%).M.P.：89℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.56(br.s，4H)；7.40-7.22(m，6H)；4.64(d，J＝5.4，2H)；3.80(br.s，1H)；3.68(br.s，1H)；2.14(br.d，J＝8.1，1H)；2.00(br.d，J＝5.7，2H)；1.74(d，J＝8.4，1H)；1.26-1.20(m，2H)。IR(KBr,cm
-1)：3321(m)，2937(m)，2868(m)，1649(s)，1590(m)，1551(s)，1499(s)，1455(m)，1347(s)，1275(m)，1241(m)，1121(m)，1070(m)，1005(m)，975(m)，825(m)。MS(m/z)：422.1([M+H]
+)。
Embodiment 277
N (3)-phenyl amino-1-(4-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 19 (100mg, 0.30mmol), DMF (1.0ml), Et
3N (50 μ l, 0.36mmol), bop reagent (146mg, 0.33mmol) and phenylhydrazine (29 μ l 0.30mmol) obtain title compound (90mg, 71%).M.P.：138℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.54(br.s，1H)；7.61(s，4H)；7.24(t，J＝7.8，2H)；6.95(d，J＝8.4，2H)；6.90(t，J＝7.2，1H)；3.72(br.,2H)；2.13(br.d，J＝8.0，1H)；1.99(br.d，J＝7.8，2H)；1.73(br.d，J＝8.0，1H)；1.40-1.15(m，2H)。IR(KBr，cm
-1)：3262(m)，2948(m)，2869(m)，1666(s)，1603(s)，1591(s)，1545(m)，1497(s)，1401(m)，1357(m)，1279(m)，1252(m)，1227(m)，1124(m)，1083(m)，1070(m)，1005(m)，894(m)。MS(m/z)：422.9([M+H]
+)。
Embodiment 278
N (3)-[(2-fluorophenyl) amino]-1-(4-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 19 (100mg, 0.30mmol), DMF (1.0ml), Et
3N (63 μ l, 0.45mmol), bop reagent (146mg, 0.33mmol) and the 2-fluorophenyl hydrazine hydrochloride (48mg 0.30mmol) obtains title compound (50mg, 38%).M.P.：123℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.57(br.s，1H)；7.61(s，4H)；7.10-6.70(m，3H)；7.00-680(m，1H)；3.71(s，2H)；2.17(br.d，J＝8.4，1H)；2.10-1.90(m，2H)；1.73(d，J＝8.7，1H)；1.35-1.15(m，2H)。MS(m/z)：441.1([M+H]
+)。
Embodiment 279
N (3)-cyclohexyl-1-(4-fluorophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 20 (100mg, 0.37mmol), DMF (1.0ml), Et
3N (61 μ l, 0.44mmol), bop reagent (178mg, 0.40mmol) and hexahydroaniline (42 μ l 0.37mmol) obtain title compound (72mg, 56%).M.P.：127℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.64-7.62(m，2H)；7.17(t，J＝8.4，2H)；6.75(br.d，J＝7.7，1H)；4.05-3.80(m，1H)；3.75(br.s，1H)；3.64(br.s，1H)；2.20-1.90(br.s，5H)；1.74-1.66(m，5H)；1.44-1.10(m，6H)。IR(KBr，cm
-1)：3352(m)，3310(w)，2934(m)，2834(m)，1656(s)，1642(s)，1517(s)，1499(s)，1451(m)，1350(m)，1276(w)，1252(w)，1223(s)，1163(m)，1123(m)，842(m)。MS(m/z)：354.1([M+H]
+)。
Embodiment 280
N (3)-benzyl-1-(4-fluorophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 20 (100mg, 0.37mmol), DMF (1.0ml), Et
3N (61 μ l, 0.44mmol), bop reagent (178mg, 0.40mmol) and benzylamine (39 μ l 0.36mmol) obtain title compound (43mg, 33%).M.P.：104℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.62(br.s，2H)；7.38-7.00(m，8H)；4.63(br.d，J＝5.1，2H)；3.78(br.s，1H)；3.66(br.s，1H)；2.12(br.d，J＝8.4，1H)；1.90-2.10(m，2H)；1.73(d，J＝8.4，1H)；1.40-1.10(m，2H)。IR(KBr，cm
-1)：3411(m)，3009(w)，2869(w)，1670(s)，1543(s)，1500(s)，1492(s)，1454(m)，1416(m)，1349(s)，1276(m)，1226(s)，1212(s)，1164(m)，1124(m)，954(w)；835(s)。MS(m/z)：362.1([M+H]
+)。
Embodiment 281
N5-(diamantane-2-yl)-3-(4-fluorophenyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 20 (100mg, 0.36mmol), DMF (1.0ml), Et
3N (124 μ l, 0.88mmol), bop reagent (170mg, 0.38mmol) and 2-adamantyl amine hydrochlorate (103mg 0.55mmol) obtains title compound (120mg, 80%).M.P.：196-198℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.69-7.63(m，2H)；7.17(t，J＝8.1，2H)；4.23(d，J＝8.4，1H)；3.75(br.s，1H)；3.65(br.s，1H)，2.14-1.87(m，14H)，1.78-1.54(m，4H)，1.26-1.21(m，2H)。IR(cm
-1，KBr)：3414(s)，2979(w)，2901(s)，2851(s)，1663(s)，1542(s)，1517(s)，1488(s)，1454(m)，1445(m)，1347(w)，1255(w)，1224(m)，1213(s)，1159(m)，1126(m)，1091(m)，953(w)，833(m)。MS(m/z)：406.2([M+H]
+)。
Embodiment 282
N5-(1-methyl isophthalic acid-phenylethyl)-3-(4-fluorophenyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 20 (100mg, 0.36mmol), DMF (1.0ml), Et
3N (41 μ l, 0.40mmol), (170mg, 0.38mmol) and α, (75mg 0.55mmo1) obtains title compound (77mg, 54%) to the alpha-alpha-dimethyl benzylamine to bop reagent.M.P.：119-122℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.68-7.62(m，2H)；7.51-7.46(m，2H)；7.37-7.30(m，2H)；7.27-7.13(m，3H)；3.70(br.s，1H)；3.63(br.s，1H)；2.08(d，J＝9.0，1H)，1.95(d，J＝7.8，2H)；1.84(s，6H)；1.68(d，J＝8.4，1H)，1.23(d，J＝12.0，2H)。IR(cm
-1，KBr)：3358(m)，2972(m)，2927(m)，2870(m)，1664(s)，1605(w)，1542(m)，1515(s)，1489(m)，1383(w)，1357(m)，1276(m)1219(m)，1136(m)，1117(m)，1093(m)，1031(w)，1088(w)，949(w)，858(w)，839(m)。MS(m/z)：390.0(M+H
+)。
Embodiment 283
N5-(diamantane-1-yl)-3-(4-fluorophenyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 20 (100mg, 0.36mmol), DMF (1.0ml), Et
3N (41 μ l, 0.40mmol), bop reagent (170 the gram, 0.38mmol) and the 1-adamantanamines (83mg 0.54mmol) obtains title compound (127mg, 85%).M.p.：189-191℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.66-7.60(m，2H)；7.19-7.12(m，2H)；6.66(br.s，1H)；3.74(br.s，1H)；3.63(br.s，1H)；2.15-2.10(m，9H)；1.97(d，J＝8.7，2H)；1.75-1.68(m，8H)；1.30-1.20(m，2H)。IR(cm
-1，KBr)：3361(m)，2986(m)，2909(s)，2849(m)，1658(s)，1517(s)，1550(s)，1493(s)，1445(m)，1412(m)，1308(w)，1289(w)，1278(w)，1256(s)，1219(s)，868(m)。MS(m/z)：406.1([M+H]
+)。
Embodiment 284
N (3)-phenyl amino-1-(4-fluorophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 20 (100mg, 0.37mmol), DMF (1.0ml), Et
3N (61 μ l, 0.44mmol), bop reagent (178mg, 0.40mmol) and phenylhydrazine (36 μ l 0.37mmol) obtain title compound (72mg, 54%).M.P.：163℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.55(s，1H)；7.69(dd，J＝9.3，5.2，2H)；7.27-7.16(m，4H)；6.95(d，J＝7.5，2H)；6.90(t，J＝7.2，1H)；3.73(br.s，1H)；3.69(br.s，1H)；2.15(br.d，J＝9.0，1H)；2.06-1.99(m，2H)；1.73(d，J＝8.7，1H)；1.25(br.d，J＝7.2，2H)。IR(KB?r，cm
-1)：3376(m)，2991(m)，2952(m)，2871(m)，1674(s)，1604(s)，1517(s)，1497(s)；1441(m)，1350(m)，1279(m)，1223(s)，1154(m)，1127(m)，1093(m)，1083(m)，1066(m)，1041(w)，889(m)，841(m)。MS(m/z)：363.1([M+H]
+)。
Embodiment 285
N (3)-phenyl amino-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.36mmol), DMF (1.0ml), Et
3N (44 μ l, 0.32mmol), bop reagent (125mg, 0.28mmol) and phenylhydrazine (34 μ l 0.34mmol) obtain title compound (87mg, 44%).M.P.：161℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.50(br.s，1H)；7.70(m，1H)；7.24(t，J＝7.8，2H)；7.09-6.99(m，2H)；6.99-6.86(m，3H)；3.72(br.s，1H)；3.48(br.s，1H)；2.09(br.d，J＝8.4，1H)，1.97(br.d，J＝9.3，2H)；1.69(br.d，J＝8.7，1H)；1.27(br.d，J＝9.3，2H)。IR(cm
-1，KBr)：3274(s)，2991(m)，2957(m)，1672(s)，1605(s)，1525(s)，1497(s)，1441(m)，1352(m)，1273(s)，1230(m)，1146(m)，1126(m)，1085(m)，966(m)，889(m)，851(m)。MS(m/z)：381.0([M+H]
+)。
Embodiment 286
N (3)-[(2-chloro-phenyl-) amino]-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (114 μ l, 0.83mmol), bop reagent (152mg, 0.34mmol) and 2-chlorophenyl hydrazine hydrochloride (61mg 0.34mmol) obtains title compound (108mg, 76%).M.P.：126-129℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.55(br.s，1H)；7.75-7.65(m，1H)；7.29(d，J＝7.2，1H)；7.14(t，J＝8.1，1H)；7.04(br.t，J＝8.1，3H)；6.83(t，J＝6.9，1H)；3.71(br.s，1H)；3.49(br.s，1H)；2.09(d，J＝9.0，1H)；1.97(d，J＝9.0，2H)；1.70(d，J＝9.0，1H)；1.26(br.d，J＝8.4，2H)。IR(KBr，cm
-1)：3247(br.m)，2956(m)，2873(m)，1670(s)，159(m)，1524(s)，1494(s)，1439(m)，1349(m)，1270(s)，1254(m)，1141(m)，1048(m)，1034(m)，964(m)，887(w)，848(m)，750(s)。MS(m/z)：415.10([M+H]
+)。
Embodiment 287
N (3)-[(2-bromophenyl) amino]-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (114 μ l, 0.83mmol), bop reagent (152mg, 0.34mmol) and the 2 bromo phenyl hydrazine hydrochloride (76mg 0.34mmol) obtains title compound (125mg, 79%).M.P.：134-137℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.57(br.s，1H)；7.74-7.65(m，1H)；7.46(d，J＝7.8，1H)；7.19(t，J＝7.8，1H)；7.10-6.90(m，3H)；6.77(t，J＝8.1，1H)；3.72(br.s，1H)；3.49(br.s，1H)；2.12(br.d，J＝8.7，1H)；1.97(br.d，J＝9.0，2H)；1.70(br.d，J＝8.7，1H)；1.27(br.d，J＝9.0，2H)。IR(KBr，cm
-1)：3327(s)，3295(m)，2969(m)，2869(m)，1656(s)，1609(m)，1594(m)，1524(s)，1481(s)，1449(m)，1353(m)，1271(s)，1229(m)，1093(s)，1071(m)，1046(m)，1021(m)，846(s)。
Embodiment 288
N (3)-[(2-fluorophenyl) amino]-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (114 μ l, 0.83mmol), bop reagent (152mg, 0.34mmol) and the 2-fluorophenyl hydrazine hydrochloride (55mg 0.34mmol) obtains title compound (94mg, 69%).M.P.：172-175℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.54(br.s，1H)；7.71(dt，J＝8.4，2.4，1H)；7.10-6.96(m，5H)；6.90-6.80(m，1H)；3.72(br.s，1H)；3.49(br.s，1H)；2.11(br.d，J＝7.2，1H)；1.97(d，J＝9.3，2H)；1.71(d，J＝9.0，1H)；1.30-1.25(m，2H)。IR(KBr，cm
-1)：3339(s)，2989(m)，2871(m)，1685(s)，1614(m)，1523(s)，1498(s)，1439(s)，1271(m)，1233(m)，1192(m)，1143(m)，1061(m)，1027(m)，966(m)，862(m)。MS(m/z)：399.10([M+H]
+)。
Embodiment 289
N (3)-piperidines-1-base-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (58 μ l, 0.42mmol), bop reagent (166mg, 0.38mmol) and the 1-amino piperidine (37 μ l 0.34mmol) obtain title compound (42mg, 33%).M.P.：143℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.72-7.61(m，1H)；7.58(br.s，1H)；7.02(t，J＝8.4，2H)；3.75(br.s，1H)；3.44(br.s，1H)，2.88(br.s，4H)；2.09(br.d，J＝8.7，1H)；2.10-1.90(m，2H)；1.78-1.65(m，5H)；1.50-1.34(m，2H)；1.34-1.08(m，2H)。IR(KBr，cm
-1)：3263(m)，2994(m)，2942(m)，2872(m)，2853(m)，1658(s)，1611(m)，1521(s)，1444(m)；1353(m)，1269(s)，1233(m)，1143(m)，1121(m)，1089(m)，965(m)，907(m)。MS(m/z)：373.2([M+H]
+)。
Embodiment 290
N (3)-cyclohexyl-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (57 μ l, 0.42mmol), bop reagent (166mg, 0.38mmol) and hexahydroaniline (39 μ l 0.34mmol) obtain title compound (41mg, 32%).M.P.：119℃.
1H-NMR(δppm，CDCl
3，300MHz)：7.70-7.60(m，1H)；7.01(t，J＝7.8，2H)；6.72(br.d，J＝8.1，1H)；4.03-3.85(m，1H)；3.75(br.s，1H)，3.44(br.s，1H)；2.10-1.95(m，5H)；1.80-1.42(m，5H)；1.40-1.15(m，6H)。IR(KBr，cm
-1)：3294(m)，2995(m)，2933(s)，2853(m)，1641(s)，1610(m)，1548(s)，1520(s)，1499(s)，1451(m)，1352(m)，1269(m)，1251(m)，1239(m)，1160(m)，1142(m)，1122(m)，1090(m)，964(m)，851(m)。MS(m/z)：372.1([M+H]
+)。
Embodiment 291
N (3)-(cyclohexyl methyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (57 μ l, 0.41mmol), bop reagent (152mg, 0.34mmol) and 2-cyclohexyl methyl amine (44 μ l 0.34mmol) obtain title compound (87mg, 65%).M.P.：94-97℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.67(m，1H)；7.01(t，J＝8.1，2H)；6.91(br.s，1H)；3.75(br.s，1H)；3.44(br.s，1H)；3.26(t，J＝6.6，2H)；2.08(br.d，J＝8.7，1H)；2.05-1.85(m，2H)；1.83-1.50(m，6H)；1.26-1.18(m，6H)；1.05-0.85(m，2H)。IR(KBr，cm
-1)：3379(m)，2926(s)，2848(m)，1655(s)，1556(m)，1519(s)，1499(m)，1450(m)，1271(m)，1241(m)，1142(m)，1088(m)，962(w)，852(w)。MS(m/z)：386.20([M+H]
+)。
Embodiment 292
N (3)-[S-(1-phenylethyl)]-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole 3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (57 μ l, 0.41mmol), bop reagent (152mg, 0.34mmol) and S-(-)-1-styroyl amine (44 μ l 0.34mmol) obtain title compound (85mg, 63%).M.P.：54-57℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.66(dt，J＝9.0，5.7，1H)；7.40-7.20(m，5H)；7.11(br.d，J＝7.5，1H)；7.00(t，J＝8.7，2H)；5.35-5.28(m，1H)；3.74(br.s，1H)；3.44(br.s，1H)；2.07(br.t，J＝8.6，1H)；1.94(br.s，2H)；1.70-1.55(m，4H)；1.33-1.25(m，2H)。IR(KBr,cm
-1)：3412(m)，3310(w)，2971(m)，2872(m)，1664(s)，1611(m)，1523(s)，1493(s)，1447(s)，1359(m)，1271(s)，1232(m)，1180(m)，1144(s)，1121(m)，1091(m)，965(m)，850(m)。MS(m/z)：394.0([M+H]
+)。
Embodiment 293
N (3)-(R-1-phenylethyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (54 μ l, 0.38mmol), (152mg, 0.36mmol) (44 μ l 0.37mmol) obtain title compound (75mg, 56%) to bop reagent with the R-1-phenyl ethyl amine.M.P.：40-45℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.72-7.60(m，1H)；7.46-7.19(m，5H)；7.15-6.90(m，3H)；5.31(br.s，1H)；3.74(br.s，1H)；3.43(br.s，1H)；2.07(br.s，1H)；1.95(br.s，2H)；1.72-1.51(m，4H)；1.44-1.17(m，2H)。IR(cm
-1，KBr)：3412(s)，3062(m)，3029(m)，2970(s)，29230(s)，2872(m)，1663(s)，1610(s)，1523(s)，1493(s)，1447(s)，1358(m)，1326(m)，1270(s)，1252(s)，1232(s)，1210(m)，1160(s)，1143(s)，1121(s)，1191(s)，965(m)850(m)，831(m)。MS(m/z)：394.2(87，[M+H]
+)；290.2(100)。
Embodiment 294
N (3)-(1-methyl isophthalic acid-phenylethyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (54 μ l, 0.38mmol), (152mg, 0.36mmol) and α, (56mg 0.41mmol) obtains title compound (80mg, 58%) to α-Er Jiajibianji amine to bop reagent.M.P.：105℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.69(dt，J＝9.6，6.0，1H)；7.49(d，J＝7.8，2H)；7.34(t，J＝7.8，2H)；7.28-7.18(m，2H)；7.06-6.96(m，2H)；3.70(br.s，1H)；3.43(br.s，1H)；2.06(br.d，J＝8.7，1H)；2.00-1.86(m，2H)；1.66(br.d，J＝8.4，1H)；1.35-1.17(m，2H)。IR(cm
-1，KBr)：3334(s)，2965(s)，2929(s)，2873(m)，1656(s)，1609(s)，1522(s)，1495(s)，1449(s)，1385(m)，1362(m)，1326(w)，1308(m)，1271(s)，1252(s)，1237(s)，1194(m)，1156(w)，1143(m)，1121(m)，1106(m)，1091(m)，965(m)848(m)，831(m)。MS(m/z)：408.1(40，[M+H]
+)；290.3(100)。
Embodiment 295
N5-[1-(2-chloro-phenyl-)-1-methylethyl]-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (54 μ l, 0.37mmol), bop reagent (152mg, 0.37mmol) and 2-(2-chloro-phenyl-)-(87mg 0.51mmol) obtains title compound (87mg, 57%) to third-2-base amine.M.P.：176-179℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.75-7.60(m，1H)；7.58(d，J＝7.8，1H)；7.41-7.12(m，4H)；7.06-6.95(m，2H)；3.64(s，1H)；3.42(s，1H)；2.04(d，J＝8.4，1H)；1.95-1.85(m，8H)，1.62(d，J＝9.3，1H)，1.23(d，J＝9.0，2H)。IR(cm
-1，KBr)：3413(m)，2975(m)，2871(m)，1675(s)，1613(w)，1522(s)，1491(m)，1447(m)，1383(w)，1362(w)，1270(s)，1244(m)，1144(m)，1091(w)，1037(w)，965(w)，853(w)，755(w)。MS(m/z)：442.1([M+H]
+)。
Embodiment 296
N (3)-(1,3,3-trimethylammonium two ring [2.2.1] heptan-2-yl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (120mg, 0.41mmol), DMF (1.0ml), Et
3N (137 μ l, 0.99mmol), (182mg, 0.41mmol) and 1S, in 2-1,3,3-trimethylammonium-two ring [2.2.1] heptan-(77mg 0.41mmol) obtains title compound (86mg, 49%) to 2-base amine hydrochlorate to bop reagent.M.P.：114-117℃。
1H-NMR(δppm，DMSO-d
6，300MHz)：7.86-7.76(m，1H)，7.60(br.t，J＝9.3，1H)；7.29(br.t，J＝8.1，1H)；7.00(d，J＝9.6，1H)；3.63(d，J＝9.3，1H)；3.52(br.s，1H)；3.46(br.s，1H)；2.05-1.85(m，3H)；1.75-1.55(m，4H)；1.50-1.35(m，2H)；1.25-0.95(m，10H)；0.77(d，J＝5.1，3H)。IR(cm
-1，KBr)：3390(m)，2952(s)，2873(m)，1658(s)，1607(w)，1520(s)，1496(s)，1451(m)，1475(m)，1368(w)，1329(m)，1252(m)，1232(m)，1158(m)，1148(m)，964(m)，822(w)。MS(m/z)：426.3([M+H]
+)。
Embodiment 297
N5-(2-benzyl chloride base)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (57 μ l, 0.41mmol), bop reagent (167mg, 0.37mmol) and the 2-chlorobenzylamine (41 μ l 0.34mmol) obtain title compound (100mg, 68%).M.P.：102-105℃。
1H-NMR(δppm，DMSO-d
6，300MHz)：8.67-8.73(m，1H)，7.89-7.77(m，1H)；7.66-7.57(m，1H)；7.44(d，J＝7.2，1H)；7.34-7.30(m，4H)；4.49(br.s，2H)；3.55(br.s，1H)；3.47(br.s，1H)；2.00-1.92(m，3H)；1.66(d，J＝8.7，1H)；1.17-1.05(m，2H)。IR(cm
-1，KBr)：3337(m)，2965(m)，2868(w)，1657(m)，1645(s)，1623(m)，1526(s)，1271(m)，1243(w)，1234(w)，1160(m)，846(m)，738(w)。
Embodiment 298
N5-(4-benzyl chloride base)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (50 μ l, 0.37mmol), bop reagent (159mg, 0.36mmol) and 4-chloro-benzylamine (63 μ l 0.51mmol) obtain title compound (96mg, 67%).M.P.：121-125℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.67-7.57(m，1H)；7.30-7.25(m，4H)；7.20-7.15(m，1H)；7.05-6.95(m，2H)；4.57(d，J＝4.8，2H)；3.76(br.s，1H)；3.45(br.s，1H)，2.09(d，J＝9.0，1H)；2.00-1.93(m，2H)；1.69(d，J＝9.0，1H)；1.28-1.24(m，2H)。IR(cm
-1，KBr)：3310(m)，2964(m)，2939(m)，2874(m)，1644(s)，1607(w)，1557(s)，1520(s)，1491(s)，1454(m)，1407(w)，1358(m)，1326(w)，1272(m)，1254(m)，1232(m)，1160(m)，1142(m)，1088(m)，1013(m)，962(m)，853(m)。MS(m/z)：412.25(100％)，414.2([M+H]
+)。
Embodiment 299
N5-(1-ethyl-1-phenyl propyl)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (54 μ l, 0.37mmol), (152mg, 0.34mmol) and α, (72mg 0.44mmol) obtains title compound (85mg, 86%) to α-diethyl benzylamine to bop reagent.M.P.：45-48℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.76-7.66(m，1H)，7.42-7.10(m，6H)；7.07-6.96(m，2H)；3.70(br.s，1H)；3.45(br.s，1H)；2.23(q，J＝7.2，4H)；2.06(d，J＝9.0，1H)；1.93(d，J＝8.4，2H)；1.66(d，J＝8.7，1H)；1.26(d，J＝5.4，2H)；0.78(t，J＝7.2，6H)。IR(cm
-1，KBr)：3407(m)，3059(m)，2968(s)，2975(s)，2935(s)，1681(s)，1610(m)，1583(s)，1524(s)，1491(m)，1447(m)，1377(w)，1327(w)，1270(m)，1234(m)，1144(m)，1091(m)，965(m)，850(m)，756(m)，698(m)。MS(m/z)：436.0[M+H]
+。
Embodiment 300
N5-[(1S)-the 1-phenyl propyl]-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (54 μ l, 0.37mmol), bop reagent (152mg, 0.34mmol) and (s)-(α)-(51mg 0.37mmol) obtains title compound (70mg, 50%) to Ethylbenzyl amine.M.P.：100-103℃。
1H-NMR (δ ppm, CDCl
3, 300MHz): 7.71-7.62 (m, 1H), 7.39-7.25 (m, 5H); 7.23-6.96 (m, 3H); 5.05 (quintet, J=7.8,1H); 3.72 (br.s, 1H); 3.43 (br.s, 1H); 2.10-1.85 (m, 5H); 1.66 (d, J=9.0,1H); 1.27-1.19 (m, 2H); 1.00-0.92 (m, 3H).IR(cm
-1，KBr)：3282(m)，2968(m)，2874(m)，1641(s)，1614(m)，1522(s)，1494(s)，1454(m)，1359(m)，1269(m)，1231(m)1159(m)，1140(m)，1120(m)，1094(m)，963(m)，847(m)，701(m)。MS(m/z)：290(100％)，408.2(M+H
+)。
Embodiment 301
(2S)-and 2-[5-(2,4 difluorobenzene base)-4,5-diaza tricyclic [5.2.1.0.
2,6] last of the ten Heavenly stems-2 (6), 3-diene-3-base formamido group]-2-phenylacetic acid methyl esters
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (510mg, 1.76mmol), DMF (4.0ml), Et
3N (580 μ l, 4.20mmol), bop reagent (777mg, 1.76mmol) and (S)-(+)-(354mg 1.76mmol) obtains title compound (420mg, 55%) to 2-phenyl glycine methyl ester hydrochloride.M.p.：72-75℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.47(d，J＝7.5，1H)，7.86-7.81(m，1H)；7.61(t，J＝8.4，1H)；7.45-7.29(m，6H)；5.65(d，J＝6.9，1H)；3.66(s，3H)；3.52(br.s，1H)；3.47(br.s，1H)；1.94(br.s，3H)；1.67(br.s，1H)；1.25-1.05(m，2H)；IR(cm
-1，KBr)：3412(m)，2953(m)，2872(m)，1745(s)，1674(s)，1610(m)，1524(s)，1488(s)，1452(m)，1358(m)，1328(w)，1295(w)1270(s)，1211(m)，1160(m)，1144(m)，1121(m)，1092(m)，965(m)，850(w)，698(m)。MS(m/z)：438.2(M+H
+)。
Embodiment 302
N5-[(1S)-2-hydroxyl-1-phenylethyl]-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0.
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide
Title compound is synthetic by being similar to embodiment 191 described methods.With LiBH
4(32mg, (290mg in solution 0662mmol), and refluxes mixture and spends the night 1.52mmol) to join embodiment 301 in THF (3ml).Behind the evaporating solvent, dilute with water oily resistates with 1N HCl acidifying and with ethyl acetate extraction, with the organic layer salt water washing that merges, and passes through Na
2SO
4Dry.Through FC (3: the 7AcOEt/ sherwood oil) obtain title compound (170mg, 63%).M.P.：91℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.71-7.61(m，1H)；7.46-7.29(m，6H)；7.00(t，J＝8.4，2H)；5.23(br.q，J＝5.1，1H)，3.98(br.?s，2H)；3.73(br.s，1H)；3.44(br.s，1H)；2.92(br.s，1H)；2.14-1.93(m，3H)；1.69(d，J＝8.7，1H)；1.32-1.24(m，2H)。MS(m/z)：410.1(M+H
+)。
Embodiment 303
N (3)-(tertiary butyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide [N5-(tertiary butyl)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide]
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (57 μ l, 0.40mmol), bop reagent (165mg, 0.37mmol) and 2-amino-2-methyl propane (36 μ l 0.34mmol) obtain title compound (31mg, 26%).M.P.：109-111℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.71-7.62(m，1H)，7.04-6.97(m，2H)；6.74(br.s，1H)；3.75(br.s，1H)；3.43(br.s，1H)；2.10-2.04(m，1H)；2.01-1.90(m，2H)；1.67(d，J＝8.4，1H)；1.46(s，9H)；1.33-1.19(m，2H)。IR(cm
-1，KBr)：3323(m)，2968(m)，1652(s)，1609(s)，1547(s)，1522(s)，1495(w)，1448(m)，1391(w)，1360(m)，1272(m)1258(w)，1145(w)，1109(m)，965(m)，849(m)。MS(m/z)：346.0(M+H
+)。
Embodiment 304 and embodiment 305
(4R is 7S) with (4S, 7R) N (3)-(tertiary butyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Preparation I: title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21a (the later enantiomer that elutes, 100mg, 0.34mmol), DMF (1.0ml), Et
3N (57 μ l, 0.41mmol), bop reagent (167mg, 0.37mmol) and 2-amino-2-methyl propane (36 μ l 0.34mmol) obtain title compound (91mg, 76%).HPLC:R
tThe 1ml/ branch)=26.59 minute (CHIRALCEL OD-H post, size: 250 * 4.6mm, particle size: 5 μ, elutriant: 0.2% Virahol in normal hexane, flow velocity:; E.e=92.3%.M.P.：89-92℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.72-7.60(m，1H)，7.04-6.96(m，2H)；6.74(br.s，1H)；3.75(br.s，1H)；3.43(br.s，1H)；2.07(d，J＝8.1，1H)；2.01-1.90(m，2H)；1.67(d，J＝8.7，1H)；1.46(s，9H)；1.33-1.19(m，2H)。
Preparation II: title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21b (enantiomorph that elutes earlier, 70mg, 0.24mmol), DMF (1.0ml), Et
3N (38 μ l, 0.28mmol), bop reagent (118mg, 0.26mmol) and 2-amino-2-methyl propane (25 μ l 0.24mmol) obtain title compound (63mg, 75%).HPLC:R
tThe 1ml/ branch)=24.73 minute (CHIRALCEL OD-H tubing string, size: 250 * 4.6mm, particle size: 5 μ, elutriant: 0.2% Virahol in normal hexane, flow velocity:; E.e.:90%.M.P.：89-90℃。Embodiment 305 is latent chirality (C=0.5) in chloroform under 25 ℃.
1H-NMR(δppm，CDCl
3，300MHz)：7.72-7.62(m，1H)，7.00(t，J＝10.8，2H)；6.74(br.s，1H)；3.75(br.s，1H)；3.43(br.s，1H)；2.07(d，J＝8.4，1H)；2.01-1.89(m，2H)；1.67(d，J＝8.1，1H)；1.46(s，9H)；1.33-1.19(m，2H)。
Embodiment 306
N5-n-pentyl-3-(2,4 difluorobenzene base)-3,4-two assorted three ring [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (54 μ l, 0.37mmol), bop reagent (152mg, 0.34mmol) and n-pentyl amine (32mg 0.37mmol) obtains title compound (50mg, 40%).M.P.：75-78℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.70-7.61(m，1H)，7.01(t，J＝8.4，2H)，6.83(br.s，1H)；3.75(br.s，1H)；3.43-3.36(m，3H)；2.08(d，J＝8.7，1H)，2.02-1.89(m，2H)，1.68(d，J＝8.7，1H)，1.62-1.56(m，2H)；1.38-1.24(m，6H)；0.94(t，J＝7.2，3H)。IR(cm
-1，KBr)：3338(m)，2960(m)，2932(m)，2872(m)，2857(m)，1648(s)，1607(w)，1552(s)，1453(s)，1519(m)，1356(m)，1251(m)，1235(m)1159(m)，1142(m)，1112(w)，1144(m)，1087(m)，1013(m)，853(m)，624(m)。MS(m/z)：360.1(M+H
+)。
Embodiment 307
N5-(2, the 4-dichloro benzyl)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (54 μ l, 0.37mmol), (152mg, 0.34mmol) and 2, (66mg 0.34mmol) obtains title compound (110mg, 71%) to the 4-dichloro-benzylamine to bop reagent.M.P.：105-108℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.69-7.60(m，1H)，7.44(d，J＝7.8，1H)；7.39(d，J＝1.8，2H)；7.29-7.19(m，2H)；7.00(t，J＝8.1，2H)，4.65(d，J＝6.3，2H)；3.74(br.s，1H)；3.45(br.s，1H)，2.08(d，J＝8.4，1H)；1.98-1.93(m，2H)；1.68(d，J＝8.4，1H)；1.56(d，J＝8.4，2H)。IR(cm
-1，KBr)：3394(m)，2973(m)，2933(m)，2871(m)，1660(s)，1607(w)，1551(w)，1587(m)，1519(s)，1493(m)，1350(m)，1326(w)，1270(m)1231(m)，1162(m)，1142(m)，1125(m)，1091(m)，1050(m)，985(w)，961(m)，856(m)，824(m)。MS(m/z)：448.1(M+H
+)。
Embodiment 308
N5-(1-phenycyclopropyl)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (54 μ l, 0.37mmol), (152mg, 0.34mmol) and α, (59mg 0.44mmol) obtains title compound (55mg, 40%) to α-cyclopropyl benzylamine to bop reagent.M.P.：90℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.72-7.61(m，1H)，7.51(br.s，1H)；7.35-7.14(m，5H)；7.06-6.96(m，2H)；3.73(br.s，1H)；3.44(br.s，1H)；2.06(d，J＝8.7，1H)；2.00-1.92(m，2H)；1.67(d，J＝8.7，1H)；1.43-1.23(m，6H)。IR(cm
-1，KBr)：3407(w)，3296(m)，3088(w)，3056(w)，2953(m)，1660(s)，1607(m)，1522(s)，1491(m)，1453(m)，1355(m)，1322(w)，1270(m)，1230(m)，1158(m)，1142(m)，1089(m)，965(m)，851(w)。MS(m/z)：406.1[M+H]
+。
Embodiment 309
N5-(2-adamantyl)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 1 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (54 μ l, 0.37mmol), bop reagent (152mg, 0.34mmol) and the 2-adamantanamine hydrochloride (71mg 0.37mmol) obtains title compound x (123mg, 84%).M.P.：159-161℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.74-7.64(m，1H)，7.21(d，J＝7.8，1H)，7.05-6.95(m，2H)；4.23(d，J＝8.4，1H)；3.73(br.s，1H)；3.44(br.s，1H)；2.10-1.79(m，13H)；1.77-1.55(m，7H)。IR(cm
-1，KBr)：3414(m)，2909(s)，2855(m)，1659(s)，1614(w)，1603(w)，1545(s)，1530(s)，1494(m)，1470(w)，1448(w)，1346(w)1290(s)，1272(m)，1226(m)，1154(m)，1122(m)，967(m)，869(m)。MS(m/z)：424.3(M+H
+)。
Embodiment 310
N5-(2-methyl-2-adamantyl)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (54 μ l, 0.37mmol), bop reagent (152mg, 0.34mmol) and 2-methyl-2-adamantanamines (73mg 0.44mmol) obtains title compound (110mg, 73%).M.P.：60℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.71-7.63(m，1H)，7.02-6.95(m，2H)；6.82(br.s，1H)；3.74(br.s，1H)；3.44(br.s，1H)；2.30(br.s，2H)；2.04-1.79(m，9H)；1.73-1.62(m，10H)；1.25(s，3H)。IR(cm
-1，KBr)：3406(m)，2920(s)，2861(s)，1672(s)，1610(m)，1543(s)，1524(s)，1493(s)，1446(s)，1377(w)，1368(w)，1353(m)，1270(s)，1256(m)，1227(m)，1161(m)，1144(m)，1105(m)，965(m)，849(m)，815(w)，578(m)。MS(m/z)：438.1。
Embodiment 311
N7-(3-hydroxyadamantane-1-yl)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (200mg, 0.68mmol), DMF (2.0ml), Et
3N (110 μ l, 0.82mmol), bop reagent (335mg, 0.75mmol) and 3-amino-1-Buddha's warrior attendant alcohol (adamantanol) (115mg 0.68mmol) obtains title compound (185mg, 55%).M.P.：180-182℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.70-7.61(m，1H)；7.04-6.96(m，2H)；6.69(br.s，1H)；3.72(br.s，1H)；3.43(br.s，1H)，2.30(br.s，2H)；2.13(br.s，2H)；2.10-1.94(m，7H)；1.73-1.51(m，8H)；1.33-1.19(m，2H)。IR(cm
-1，KBr)：3418(s)，3369(s)，2913(s)，2885(s)，1651(s)，1610(m)，1548(s)，1519(s)，1495(s)，1455(m)，1421(w)，1359(m)，1341(w)，1314(m)，1270(s)，1233(s)，1145(m)，1115(m)，1102(m)，1049(w)，1032(w)，965(m)，846(m)。MS(m/z)：440.1([M+H]
+)。
Embodiment 312
4-[5-(2,4 difluorobenzene base)-4,5-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 3-diene-3-base formamido group] morpholine
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (53 μ l, 0.37mmol), bop reagent (159mg, 0.36mmol) and the amino morpholine (4-morpholinamine) of 4-(115mg 0.68mmol) obtains title compound (100mg, 78%).M.P.：106-110℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.70-7.61(m，2H)；7.06-6.98(m，2H)；3.85(t，J＝4.5，4H)；3.74(br.s，1H)；3.44(br.s，1H)；2.96(t，J＝4.5，4H)；2.08(d，J＝8.7，1H)；1.97-1.94(m，2H)；1.69(d，J＝9.0，1H)；1.27-1.23(m，2H)。IR(cm
-1，KBr)：3435(m)，3262(m)，3085(w)，2954(m)，2925(m)，2870(m)，1670(s)，1614(m)，1523(s)，1498(m)，1450(m)，1387(w)，1357(m)，1326(w)，1269(s)，1232(s)，1145(m)，1108(m)，1093(m)，1002(m)，966(m)，847(m)。MS(m/z)：375.2([M+H]
+)。
Embodiment 313
N (3)-(tert-pentyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (53 μ l, 0.37mmol), bop reagent (159mg, 0.36mmol) and tert.-amylamine (60 μ l 0.52mmol) obtain title compound (109mg, 88%).M.P.：78-80℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.71-7.61(m，1H)；7.04-7.02(m，2H)；6.66(br.s，1H)；3.74(br.s，1H)；3.43(br.s，1H)，2.07(d，J＝8.4，1H)；1.98-1.78(m，4H)；1.67(d，J＝9.0，1H)；1.41(s，6H)；1.26-1.20(m，2H)；0.91(t，J＝7.2，3H)。MS(m/z)：360.2([M+H]
+)。
Embodiment 314
N (3)-cyclopropane methyl isophthalic acid-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (116 μ l, 0.83mmol), bop reagent (159mg, 0.36mmol) and the amino methyl cyclopropane hydrochloride (55mg 0.51mmol) obtains title compound (101mg, 85%).M.P.：113-115℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.72-7.62(m，1H)；7.06-6.92(m，3H)；3.75(br.s，1H)；3.44(br.s，1H)，3.28(t，J＝5.7，2H)；2.08(d，7.8，1H)；1.96(br.s，2H)；1.68(d，J＝9.3，1H)；1.26(br.s，2H)；1.06-1.02(m，1H)；0.52(d，J＝7.5，2H)；0.26(d，J＝4.2，2H)。MS(m/z)：344.1([M+H]
+)。
Embodiment 315
N (3)-cyclobutyl-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0m1), Et
3N (116 μ l, 0.83mmo1), bop reagent (160mg, 0.36mmol) and the cyclobutyl amine hydrochlorate (115mg 0.68mmol) obtains title compound (92mg, 77%).M.P.：123-125℃。
1H-NMR (δ ppm, CDCl
3, 300MHz): 7.70-7.62 (m, 1H); 7.06-6.96 (m, 3H); 4.56 (quintet, J=7.5,1H); 3.74 (br.s, 1H); 3.43 (br.s, 1H), 2.46-2.36 (m, 2H); 2.07 (d, J=7.8,1H), 2.04-1.95 (m, 5H); 1.78-1.60 (m, 2H); 1.25 (br.s, 2H).MS(m/z)：344.2([M+H]
+)。
Embodiment 316
N (3)-(tetrahydrochysene-2H-4-pyrans methyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (54 μ l, 0.37mmol), bop reagent (160mg, 0.36mmol) and tetrahydrochysene-2H-4-pyranyl methylamine (60mg 0.51mmol) obtains title compound (103mg, 77%).M.P.：107-109℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.70-7.60(m，1H)；7.05-6.96(m，3H)；4.10-3.94(m，2H)；3.75(br.s，1H)；3.46-3.29(m，5H)，2.12-2.02(m，1H)；2.00-1.62(m，5H)；1.44-1.20(m，5H)。MS(m/z)：386.0([M+H]
+)。
Embodiment 317
N (3)-cyclopropyl-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmo1), DMF (1.0ml), Et
3N (54 μ l, 0.37mmol), bop reagent (160mg, 0.36mmol) and cyclopropylamine (36 μ l 0.51mmol) obtain title compound (103mg, 86%).M.P.：59-61℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.70-7.62(m，1H)；7.00(t，J＝9.9，2H)；6.90(br.s，1H)；3.75(br.s，1H)；3.43(br.s，1H)，2.88-2.84(m，1H)；2.07(d，J＝8.7，1H)；2.02-1.90(m，2H)；1.68(d，J＝8.7，1H)；1.32-1.15(m，2H)；0.82(d，J＝5.1，2H)；0.62(br.s，2H)。MS(m/z)：328.0([M+H]
+)。
Embodiment 318
N (3)-(4-methylpiperazine subbase)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (51 μ l, 0.37mmol), bop reagent (165mg, 0.37mmol) and N-amino-N methyl piperazine (61 μ l 0.51mmol) obtain title compound (97mg, 72%).M.P.：154-156℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.70-7.62(m，1H)；7.58(br.s，1H)；7.08-6.96(m，2H)；3.74(br.s，1H)；3.44(br.s，1H)；3.03(br.s，4H)；2.76(br.s，4H)；2.41(s，3H)；2.08(d，J＝9.3，1H)；2.00-1.94(m，2H)；1.68(d，J＝8.1，1H)；1.30-1.24(m，2H)。
Embodiment 319
(2R)-and 2-[5-(2,4 difluorobenzene base)-4,5-diaza tricyclic [5.2.1.0.
2,6] last of the ten Heavenly stems-2 (6), 3-diene-3-base formamido group]-2-phenylacetic acid methyl esters
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (300mg, 1.03mmol), DMF (3.0ml), Et
3N (343 μ l, 2.48mmol), bop reagent (502mg, 1.13mmol) and R-(-)-2-phenyl glycine methyl ester hydrochloride (208mg 1.03mmol) obtains title compound (334mg, 74%).M.P.：61-63℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.78-7.64(m，2H)；7.45(d，J＝7.8，2H)；7.40-7.31(m，3H)；7.04-6.95(m，2H)；5.76(dd，J＝2.1，7.2，1H)；3.76(2s，3H)；3.71(br.S，1H)；3.44(br.S，1H)；2.11-2.01(m，1H)；1.99-1.90(m，2H)；1.66(d，J＝8.7，1H)；1.30-1.21(m，2H)。IR(cm
-1，KBr)：3411(m)，3065(w)，2953(m)，2872(w)，1744(s)，1672(s)，1610(m)，1541(s)，1523(s)，1489(s)，1454(m)，1358(m)，1328(w)，1295(w)，1271(s)，1213(m)，1160(m)，1145(m)，1122(m)，1093(w)，966(m)，851(m)。MS(m/z)：480.24([M+H]
+)。
Embodiment 320
N (3)-[(1R)-2-hydroxyl-1-phenylethyl]-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
Title compound is synthetic by being similar to embodiment 191 described methods.Use embodiment 319 (235mg, 0.54mmol), THF (4ml) and LiBH
4(24mg 1.09mmol) obtains title compound (153mg, 69%).M.P.：68-70℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.25(d，J＝9.0，1H)；7.87-7.82(m，1H)；7.63-7.58(m，1H)；7.36-7.22(m，6H)；5.05-4.94(m，2H)，3.73-3.67(m，2H)；3.50(br.s，1H)；3.45(br.s，1H)；2.05-1.84(m，3H)；1.70-1.62(m，1H)；1.24-1.20(m，2H)。MS(m/z)：452.17(M+H
+)。
Embodiment 321
N (3)-(tertiary butyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 16 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (52 μ l, 0.38mmol), bop reagent (157mg, 0.35mmol) and 2-amino-2-methyl propane (53 μ l 0.51mmol) obtain title compound (56mg, 47%).M.P.：170-173℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.62(d，J＝8.7，2H)；7.43(d，J＝8.7，2H)；6.78(br.s，1H)；3.75(br.s，1H)；3.65(br.s，1H)；2.08-1.99(m，1H)；2.02-1.94(m，2H)；1.70(d，J＝8.4，1H)；1.47(s，9H)；1.28-0.99(m，2H)。
Embodiment 322
N (3)-(tetrahydrochysene-2-furyl methyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (54 μ l, 0.37mmol), bop reagent (160mg, 0.36mmol) and tetrahydrochysene-2-furyl methyl amine (54 μ l 0.51mmol) obtain title compound (82mg, 64%).M.P.：91-93℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.74-7.62(m，1H)；7.15(br.s，1H)；7.08-6.94(m，2H)；4.12-4.00(m，1H)；3.94-3.86(m，1H)；3.80-3.68(m，3H)；3.50-3.30(m，2H)，2.10-1.85(m，6H)；1.72-1.58(m，1H)；1.25(br.s，3H)。MS(m/z)：374.2([M+H]
+)。
Embodiment 323
N (3)-(tertiary butyl)-1-(4-fluorophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 20 (100mg, 0.36mmol), DMF (1.0ml), Et
3N (54 μ 1,0.40mmol), bop reagent (170g, 0.38mmol) and tert-butylamine (57 μ l 0.55mmol) obtain title compound (102mg, 85%).M.P.：131-133℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.66-7.60(m，2H)；7.20-7.12(m，2H)；6.78(br.s，1H)；3.76(br.s，1H)；3.63(br.s，1H)；2.15-2.10(m，1H)；2.00-1.92(m，2H)；1.74-1.68(m，1H)；1.47(s，9H)；1.30-1.16(m，2H)。MS(m/z)：328.15([M+H]
+)。
Embodiment 324
N (3)-(tertiary butyl)-1-(4-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 19 (100mg, 0.30mmol), DMF (1.0ml), Et
3N (45 μ l, 0.33mmol), bop reagent (139mg, 0.31mmol) and 2-amino-2-methyl propane (47 μ l 0.45mmol) obtain title compound (87mg, 75%).M.P.：157-159℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.57(s，4H)；6.78(br.s，1H)；3.75(br.s，1H)；3.65(br.s，1H)；2.18-2.07(m，1H)；2.02-1.92(m，2H)；1.70(d，J＝9.0，1H)；1.47(s，9H)；1.28-0.99(m，2H)。
Embodiment 325
N (3)-(tertiary butyl)-1-(3, the 4-dichlorophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 29 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (47 μ l, 0.34mmol), bop reagent (143mg, 0.32mmol) and 2-amino-2-methyl propane (48 μ l 0.46mmol) obtain title compound (77mg, 66%).M.P.：205-207℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.83(s，1H)；7.52(s，2H)；6.77(br.s，1H)；3.75(br.s，1H)；3.67(br.s，1H)；2.11(d，J＝8.7，1H)；1.99(d，6.3，2H)；1.71(d，J＝8.7，1H)；1.48(s，9H)；1.28-1.16(m，2H)。
Embodiment 326
(2S)-and 2-[5-(2,4 difluorobenzene base)-4,5-diaza tricyclic [5.2.1.0.
2,6] last of the ten Heavenly stems-2 (6), 3-diene-3-base formamido group]-2-(4-fluorophenyl) methyl acetate
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (400mg, 1.37mmol), DMF (4.0ml), Et
3N (450 μ l, 3.31mmol), bop reagent (670mg, 1.51mmol) and (S)-(-)-(302mg 1.37mmol) obtains title compound (543mg, 86%) to 2-(4-fluorophenyl) glycine methyl ester hydrochloride.M.P.：51-52℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.78-7.68(m，2H)；7.44-7.41(m，2H)；7.06-6.95(m，4H)；5.63(d，J＝6.9，1H)；3.77，3.76(2s，3H)；3.70(brs，1H)；3.44(br.s，1H)；2.10-2.02(m，1H)；2.00-1.90(m，2H)；1.67(d，J＝7.8，1H)；1.30-1.19(m，2H)。
Embodiment 327
N (3)-(tertiary butyl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 17 (100mg, 0.30mmol), DMF (1.0ml), Et
3N (48 μ l, 0.34mmol), bop reagent (144mg, 0.32mmol) and 2-amino-2-methyl propane (48 μ l 0.46mmol) obtain title compound (90mg, 77%).M.P.：129-131℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.55(d，J＝2.4，1H)；7.45(d，J＝8.4，1H)；7.37(dd，J＝8.4，2.1，1H)；6.71(br.s，1H)；3.76(br.s，1H)；3.34(br.s，1H)；2.11(d，J＝9.0，1H)；2.02-1.82(m，2H)；1.68(d，J＝8.7，1H)；1.45(s，9H)；1.33-1.12(m，2H)。
Embodiment 328
N (3)-(4-hydroxy phenyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (51 μ l, 0.37mmol), bop reagent (160mg, 0.36mmol) and 4-amino-phenol (56mg 0.51mmol) obtains title compound (112mg, 85%).M.P.：189-191℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.56(br.s，1H)；7.75-7.64(m，1H)；7.52(d，J＝9.3，2H)；7.08-6.99(m，2H)；6.82(d，J＝8.7，2H)；5.30(br.s，1H)；3.79(br.s，1H)；3.47(br.s，1H)；2.11(d，J＝8.7，1H)；2.00-1.94(m，2H)；1.71(d，J＝8.7，1H)；1.32-1.22(m，2H)。
Embodiment 329
N (3)-(tertiary butyl)-1-(2-oxyethyl group, 4-fluorophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 30 (100mg, 0.31mmol), DMF (1.0ml), Et
3N (50 μ l, 0.34mmol), bop reagent (146mg, 0.33mmol) and 2-amino-2-methyl propane (40 μ l 0.37mmol) obtain title compound (96mg, 82%).M.P.：117-120℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.54-7.44(m，1H)，6.82-6.69(m，3H)；4.12-4.00(m，2H)；3.73(br.s，1H)；3.31(br.s，1H)；2..06(d，J＝8.1，1H)；1.98-1.82(m，2H)；1.65(d，J＝8.4，1H)；1.45(s，9H)；1.38(t，J＝6.9，3H)；1.28-1.20(m，2H)。
Embodiment 330
N (3)-(2-furyl methyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (57 μ l, 0.41mmol), bop reagent (167mg, 0.37mmol) and furfuryl group amine (38 μ l 0.41mmol) obtain title compound (98mg, 77%).M.P.：99-100℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.71-7.61(m，1H)；7.36(br.s，1H)；7.19-7.11(m，1H)；7.00(t，J＝8.4，2H)；6.30(d，J＝7.5，2H)；4.60(d，J＝5.1，2H)；3.76(br.s，1H)；3.44(br.s，1H)；2.08(d，J＝7.5，1H)；2.02-1.90(m，2H)，1.68(d，J＝8.1，1H)；1.32-1.22(m，2H)。
Embodiment 331
N (3)-(2-thenyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (57 μ l, 0.37mmol), bop reagent (167mg, 0.37mmol) and 2-thenyl amine (42 μ l 0.41mmol) obtain title compound (106mg, 80%).M.P.：103-105℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.70-7.58(m，1H)；7.24-7.12(m，2H)；7.05-6.94(m，4H)；4.78(d，J＝4.5，2H)；3.77(br.s，1H)；3.44(br.s，1H)；2.08(d，J＝6.3，1H)；2.02-1.89(m，2H)，1.69(d，J＝9.0，1H)；1.34-1.20(m，2H)。
Embodiment 332
N (3)-[(1S)-2-hydroxyl-1-(4-fluorophenyl) ethyl]-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
Title compound is synthetic by being similar to embodiment 191 described methods.Use embodiment 326 (400mg, 0.87mmol), THF (6ml) and LiBH
4(38mg 1.75mmol) obtains title compound (288mg, 76%).M.P.：116-119℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.65(q，J＝8.4，1H)；7.49-7.41(m，1H)；7.40-7.32(m，2H)；7.08-6.96(m，4H)；5.24-5.18(m，1H)，3.96(d，J＝5.1，2H)；3.72(br.s，1H)；3.44(br.s，1H)；2.12-2.02(m，2H)；1.99-1.92(m，2H)；1.68(d，J＝8.7，1H)；1.28-1.20(m，2H)。
Embodiment 333
(2S)-and 2-[5-(2,4 difluorobenzene base)-4,5-diaza tricyclic [5.2.1.0.
2,6] last of the ten Heavenly stems-2 (6), 3-diene-3-base formamido group]-4-methylvaleric acid methyl esters
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (104 μ l, 0.74mmol), bop reagent (159mg, 0.37mmol) and L-leucine methyl ester hydrochloride (75mg 0.50mmol) obtains the title compound (87mg, 60%) of waxy solid.
1H-NMR(δppm，CDCl
3，300MHz)：7.78-7.65(m，1H)；7.21-7.10(m，1H)；7.12-6.95(m，2H)；4.90-4.75(m，1H)；3.75(s，4H)；3.45(br.s，1H)；2.12-2.02(m，1H)；2.00-1.90(m，2H)；1.80-1.60(m，6H)；1.34-1.18(m，2H)，1.02-0.90(m，4H)。
Embodiment 334
N (3)-(diamantane-1-yl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 21 (100mg, 0.34mmol), DMF (1.0ml), Et
3N (50 μ l, 0.37mmol), bop reagent (159mg, 0.36mmol) and the 1-adamantanamines (78mg 0.51mmol) obtains title compound (88mg, 60%).M.P.：146-148℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.72-7.60(m，1H)；7.04-6.94(m，2H)；6.61(br.s，1H)；3.73(br.s，1H)；3.42(br.s，1H)；2.20-2.03(m，10H)；1.98-1.92(m，2H)；1.80-1.52(m，4H)；1.44-1.19(m，5H)。
Embodiment 335a
N (3)-(tertiary butyl)-1-(4-luorobenzyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 32a (100mg, 0.34mmol), DMF (1.0ml), Et
3N (55 μ l, 0.39mmol), bop reagent (162mg, 0.36mmol) and 2-amino-2-methyl propane (44 μ l 0.41mmol) obtain buttery title compound (85mg, 71%).
1H-NMR(δppm，CDCl
3，300MHz)：7.24-7.14(m，2H)；7.04(t，J＝8.4，2H)；6.67(br.s，1H)；5.18(s，2H)；3.64(br.s，1H)；3.03(br.s，1H)；1.98-1.65(m，3H)，1.55(d，J＝8.7，1H)；1.45(s，9H)；1.18-1.08(m，1H)；0.86-0.74(m，1H)。
Embodiment 335b
N (3)-(tertiary butyl)-2-(4-luorobenzyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 32b (50mg, 0.17mmol), DMF (1.0ml), Et
3N (30 μ l, 0.19mmol), bop reagent (80mg, 0.18mmol) and 2-amino-2-methyl propane (20 μ l 0.19mmol) obtain title compound (40mg, 67%).M.P.：130-134℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.30-7.20(m，2H)；6.94(t，J＝8.7，2H)；5.80(d，J＝14.7，1H)；5.72(br.s，1H)；5.43(d，J＝14.4，1H)；3.40(br.s，1H)；3.29(br.s，1H)，1.98-1.88(m，3H)；1.68(d，J＝8.4，1H)；1.42(s，9H)；1.21(d，J＝9.6，2H)。
Embodiment 336a
N (3)-(tertiary butyl)-1-(4-methyl-benzyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 31a (100mg, 0.35mmol), DMF (1.0ml), Et
3N (55 μ l, 0.39mmol), bop reagent (164mg, 0.37mmol) and 2-amino-2-methyl propane (56 μ l 0.53mmol) obtain title compound (71mg, 65%).
1H-NMR(δppm，CDCl
3，300MHz)：7.16(d，J＝8.1，2H)；7.10(d，J＝8.1，2H)；6.69(br.s，1H)；5.17(s，2H)；3.63(br.s，1H)；2.99(br.s，1H)；2.34(s，3H)，1.94-1.78(m，2H)；1.72-1.64(m，1H)；1.53(d，J＝8.7，1H)；1.45(s，9H)；1.18-1.08(m，1H)；0.90-0.78(m，1H)。
Embodiment 336b
N (3)-(tertiary butyl)-2-(4-methyl-benzyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
Title compound is synthetic by being similar to embodiment 101 described methods.By use intermediate 32b (68mg, 0.24mmol), DMF (1.0ml), Et
3N (38 μ l, 0.26mmol), bop reagent (111mg, 0.25mmol) and 2-amino-2-methyl propane (38 μ l 0.41mmol) obtain title compound (44mg, 54%).M.P.：142-144℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.18(d，J＝7.8，2H)；7.07(d，J＝7.8，2H)；5.80(d，J＝14.7，1H)；5.71(br.s，1H)；5.41(d，J＝14.7，1H)；3.39(br.s，1H)；3.28(br.s，1H)；2.28(s，3H)；1.98-1.89(m，3H)；1.70-1.62(m，1H)；1.42(s，9H)，1.20(d，J＝9.0，2H)。
Embodiment 401
N (3)-phenyl-1-(2,4 dichloro benzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 22 (100mg, 0.27mmol), DMF (1.0ml), Et
3N (43 μ l, 0.30mmol), bop reagent (127mg, 0.29mmol) and aniline (28 μ l 0.30mmol) obtain title compound (85mg, 71%).M.P.：112-115℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.64(br.s，1H)；7.67(d，J＝7.8，2H)；7.59(br.s，1H)；7.47-7.25(m，4H)；7.09(t，J＝7.5，1H)；3.29(d，J＝3.6，1H)；2.22-2.08(m，1H)；1.83(br.t，J＝9.3，1H)；1.43-1.20(m，2H)；0.93(s，6H)；0.85(s，3H)。IR(cm
-1，KBr)：3274(s)，3251(s)，2955(m)，2928(s)，2869(m)，1663(s)，1517(s)，1546(s)，1533(m)，1596(s)，1502(s)，1474(m)，1436(s)，1388(m)，1345(m)，1323(s)，1252(m)，1220(m)，1229(m)，1129(m)，1117(m)，1102(m)，1077(m)，1062(s)，1014(m)，1001(m)。MS(m/z)：440.3([M+H]
+)。
Embodiment 402
N (3)-[(2-fluorophenyl) amino]-1-(2,4 dichloro benzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 22 (100mg, 0.27mmol), DMF (1.0ml), Et
3N (43 μ l, 0.30mmol), bop reagent (127mg, 0.29mmol) and 2-fluorobenzene hydrazine (49mg 0.30mmol) obtains title compound (85mg, 83%).M.P.：72-80℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.54(br.s，1H)；7.60(br.s，1H)；7.42(d，J＝8.4，1H)；7.38(d，J＝8.7，1H)；7.14-6.95(m，3H)；6.87-6.78(m，1H)；3.21(d，J＝3.3，1H)；2.20-2.06(m，1H)；1.82(br.t，J＝9.0，1H)；1.41-1.18(m，2H)；0.93(s，3H)；0.91(s，3H)；0.82(s，3H)。IR(cm
-1，KBr)：3413(m)，2912(s)，2845(m)，1667(s)，1535(s)，1497(s)，1478(s)，1352(m)，1233(m)，1219(m)，1162(m)，1103(m)，1088(m)，996(m)，866(w)。MS(m/z)：473.10([M+H]
+)。
Embodiment 403
N (3)-[(2,4 difluorobenzene base) amino]-1-(2,4 dichloro benzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 22 (100mg, 0.27mmol), DMF (1.0ml), Et
3N (43 μ l, 0.31mmol), (127mg, 0.29mmol) and 3, (55mg 0.31mmol) obtains title compound (90mg, 67%) to 5-difluorophenyl hydrazine hydrochloride to bop reagent.M.P.：145-148℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.78(br.s，1H)；7.60(d，J＝1.8，1H)；7.45-7.35(m，2H)；7.10-6.98(m，1H)；6.86-6.70(m，2H)；3.22(d，J＝3.6，1H)；2.20-2.05(m，1H)；1.88-1.80(m，1H)；1.40-1.20(m，2H)；0.93，0.88，0.82(3s，9H)。IR(cm
-1，KBr)：3339(m)，3269(m)，2979(m)，2961(m)，1678(s)，1508(s)，1472(m)，1211(m)，1132(m)，1102(m)，959(m)，844(m)。MS(m/z)：491.10([M+H]
+)。
Embodiment 404
N (3)-[(3-chloropyridine-2-yl) amino]-1-(2,4 dichloro benzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 22 (100mg, 0.27mmol), DMF (1.0ml), Et
3N (43 μ l, 0.31mmol), bop reagent (127mg, 0.29mmol) and 3-chloro-2-hydrazino pyridine (45mg 0.31mmol) obtains title compound (75mg, 56%).M.P.：142-145℃。
1H-NMR(δppm，DMSO-d
6，300MHz)：9.88(br.s，1H)；8.42(br.s，1H)；8.00(d，J＝9.6，2H)；7.30-7.55(m，3H)；6.75(br.s，1H)；3.05(br.s，1H)；2.09(br.s，1H)；1.80(br.s，1H)；1.40-1.05(m，2H)；0.88，0.86，0.80(3s，9H)。IR(cm
-1，KBr)：3339(m)，3269(m)，2961(m)，2979(m)，1678(s)，1508(s)，1472(m)，1437(m)，1312(m)，1211(m)，1132(m)，1102(m)，959(m)，844(m)。MS(m/z)：490.00([M+H]
+)。
Embodiment 405
N (3)-(diamantane-1-yl)-1-(2,4 difluorobenzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 23 (120mg, 0.36mmol), DMF (1.0ml), Et
3N (60 μ l, 0.43mmol), bop reagent (159mg, 0.36mmol) and the 1-adamantanamines (54mg 0.36mmol) obtains title compound (120mg, 71%).M.P.：162-165℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.50-7.40(m，1H)；7.03-6.93(m，2H)；6.59(s，1H)；3.21(d，J＝3.6，1H)；2.13-2.07(m，9H)；1.84-1.63(m，7H)；1.37-1.24(m，3H)；0.97(s，3H)；0.90(s，3H)；0.77(s，3H)。IR(cm
-1，KBr)：3299(m)，2958(m)，2910(s)，1652(s)，1614(m)，1605(m)，1548(s)，1524(s)，1499(s)，1454(m)，1358(m)，1324(w)，1269(m)，1224(s)，1202(m)，1143(m)，1121(w)，1017(w)，981(w)，945(w)，847(m)。MS(m/z)：466.2([M+H]
+)。
Embodiment 406
N (3)-(1,3,3-trimethylammonium two ring [2.2.1] heptan-2-yl)-1-(2,4 difluorobenzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 23 (120mg, 0.36mmol), DMF (1.0ml), Et
3N (120 μ l, 0.86mmol), (159mg, 0.36mmol) and 1S, in 2-1,3,3-trimethylammonium-two ring [2.2.1] heptan-(68mg 0.36mmol) obtains title compound (95mg, 57%) to 2-base amine hydrochlorate to bop reagent.M.p.：171-173℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.56-7.45(m，1H)，7.05-6.90(m，2H)；6.89(d，J＝9.0，1H)；3.76(d，J＝9.0，1H)；3.22(t，J＝3.9，1H)；2.19-2.06(m，1H)；1.86-1.62(m，4H)；1.54-0.74(m，24H)。IR(cm
-1，KBr)：3419(m)，2954(s)，2871(s)，1672(s)，1612(m)，1542(s)，1521(s)，1493(s)，1388(m)，1328(w)，1318(w)，1220(m)，1176(w)，1117(s)，1087(m)，1018(m)，962(m)，859(m)，791(w)。MS(m/z)：468.3([M+H]
+)。
Embodiment 407
N (3)-(1-methyl isophthalic acid-phenylethyl))-and 1-(2,4 difluorobenzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 23 (120mg, 0.36mmol), DMF (1.0ml), Et
3N (60 μ l, 0.43mmol), bop reagent (159mg, 0.36mmol) and 2-phenyl third-2-base amine (48mg 0.36mmol) obtains title compound (107mg, 66%).M.P.：114-117℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.82-7.73(m，1H)；7.66-7.54(m，2H)；7.39(d，J＝7.8，2H)；7.35-7.26(m，3H)；7.22-7.15(m，1H)；2.95(br.d，J＝2.7，1H)；2.12-2.05(m，1H)；1.85-1.74(m，1H)；1.65(d，J＝9.6，2H)；1.30-0.95(m，1H)；0.90(s，3H)；0.85(s，3H)；0.71(s，3H)。IR(cm
-1，KBr)：3390(m)，2973(m)，2931(m)，2871(m)，1605(w)，1583(w)，1542(s)，1526(s)，1494(s)，1446(m)，1392(w)，1378(w)，1360(w)，1319(w)，1268(m)，1108(m)，928(m)，870(m)，766(m)。MS(m/z)：450.0([M+H]
+)。
Embodiment 408
N (the 3)-tertiary butyl-1-(2,4 difluorobenzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-methylene radical-indazole-3-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 23 (100mg, 0.30mmol), DMF (1.0ml), Et
3N (46 μ l, 0.33mmol), bop reagent (139mg, 0.31mmol) and tert-butylamine (32mg 0.45mmol) obtains title compound (90mg, 77%).M.P.：150-154℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.53-7.43(m，1H)；7.03-6.95(m，2H)；6.71(br.s，1H)；3.22(d，J＝3.9，1H)；2.13-2.06(m，1H)；1.84-1.76(m，1H)；1.45(s，9H)；1.32-1.24(m，2H)；0.97，0.90，0.78(3s，9H)。IR(cm
-1，KBr)：3402(s)，3070(w)，2966(s)，2873(m)，1671(s)，1613(m)，1549(m)，1500(s)，1472(w)，1448(m)，1390(m)，1364(m)，1322(m)，1268(s)，1219(m)，1139(s)，1116(m)，1090(m)，1018(m)，961(m)，861(m)，846(m)。MS(m/z)：388.2([M+H]
+)。
Embodiment 409
(2R)-and 2-[1-(2,4 difluorobenzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formamido group]-2-phenylacetic acid methyl esters
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 23 (300mg, 0.90mmol), DMF (4.0ml), Et
3N (284 μ l, 0.33mmol), bop reagent (418mg, 0.94mmol) and (R)-(-)-(272mg 1.35mmol) obtains title compound (290mg, 67%) to 2-phenyl glycine methyl ester hydrochloride.M.P.：107-109℃。
1H-NMR(δppm，DMSO-d
6，300MHz)：8.42-8.36(m，1H)；7.78-7.72(m，1H)；7.63-7.56(m，1H)；7.44-7.28(m，6H)；5.64(d，J＝7.5，1H)；3.65，3.64(2s，3H)；3.03(br.s，1H)；2.12-2.02(m，1H)；1.84-1.76(m，1H)；1.26-1.20(m，1H)；1.12-1.00(m，1H)；0.91，0.88(2s，6H)；0.74，0.70(2s，3H)。MS(m/z)：480.24([M+H]
+)。
Embodiment 410
N (3)-[(1R)-2-hydroxyl-1-phenylethyl]-1-(2,4 difluorobenzene base)-7,8, the 8-trimethylammonium)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide:
Title compound is synthetic by being similar to embodiment 192 described methods.Use embodiment 409 (170mg, 0.34mmol), THF (3ml) and LiBH
4(15mg 0.68mmol) obtains title compound (120mg, 75%).M.P.：68-70℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.52-7.42(m，1H)；7.40-7.30(m，6H)；7.04-6.94(m，2H)；5.26-5.16(m，1H)，4.04-3.94(m，2H)；3.20(d，J＝3.6，1H)；3.02(br.s，1H)；2.13-2.06(m，1H)；1.84-1.76(m，1H)；1.34-1.20(m，2H)；0.98，0.91(2s，6H)；0.79，0.76(2s，3H)。MS(m/z)：452.17(M+H
+)。
Embodiment 411
(4S, 7R)-N (the 3)-tertiary butyl-1-(2,4 difluorobenzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-methylene radical-indazole-3-methane amide:
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 23 (100mg, 0.30mmol), DMF (1.0ml), Et
3N (45 μ l, 0.33mmol), bop reagent (139mg, 0.31mmol) and 2-amino-2-methyl propane (47 μ l 0.45mmol) obtain title compound (65mg, 56%).M.P.：173-175℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.54-7.44(m，1H)；7.04-6.94(m，2H)；6.73(br.s，1H)；3.22(d，J＝3.6，1H)；2.13-2.06(m，1H)；1.85-1.76(m，1H)；1.45(s，9H)；1.33-1.24(m，2H)；0.97，0.90，0.78(3s，9H)。
Embodiment 501
N (12)-benzyl-10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,70
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 24 (90mg, 0.23mmol), DMF (1.0ml), Et
3N (36 μ l, 0.26mmol), bop reagent (103mg, 0.23mmol) and benzylamine (25 μ l 0.23mmol) obtain title compound (40mg, 33%).M.P.：164-166℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.60(s，1H)；7.40-7.22(m，8H)；7.20-7.00(m，4H)；5.06(s，1H)；4.60(d，J＝6.3，2H)；4.28(s，1H)；2.00-1.70(m，4H)。MS(m/z)：474.0([M+H]
+)。
Embodiment 502
N (12)-piperidines-1-base-10-(2,4-two-chloro-phenyl-)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 24 (90mg, 0.23mmol), DMF (1.0ml), Et
3N (36 μ l, 0.26mmol), bop reagent (105mg, 0.24mmol) and the 1-amino piperidine (26 μ l 0.23mmol) obtain title compound (40mg, 37%).M.P.：164-166℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.61(s，1H)；7.44-7.32(m，3H)；7.16-7.05(m，4H)；5.02(s，1H)；4.27(s，1H)；2.83(br.s，4H)；2.20-1.70(m，8H)；1.41(br.s，2H)。IR(cm
-1，KBr)：2934(s)，2854(m)，1648(s)，1551(m)，1509(s)，1488(s)，1441(s)，1381(m)，1355(m)，1342(m)，1146(m)，1097(m)，1070(m)，898(m)，818(w)。MS(m/z)：467.0([M+H]
+)。
Embodiment 503
N (12)-piperidines-1-base-10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-carboxamide hydrochloride
(250mg, 0.53mmol) solution in ether (5ml) is handled with the full diethyl ether solution that closes of HCl (10ml), and at room temperature keeps 1 hour, and precipitated solid is concentrated, and obtains title compound (200mg, 74%) with embodiment 502.M.P.：100-110℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.61(s，1H)；7.58(br.s，1H)；7.41(s，2H)；7.33(d，J＝7.5，1H)；7.15-7.00(m，3H)；5.03(br.s，1H)；4.27(br.s，1H)；2.86(br.s，4H)；1.80-1.70(m，8H)；1.43(br.s，2H)。
Embodiment 504
N (12)-[(N '-cyclohexyl-N '-methyl) amino]-10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 24 (100mg, 0.26mmol), DMF (1.0ml), Et
3N (40 μ l, 0.29mmol), bop reagent (121mg, 0.27mmol) and N-cyclohexyl-N-methyl hydrazine (37mg 0.29mmol) obtains title compound (70mg, 55%).M.P.：127-132℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.62(s，1H)；7.52(br.s，1H)；7.42-7.20(m，3H)；7.20-7.00(m，3H)；5.05(s，1H)；4.28(s，1H)；2.69(s，3H)；2.82-2.55(m，1H)；1.96(br.s，2H)；1.88-1.70(m，6H)；1.40-1.00(m，6H)。IR(cm
-1，KBr)：3422(s)，2930(s)，2854(s)，1667(s)，1508(s)，1474(s)，1381(m)，1354(m)，1280(m)，1248(w)，1134(m)，1118(m)，1083(m)，1012(m)，815(m)。MS(m/z)：495.1([M+H]
+)。
Embodiment 505
N (12)-N '-[(2,4 dichloro benzene base)-N '-methyl] amino)-10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 24 (100mg, 0.26mmol), DMF (1.0ml), Et
3N (40 μ l, 0.29mmol), bop reagent (120mg, 0.27mmol) and N-(2,4 dichloro benzene base)-N-methyl hydrazine (88mg 0.46mmol) obtains title compound (80mg, 55%).M.P.：220-223℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.82(s，1H)；7.61(d，J＝1.2，1H)；7.42-7.24(m，6H)；7.15-7.05(m，3H)；4.94(s，1H)；4.28(s，1H)；3.33(s，3H)；1.79-1.69(m，4H)。IR(cm
-1，KBr)：3376(s)，3005(w)，2964(m)，2867(m)，1682(s)，1546(m)，1500(s)，1471(s)，1352(m)，1271(m)，1241(m)，1116(m)，1100(m)，811(m)，759(m)。MS(m/z)556.9([M+H]
+)。
Embodiment 506
N (12)-(diamantane-1-yl)-10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate
24 (100mg, 0.26mmol), DMF (1ml), Et
3N (40 μ l, 0.28mmol), bop reagent (121mg, 0.27mmol) and the 1-adamantanamines (43mg 0.28mmol) obtains title compound (80mg, 59%).M.P.：120-124℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.60(s，1H)；7.46-7.31(m，3H)；7.20-6.99(m，3H)；6.59(br.s?3H)；5.04(br.s，1H)；4.26(br.s，1H)；2.12(br.s，9H)；1.90-1.54(m，10H)。IR(cm
-1，KBr)：3396(m)，2906(s)，2849(s)，1670(s)，1548(s)，1537(s)，1508(s)，1483(s)，1457(m)，1356(m)，1279(w)，1167(m)，1072(m)，818(m)。MS(m/z)：540.2(100，[M+Na]+)，518.2(25，[M+H]
+)。
Embodiment 507
N12-(1,3,3-trimethylammonium two ring [2.2.1] heptan-2-yl)-10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2 (7), 3,5,9 (13), 11-pentaene-12-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 24 (100mg, 0.26mmol), DMF (1.0ml), Et
3N (40 μ l, 0.28mmol), (120mg, 0.27mmol) and 1S, in 2-amino-1,3, (43mg 0.28mmol) obtains title compound (95mg, 70%) to 3-trimethylammonium-two ring [2.2.1] heptane to bop reagent.M.P.：82-85℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.60(br.s，1H)，7.43-7.07(m，6H)；6.92(d，J＝7.8，1H)；5.04(br.s，1H)；4.29(br.s，1H)；3.77(br.s，1H)；1.92-1.58(m，8H)；1.42-0.76(m，12H)。
Embodiment 508
N12-(1-methyl isophthalic acid-phenylethyl)-10-(2,4, dichlorophenyl)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 24 (100mg, 0.26mmol), DMF (1.0ml), Et
3N (41 μ l, 0.28mmol), (120mg, 0.27mmol) and α, (56mg 0.41mmol) obtains title compound (70mg, 53%) to the alpha-alpha-dimethyl benzylamine to bop reagent.M.P.：190℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.61(br.s，1H)；7.45-7.05(m，12H)；4.98(br.s，1H)；4.26(br.s，1H)；1.80(s，3H)；1.77(s，3H)；1.75-1.58(m，4H)。
Embodiment 509
N12-(1-methyl isophthalic acid-phenylethyl)-10-(2,4 difluorobenzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,70
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 25 (100mg, 0.28mmol), DMF (1.0ml), Et
3N (44 μ l, 0.31mmol), (131mg, 0.29mmol) and α, (58mg 0.42mmol) obtains title compound (78mg, 58%) to the alpha-alpha-dimethyl benzylamine to bop reagent.M.P.：175-178℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.64-7.54(m，1H)；7.43(d，J＝7.5，2H)；7.35-7.02(m，10H)；4.98(br.s，1H)；4.35(br.s，1H)；1.81，1.77(2s，6H)；1.80-1.68(m，4H)。IR(cm
-1，KBr)：3403(s)，3077(m)，2961(m)，2973(m)，1665(s)，1609(m)，1526(s)，1493(s)，1471(m)，1446(m)，1383(w)，1361(w)，1328(w)，1269(m)，1256(m)，1160(m)，1146(m)，1095(m)，846(m)，758(m)，699(m)。MS(m/z)：470.2([M+H]
+)。
Embodiment 601
N (12)-benzyl-16-(4-chloro-phenyl-)-10-(2,4 dichloro benzene base)-15,17-dioxo-10,11,16-three azepine five rings [6.5.5.0
2,7.0
9,13.0
14,18] 18 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 26 (100mg, 0.29mmol), DMF (1.0ml), Et
3N (49 μ l, 0.35mmol), (130mg, 0.29mmol) and α, (47mg 0.35mmol) obtains title compound (90mg, 67%) to α-Er Jiajibianji amine to bop reagent.M.P.：84-87℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.92-7.79(m，2H)，7.71-7.61(m，1H)；7.41-7.15(m，8H)；6.98-6.90(m，2H)；4.43(br.s，1H)；4.36(s，1H)；2.88(d，J＝7.8，1H)；2.70(d，J＝7.5，1H)；1.66，1.64(2s，6H)；IR(cm
-1，KBr)：3404(m)，2974(w)，2933(w)，2867(w)，1679(s)，1608(w)，1522(s)，1507(m)，1447(m)，1382(w)，1362(w)，1347(w)，1270(m)，1257(m)，1209(m)，1133(m)，1029(w)，1006(w)，965(m)，847(m)，786(w)，761(m)。MS(m/z)：456.2[M+H]
+)；338.1(100)。
Embodiment 602
N (12)-piperidines-1-base-16-(4-chloro-phenyl-)-10-(2,4 dichloro benzene base)-15,17-dioxo-10,11,16-three azepine five rings [6.5.5.0
2,7.0
9,13.0
14,18] 18 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 26 (100mg, 0.18mmol), DMF (1.0ml), Et
3N (30 μ l, 0.20mmol), bop reagent (85mg, 0.19mmol) and the 1-amino piperidine (22 μ l 0.20mmol) obtain title compound (35mg, 31%).M.P.：150℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.66(s，1H)；7.60(br.s，1H)；7.46-7.40(m，3H)；7.26-7.17(m，5H)；6.44(d，J＝8.4，2H)；5.58(d，J＝3.3，1H)；4.81(d，J＝3.3，1H)；3.58(dd，J＝8.4，3.3，1H)；3.46(dd，J＝8.1，3.3，1H)；2.89-1.20(m，10H)。IR(cm
-1，KBr)：MS(m/z)：646.2([M+H]
+)。
Embodiment 701
N12-benzyl-10-(2,4 difluorobenzene base)-10,11-diaza Fourth Ring [6.5.1.0
2,7.0
9,13] 14 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 27 (100mg, 0.29mmol), DMF (1.0ml), Et
3N (49 μ l, 0.35mmol), bop reagent (130mg, 0.29mmol) and benzylamine (32 μ l 0.29mmol) obtain title compound (90mg, 71%).M.P.：65-67℃。
1H-NMR(δppm，CDCl
3，300MHz)：8.70(br.s，1H)；7.85-7.75(m，1H)；7.65(t，J＝9.0，1H)；7.23-7.30(m，8H)；6.95(br.d，J＝2.9，2H)；4.39-4.47(m，4H)；2.89(d，J＝7.5，1H)；2.73(d，J＝7.5，1H)。IR(cm
-1，KBr)：3404(m)，3063(w)，2974(w)，2933(w)，2867(w)，1679(s)，1608(w)，1522(s)，1507(s)，1447(m)，1382(w)，1362(w)，1347(w)，1270(m)，1257(m)，1209(m)，1133(m)，965(m)，847(w)，761(m)。MS(m/z)：428.2[M+H]
+。
Embodiment 702
N (the 12)-tertiary butyl-10-(2,4 difluorobenzene base)-10,11-diaza Fourth Ring [6.5.1.0
2,7.0
9,13] 14 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide:
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 27 (100mg, 0.29mmol), DMF (1.0ml), Et
3N (49 μ l, 0.35mmol), bop reagent (143mg, 0.32mmol) and 2-amino-2-methyl propane (31 μ l 0.29mmol) obtain title compound (91mg, 78%).M.P.：59℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.72-7.62(m，1H)；7.41(d，J＝5.7，1H)；7.32-7.26(m，1H)；7.07-6.92(m，4H)；6.65(br.s，1H)；4.62(br.s，1H)；4.29(br.s，1H)；2.96(d，J＝7.5，1H)；2.82(d，J＝7.5，1H)；1.43(s，9H)。
Embodiment 801
N5-(tertiary butyl)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.2.0
2,6] 11 carbon-2 (6), 4-diene-5-methane amide:
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate
28 (100mg, 0.32mmol), DMF (1.0ml), Et
3N (54 μ l, 0.35mmol), bop reagent (159mg, 0.36mmol) and 2-amino-2-methyl propane (34 μ l 0.32mmol) obtain title compound (96mg, 81%).M.P.：105-108℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.62-7.54(m，1H)；7.08-6.99(m，2H)；6.82(br.s，1H)；3.83(br.s，1H)；3.11(br.s，1H)；1.75(d，J＝6.6，4H)；1.52-1.26(m，4H)；1.47(s，9H)。
Embodiment 802
N (5)-(tert-pentyl)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.2.0
2,6] 11 carbon-2 (6), 4-diene-5-methane amide:
Title compound is synthetic by being similar to embodiment 101 described methods.Use intermediate 28 (100mg, 0.32mmol), DMF (1.0ml), Et
3N (54 μ l, 0.39mmol), bop reagent (159mg, 0.36mmol) and tert.-amylamine (38 μ l 0.32mmol) obtain title compound (81mg, 66%).M.P.：102-105℃。
1H-NMR(δppm，CDCl
3，300MHz)：7.66-7.54(m，1H)；7.10-6.96(m，2H)；6.74(br.s，1H)；3.82(br.s，1H)；3.13(br.s，1H)；1.89-1.70(m，6H)；1.42(s，6H)；1.48-1.43(m，2H)；1.30-1.20(m，2H)；0.92(t，J＝7.2，3H)。MS(m/z)：374.1([M+H]
+)。
Method
I.
Use meninx to carry out the in vitro method of rat CB1 receptors bind
In this test, use [
3H] SR141716A (5-(4-chloro-phenyl-)-1-(2, the 4-dichlorophenyl)-and 4-methyl-N-(piperidino) pyrazole-3-formamide) in conjunction with the CB1 acceptor that is present in the rat brain membrane prepare thing, it can show by the unlabelled part that the CB1 acceptor is had affinity.
People such as this test basis Thomas, the enforcement of improving one's methods of 1998 (JPET 285:285-292).Total reaction mixture (250ml) contain Tris-BSA damping fluid (50mM Tris, pH 7.4, contain 1.5%BSA) or unlabelled SR141716A (1mM) or specimen (1mM), [
3H] the rat meninx of SR141716A (2nM) and 100mg.Nonspecific combination is defined by the SR141716A of 1mM.Test mixture was cultivated 1 hour in 37 ℃.Then by under vacuum, using the WhatmanGF/B-96 microwell plate to filter termination reaction fast.Add scintillator, and use Topcount beta scintillometer to measure radiocounting.
In containing the test damping fluid of ethanol or DMSO, prepare the diluent of standard substance and specimen with 1% final concentration.
The shown percentage (%) of part to be measured calculates by comparing specificity bonded value.Test-results is shown in down Table II.
II.
Use the in vitro tests method of hCB1-CHO film
In this test, use [
3H]-CP-55,940 ((-)-3-[2-hydroxyl-4-(1,1-dimethyl heptyl)-and phenyl] the 4-[3-hydroxypropyl] hexamethylene-1-alcohol) come in conjunction with human CB1 acceptor expressed on the Chinese hamster ovary celI film (hCB1-CHO clone results from Chinese hamster ovary celI itself (in-house)) as radioligand, it can show by the unlabelled part that the CB1 acceptor is had affinity.
People such as this test basis Ross, 1999 (Br.J.Pharmacol.128, the enforcements of improving one's methods 735-743).This reaction is carried out in Millipore GFB (Glass Fibre-B) screen plate that applies in advance with PEI (poly-(ethyleneimine)) (0.2%) with the cumulative volume of 200 μ l.The stock solution of test compounds of preparation 1mM in DMSO, and measure with the final concentration of 300nM.By the CP-55 of 0.5 μ M, 940 measure nonspecific combination.Total reaction mixture contains Tris-BSA damping fluid (Tris of 50mM, the MgCl of 5mM
2, the EDTA of 1mM, pH7.4 contains 0.1% BSA), unlabelled CP-55,940 (0.5 μ M) or specimen, [
3H]-CP-55, the human CB1 acceptor prepared product of 940 (0.75nM) and 50 μ g.This test mixture (contain have or do not contain test compounds) was cultivated 1 hour in 37 ℃.By under vacuum, fast filtering termination reaction, measure radioactivity on the filter by liquid scintillation counting(LSC).Test-results is shown in down Table II.
III.
Use the spleen film to carry out the in vitro method of rat CB2 receptors bind
In this test, use [
3H] CP55,940 in conjunction with the CB2 acceptor that is present in the Rats Spleen membrane prepare thing, and it can show by the unmarked part that the CB2 acceptor is had affinity.
People such as this test basis Rinaldi-Carmona, the enforcement of improving one's methods of 1998 (JPET 284:644-650).Total reaction mixture (250ml) contains Tris-BSA damping fluid (50mM Tris, pH7.4, contain 1.5% BSA) or unlabelled SR144528 (N-[(1S)-Nei-1,3,3-trimethylammonium two ring [2.2.1] heptan-2-yl]-5-(4-chloro-3-aminomethyl phenyl)-1-(4-methyl-benzyl)-pyrazole-3-formamide)) (1mM) or specimen (300nM), [
3H] CP55, the rat meninx of 940 (1nM) and 100mg.Nonspecific combination is defined by the SR144528 of 1mM.This test mixture was cultivated 1 hour down at 37 ℃.Then by under vacuum, using Whatman GF/B-96 microwell plate to filter termination reaction fast.Add scintillation solution and use Topcount beta scintillometer to measure radiocounting.
In containing the test damping fluid of ethanol or DMSO, prepare the diluent of standard substance and specimen with 1% final concentration.
The shown percentage (%) of part to be measured calculates by comparing specificity bonded value.Test-results is shown in down Table II.
IV.
Use the in vitro tests method of hCB2-CHO film
In this test, use [
3H]-CP-55,940 is next in conjunction with human CB2 acceptor expressed on the Chinese hamster ovary celI film (hCB1-CHO clone results from Chinese hamster ovary celI itself (in-house)) as radioligand, and it can show by the unlabelled part that the CB2 acceptor is had affinity.
People such as this test basis Ross, 1999 (Br.J.Pharmacol.128, the enforcements of improving one's methods 735-743).This reaction is carried out in the Millipore GFB screen plate that applies in advance with PEI (0.2%) with the cumulative volume of 200 μ l.The stock solution of test compounds of preparation 1mM in DMSO, and measure with the final concentration of 300nM.By the CP-55 of 0.5 μ M, 940 measure nonspecific combination.Total reaction mixture contains Tris-BSA damping fluid (Tris of 50mM, the MgCl of 5mM
2, the EDTA of 1mM, pH7.4 contains 0.1% BSA), unlabelled CP-55,940 (0.5 μ M) or specimen, [
3H]-CP-55, the human CB2 acceptor prepared product of 940 (0.75nM) and 25-50 μ g.This test mixture (contain have or do not contain test compounds) was cultivated 1 hour in 37 ℃.By under vacuum, fast filtering termination reaction, and measure radioactivity on the filter by liquid scintillation counting(LSC).
The shown percentage (%) of part to be measured calculates by comparing specificity bonded value.Test-results is shown in down Table II.
V.
The hyperpathia model of DPN-part sciatic nerve ligation model (Seltzer model)
This method use 0.01,0.1,0.3 and the compound of the embodiment 294 of 1mg/ kilogram (I.P.) and the gabapentin of 100mg/ kilogram (I.P.) carry out, with the compound of estimating embodiment 294 to reducing the hyperalgesic ability of DPN.The Seltzer method also is described in people such as Seltzer, Pain1990,43:205-18 prevailingly.
1. use ketamine/xylazine (40/5mg kilogram/ml, i.p.) anesthetized rat.After the induced anesthesia, to left thigh defeathering and cleaning.
2. expose left sciatic nerve through little otch from the thigh intermediate altitude.
3. from accompanying muscle tissue, peel off nerve.
4. after making total sciatic nerve bifurcated, use half of the neural thickness of the tight ligation of 7.0 silk quality suture lines.
5. closure is come by the stitching of muscle and skin in the injury, and the coating polyvidone.
6. animal was restored after ligation 12 to 15 days.
7. (Comerio Italy) detects mechanical hyperalgesia for Ugo BasileAnalgesymeter, Cat.No.37215 to use the pawl pressure techniques in the pain model of rat DPN.
8. before medicine or vector administration (before the administration) and use pawl is received in back (after the administration) 0.5 and 1 hour to rear solid end record of homonymy and offside threshold value.
9. cut-out point is set at the pressure of 150g, and adopts receipts pawl or cry as terminal point.
Data analysis:
Represent with mean value ± SEM the time of lag of critical receipts pawl (do not test, take medicine preceding and take medicine back).Referring to Walker KM, Urban LA, Medhurst SJ, Patel S, Panesar M, Fox AJ and Mcintyre P., " VR1 antagonist capsazepine has reversed mechanical hyperalgesia in the pain model of inflammation and DPN ", J.Pharmacol.Expt.Ther.304:56-62,2003.The reverse percentage of the mechanical hyperalgesia of DPN calculates from the critical delay time value of receiving pawl according to following formula:
By unidirectional variance analysis (one-way ANOVA) and use the Tukey check of GraphPadPrism software to carry out data statistic analysis subsequently to reversing percentage.
The results are shown in Fig. 1.The compound of the embodiment 294 of 1mg/ kilogram reverses the hyperpathia of DPN significantly in this model.
VI.
Chronic contraction damage (CCI) (CCI model) of sciatic nerve model
This method use 0.1mg/ kilogram (p.o) embodiment 294 compound and carry out with the gabapentin of 100mg/ kilogram (i.p.), with the compound of assessment embodiment 294 to reducing the hyperalgesic ability of DPN.This method also be described in prevailingly Miletic G and Miletic V's " sciatic loose ligation has caused the long-term change of sciatic nerve causes in the rat A-fiber dorsal horn zone electromotive force ", Pain 84:353-359,2000.
1. use ketamine/xylazine (40/5mg/ kilogram/ml, i.p.) anesthetized rat.After the induced anesthesia, to left thigh defeathering and cleaning.
2. expose left sciatic nerve through little otch from the thigh intermediate altitude.
3. from accompanying muscle tissue, peel off nerve.
4. behind total sciatic nerve bifurcated, the neural Ethicon 4-0 chromic catgut (Johnson﹠amp that 1mm four pines at interval are set on every side; Johnson) ligation place.
5. closure is come by the stitching of muscle and skin in the injury, and the coating polyvidone.
6. the animal ligation is used for experiment after 7 days.
7. (Comerio Italy) detects mechanical hyperalgesia for Ugo BasileAnalgesymeter, Cat.No.37215 to use the pawl pressure techniques in the pain model of rat DPN.
8. before medicine or vector administration (before the administration) and use pawl is received in back (after the administration) 0.5 and 1 hour to rear solid end record of homonymy and offside threshold value.
9. cut-out point is set at the pressure of 150g, and adopts receipts pawl or cry as terminal point.
Data analysis is undertaken by method V is described.The results are shown in Fig. 2.
VII.
The sudden strain of a muscle tail pain relieving test of mouse
Use water-bath (Julabo, Germany) untried mouse measurement sudden strain of a muscle tail time of lag (basis) under 55 ℃ to handling with carrier, WIN 55212-2 (CB1 receptor stimulant) (3mg/ kilogram i.p.) or embodiment 294 (0.3,1 or 3mg/ kilogram i.p.).Referring to Murielle R., Barth F., CongyC., Martinez S., Oustric D., Perio A., Poncelet M., Maruani J., Arnone M., Finance O., Soubrie P., and Le ' Fur G. " SR147778 (5-(4-bromophenyl)-1-(2; the 4-dichlorophenyl)-4-ethyl-N-(piperidino)-1H-pyrazole-3-formamide), a kind of new effectively and optionally CB1 cannabinoid receptor antagonists: biological chemistry and pharmacology feature ", J.Pharmacol.Exp.The., 310:905-914,2004.Mouse is carried out intraperitoneal (i.p.) injection of carrier, standard substance or testing drug.After administration, estimated analgesic effect by measure dodging tail time of lag (reaction) in 1,3,6,12 and 18 hour.The cut-out point of time of lag is set at 10 seconds, and with the sudden strain of a muscle end reaction of tail as terminal point.
Data analysis
Dodging the value of tail time of lag (basis and reaction) represents with mean value ± SEM.Maximum analgesic effect (MPE%) calculates according to following formula:
By unidirectional variance analysis and the check of Tukey subsequently MPE% is carried out data statistic analysis.The results are shown in Fig. 3.
VIII.
GTP γ S is in conjunction with the method (the CB1 functional analysis in the rat cerebellum film) of test
In conjunction with in testing, measure total, the basis and nonspecific combination at this GTP γ S.Referring to Griffin G, Atkinson P.J., Showalter VM., Martin B.R. and Abood M.E. " in the rat cerebellum film, use guanosine-5 '-O-(3-(
35S) sulphur)-triguaiacyl phosphate estimates cannabinoid receptor agonists and antagonist ", J Pharmacol Exp Ther 285:553-560,1998.Under the radioligand concentration of 0.2nM, three holes are used for total binding capacity, three holes are used for basic binding capacity, also have three holes to be used for nonspecific combination.The basis is in conjunction with defining by 50 μ M GDP (guanosine diphosphate (GDP)), and the unlabelled GTP γ S of non-specific binding by 10 μ M defines.With GDP, the WIN-55212-2 of the little meninx of the rat of 10 μ g, 50 μ M or test compounds (1 μ M or 300nM), 10 μ M unlabelled GTP γ S and 0.2nM [
35S] GTP γ S adds 96 orifice plates, and with the final volume of reaction mixture with GTP γ S damping fluid (the anhydrous MgCl of 50mM Tris, 3mM
2, 0.2mM EGTA and 100mM NaCl pH 7.4) add to 200 μ l.This plate was cultivated 1 hour in 30 ℃.Use Whatman GF/B-96 microwell plate to filter termination reaction then.Use Tris-HCl washing three times.Be retained in the filter dish (Microscint PS) excessively that has added scintillation solution with meninx bonded radioactivity.Then, (Packard Instruments, IL USA) read the radiocounting of this plate to use the Beta liquid scintillation counter.
The cerebellum membrane prepare of rat is as follows:
1. put to death rat, take out whole brain and also separate cerebellum as soon as possible and it is remained on ice.
2. take by weighing little brain weight, and in the homogenate buffer (contain the 50mM Tris-HCL of 1mM EDTA and 5% sucrose, pH 7.5) of 30ml, use homogenizer homogenate down in cooling conditions.
Under 4 ℃ with 18000rpm (38000g) with centrifugal 15 minutes of the cerebellum after the homogenate.
4. throw out is resuspended among the 5ml 50mM Tris-HCL that contains 1mM EDTA, and kept 30 minutes on ice.
5. make film by insulin syringe to guarantee even suspension.
Under 4 ℃ with centrifugal this film of 18000rpm 20 minutes.
7. will precipitate reconstruct in the GTP of 3ml γ S damping fluid, and check by BCA and to estimate protein, duplicate samples is stored so that 1000 μ g are proteinic etc. with this film.
CB1 agonist and antagonistic activity shaker test
Test compounds with the final concentration of 1 μ M or 300nm at the WIN55 that is containing and do not containing 1 μ M, under the 212-2 condition according to screening in conjunction with the identical mode of test with GTP γ S.
Agonist stimulates the combination of GTP γ S on basal level.
Antagonist suppresses WIN-55212-2 (CB1 agonist) and induces GTP γ S bonded to stimulate but significantly do not change basic binding capacity.
Inverse agonist reduces basic GTP γ S combination and/or produces 100% inhibition that agonist (WIN-55212-2) inductive is stimulated.
Partial agonist generally only produces the stimulation of part on the basis, and also partly suppresses the stimulation of agonist (WIN-55212-2) inductive GTP γ S bonded.
Data analysis:
Do not containing and containing 1 μ M WIN 55, the GTP γ S bonded of each test compounds of 1 μ M or 300nM concentration stimulates percentage by making itself and relatively the calculating of specificity associated value (the basic combination-non-specific binding) on basis under the 212-2 condition.
The results are shown in down Table III.
IX. measure the agonist and the antagonistic activity test of CB1 and CB2 acceptor
1.
The antagonistic action of the CB1/CB2 acceptor of in Chinese hamster ovary celI, expressing
H-CB1/CHO or h-CB2/CHO cell are grown in HAM ' the s F12 DMEM substratum (Sigma) of the G418 (Sigma) that contains 10%FBS (Hyclone), 1% penicillin-Streptomycin sulphate solution and 400 μ g/ml.500 cells of every hole inoculation in 96 orifice plates are at 37 ℃, 5%CO
2Under cultivated 24 hours.On test same day, the Krebs damping fluid of cell with the BSA (Sigma) that contains 0.1% FAF (FAF) of temperature washed, and be resuspended in the same buffer that contains 1mM IBMX.Will with the antagonist to be measured of FAFBSA+IBMX+Krebs damping fluid dilution or reference compound (be used for CB1 (1-(2 for AM 251, the 4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(piperidino) pyrazole-3-formamide), that be used for CB2 is SR 144528) add cell, and at room temperature cultivated 10 minutes.CP 55,940 (final concentration for the CB1 test is 30nM, is 10nM for the CB2 test) is added cell, then add Buddhist SCH (10 μ M final concentration), and at room temperature cultivated 30 minutes.After cultivating end, use lysate lysing cell from cAMP estimation test kit, and quantitative according to manufacturer's the described chemiluminescence method of specification sheets (DiscoveRX) to cAMP.Use PRISM software to calculate EC according to amount effect curve by nonlinear regression analysis
50Value.
2.
The exciting mechanism of the CB1/CB2 acceptor of expressing in the Chinese hamster ovary celI
H-CB1/CHO or h-CB2/CHO cell are grown in HAM ' the s F12DMEM substratum (Sigma) of the G418 (Sigma) that contains 10%FBS (Hyclone), 1% penicillin-Streptomycin sulphate solution and 400 μ g/ml.500 cells of every hole inoculation in 96 orifice plates are at 37 ℃, 5%CO
2Under cultivated 24 hours.On test same day, the Krebs damping fluid of cell with the BSA (Sigma) that contains 0.1% FAF (FAF) of temperature washed, and be resuspended in the same buffer that contains 1mM IBMX.Will be with the testing compound of FAFBSA+IBMX+Krebs damping fluid dilution or as CP 55 with reference to compound, 940 (final concentration for CB1 test is 30nM, be 10nM for the CB2 test) add cell, then add Buddhist SCH (10 μ M final concentration), and at room temperature cultivated 30 minutes.After cultivating end, use lysate lysing cell from cAMP estimation test kit, and quantitative according to manufacturer's the described chemiluminescence method of specification sheets (DiscoveRX) to cAMP.Use PRISM software to calculate EC according to amount effect curve by nonlinear regression analysis
50Value.
The results are shown in down Table IV.
Table II
| Embodiment number | Show % | |||
| Method I | Method II | Method III | Method IV | |
| 101 | 28.8 | 5.75 | -- | 0 |
| 102 | 27.3 | 18.56 | -- | 0.74 |
| 103 | 22.2 | 0 | -- | 6.99 |
| 104 | -- | 5.41 | -- | 20.24 |
| 105 | -- | 15.03 | -- | 22.35 |
| 106 | 78.6 | 15.07 | -- | 75.06 |
| 107 | 97.4 | 82.49@1 | -- | -- |
| 108 | 82.5 | 23.19 | -- | 37.15 |
| 109 | -- | 8.36 | -- | 63.05 |
| 110 | -- | 37.69 | -- | 60.7 |
| 111 | 110.6 | 32.19 | -- | -- |
| 112 | 59.9 | 25.76 | -- | -- |
| 113 | 55.9 | 27.70 | -- | 17.02 |
| 114 | -- | 25.27 | -- | 31.67 |
| 115 | -- | 39.62 | -- | -- |
| 116 | 24.9 | 1.85 | -- | -- |
| 117 | -- | 80.08 | 59.8 | -- |
| 118 | -- | 45.43 | -- | 61.23 |
| 119 | -- | 89.21 | 85.2 | -- |
| 120 | 30.4 | 15.43 | -- | 9.18 |
| 121 | 65.4 | 3.01 | -- | 29.8 |
| 122 ＊ | 66.4 | 80.08 | -- | -- |
| 123 | 89.0 | -- | -- | 47.63 |
| 124 | 80.1 | 66.41 | -- | -- |
| 125 | 52.7 | 22.07 | -- | 5.04 |
| 126 | 118.0 | -- | -- | -- |
| 127 | 85.3 | -- | -- | -- |
| 128 | 83 | 37.28 | -- | -- |
| 129 | 65.2 | 19.78 | -- | 62.85 |
| 130 | 60.6 | 12.32 | -- | -- |
| 131 | 85.2 | 22.78 | -- | 10.84 |
| 132 | 64.5 | 16.09 | -- | 3.94 |
| 133 | 59.7 | 65.9@1 | -- | -- |
| 134 | 89.6 | 63.68 | -- | -- |
| 135 | 20.5 | 10.05 | -- | 6.48 |
| 136 | 31.3 | 1.01 | -- | 15.44 |
| 137 | 76.7 | 50.75 | -- | -- |
| 138 | -- | 79.4 | -- | 67.99 |
| 139 | 62.4 | -- | -- | -- |
| 140 | 50.4 | 57.85 | -- | 15.79 |
| 141 | 17 | -- | -- | -- |
| 142 | 25 | -- | -- | 9.86 |
| 143 | 102.2 | 81.7 | -- | -- |
| 144 | -- | 40.13 | -- | 69.24 |
| 145 | -- | 54.01 | -- | 75.88 |
| 146 | -- | 60.51 | -- | 68.16 |
| 147 | -- | 39.9 | -- | 37.14 |
| 148 | -- | 75.56 | -- | 79.21 |
| 149 | -- | 82.67 | -- | -- |
| 150 | -- | 78.72 | -- | -- |
| 151 | -- | 92.43 | -- | 69.16 |
| 152 | -- | 84.24 | -- | 60.26 |
| 153 | -- | 96.92 | -- | 99.46 |
| 154 | -- | 96.1 | -- | 70.19 |
| 155 | -- | 96.65 | -- | 72.38 |
| 156 | -- | 86.37 | -- | 89.29 |
| 157 | -- | 84.84 | -- | 88.5 |
| 158 | -- | 70.12 | -- | 95.4 |
| 158a | -- | -- | -- | 94.62 |
| 159 | -- | 81.31 | -- | 97.65 |
| 160 | 10.0 | 7.32 | -- | 20.75 |
| 161 | 27.9 | 22.54 | -- | 39.35 |
| 162 | 38.9 | 9.52 | -- | 33.8 |
| 163 | -- | 17.3 | -- | 14.46 |
| 164 | 8.2 | 19.15 | -- | 13.15 |
| 165 | 14.2 | 6.64 | -- | 45.27 |
| 166 | -- | 8.7@1 | -- | 18.16 |
| 167 | 61.3 | 44.72 | -- | 24.59 |
| 168 | 37 | 11.47 | -- | -- |
| 169 | 19 | 29.65 | -- | -- |
| 170 | 40.0 | 29.49 | -- | 27.16 |
| 171 | 0 | 19.37 | -- | 0.56 |
| 172 | 59.2 | -- | -- | 25.11 |
| 173 | 67.1 | -- | -- | -- |
| 174 | 76.4 | 21.69 | -- | 22.53 |
| 175 | 66 | 25.7 | -- | 18.48 |
| 176 | 65.6 | 39.34 | -- | 30.48 |
| 177 | 75.6 | -- | -- | 15.26 |
| 178 | 47 | -- | -- | 6.04 |
| 179 | 48 | 30.88 | -- | 18.21 |
| 180 | 40.6 | 28.65 | -- | 13.19 |
| 181 | 16.4 | -- | -- | -- |
| 182 | 39.9 | 19.35 | -- | 12.78 |
| 183 | 45.9 | 17.24 | -- | 18.23 |
| 184 | 41 | 3.24 | -- | 8.76 |
| 185 | -- | 51.98 | -- | 60.66 |
| 186 | 17.2 | 16.13 | -- | 59.06 |
| 187 | 6.0 | 15.66 | -- | 0.7 |
| 188 | 19.5 | 12.5 | -- | 36.01 |
| 189a | 7 | 21.2 | -- | 0.81 |
| 189b | 3 | 24.03 | -- | 2.56 |
| 190a | -- | -- | -- | 0 |
| 190b | -- | 100 | -- | 96.07 |
| 191 | -- | 78.71 | -- | 62.18 |
| 192 | -- | -- | -- | 19.12 |
| 201 | 9.0 | 24.91 | -- | 19.79 |
| 202 | 28.2 | 16.53 | -- | 70.13 |
| 203 | -10.4 | 56.51 | -- | -- |
| 204 | -10.3 | 23.84 | -- | 10.53 |
| 205 | -12.7 | 22.27 | -- | 15.93 |
| 206 | 27.4 | 15.15 | -- | 71.87 |
| 207 | -1.2 | 9.39 | -- | -- |
| 208 | -1.2 | -- | -- | 0 |
| 209 | 23.5 | 30.35 | -- | 50.52 |
| 210 | 12.6 | 11.58 | -- | 17.69 |
| 211 | 27.6 | 19.47 | -- | 80.4 |
| 212 | 68.4 | 72.25 | -- | -- |
| 213 | 48.5 | 17.57 | -- | 71.8 |
| 214 | 10.1 | 9.01 | -- | 41.3 |
| 215 | -- | 1.38 | -- | -- |
| 216 | 32.2 | 34.03 | -- | 20.74 |
| 217 | 20.5 | 38.55 | -- | 10.74 |
| 218 | 29.9 | 44.41 | -- | -- |
| 219 | 33.7 | 59.57 | -- | -- |
| 220 | 29.5 | 17.92 | -- | 25.29 |
| 221 | 68.6 | 0 | -- | 75.66 |
| 222 | 39.4 | -- | -- | 15.72 |
| 223 | 52.1 | 21.5 | -- | 59.5 |
| 224 | 81.6 | 42.62 | -- | -- |
| 225 | 31.1 | 46.8 | -- | -- |
| 226 | 38.4 | 72.08 | -- | -- |
| 227 | 25.3 | 3.51 | -- | -- |
| 228 | 16.1 | 0 | -- | 9.4 |
| 229 | 47.1 | 0.01 | -- | 24.6 |
| 230 | 87.2 | 72.54@ 1μm | -- | -- |
| 231 | 31.9 | 30.79 | -- | -- |
| 232 | 49.7 | 1.15 | -- | 13.76 |
| 233 | 73.2 | 10.79 | -- | 46.22 |
| 234 | 36.3 | 3.33 | -- | 10.64 |
| 235 | 46.8 | 80.94 | -- | -- |
| 236 | 75.5 | 55.25 | -- | -- |
| 237 | 65.6 | 80.77 | -- | -- |
| 238 | 73.9 | 24.52 | -- | -- |
| 239 | 23.5 | 8.09 | -- | 77.12 |
| 240 | 1.5 | 0 | -- | 7.98 |
| 241 | 92.5 | 87.5 | -- | -- |
| 242 | -- | 84.89 | -- | -- |
| 243 | 23.5 | 1.74 | -- | -- |
| 244 | -- | 1.7 | -- | 88.35 |
| 245 | -- | 30.82 | -- | 84.79 |
| 246 | 46.0 | -- | -- | 30.44 |
| 247 | -- | 22.75 | -- | 79.12 |
| 248 | -- | 40.11 | -- | -- |
| 249 | 47.7 | -- | -- | -- |
| 250 | 27.1 | 6.46 | -- | 27.93 |
| 251 | 42.3 | 20.93 | -- | 60.18 |
| 252 | 99.8 | 74.52 | -- | -- |
| 253 | 63.0 | 43.16 | -- | -- |
| 254 | 9.1 | -- | -- | -- |
| 255 | 23.9 | -- | -- | -- |
| 256 | 63.3 | 7.71 | -- | -- |
| 257 | 73.5 | 30.69 | -- | 83.94 |
| 258 | -- | 61.78 | -- | -- |
| 259 | 18.3 | 2.72 | -- | 33.33 |
| 260 | 84.4 | 30.22 | -- | 80.22 |
| 261 | -- | 34.15 | -- | -- |
| 262 | -1.6 | 21.54 | -- | 32.58 |
| 263 | 69.1 | 26.73 | -- | 79.04 |
| 264 | 85.6 | 60.85@1 μm | -- | -- |
| 265 | 31.6 | 25.85 | -- | 70.16 |
| 266 | 34.5 | 23.00 | -- | 61.98 |
| 267 | 90.0 | 60.43 | -- | -- |
| 268 | 41.0 | 74.52 | -- | -- |
| 269 | 47.7 | 57.25 | -- | -- |
| 270 | -14.6 | 18.04 | -- | 8.62 |
| 271 | 11.7 | 17.7 | -- | 45.96 |
| 272 | -4.5 | 13.99 | -- | 18.37 |
| 273 | -5.9 | 8.94 | -- | 26.25 |
| 274 | 25.7 | 7.83 | -- | 35.42 |
| 275 | 38.8 | 7.02 | -- | 72.28 |
| 276 | 25.3 | 3.97 | -- | 14.11 |
| 277 | -12.8 | 5.41 | -- | 22.13 |
| 278 | -- | 26.86 | -- | -- |
| 279 | 62.0 | 44.84 | -- | -- |
| 280 | 33.0 | 40.37 | -- | -- |
| 281 | -- | -- | -- | 97.11 |
| 282 | -- | -- | -- | 92.31 |
| 283 | -- | 58.84 | -- | 94.79 |
| 284 | 13.7 | 25.15 | -- | 0.9 |
| 285 | 61.9 | 53.9@1μm | -- | -- |
| 286 | -- | 32.35 | -- | -- |
| 287 | -- | 36.8 | -- | -- |
| 288 | -- | 1.05 | -- | 60.78 |
| 289 | 71.3 | 40.2 | -- | -- |
| 290 | 80.3 | 70.03 | -- | -- |
| 291 | -- | 64.44 | -- | -- |
| 292 | -- | 69.79 | -- | -- |
| 293 | -- | 51.88 | -- | -- |
| 294 | 110.7 | 78.08 | -- | -- |
| 295 | -- | 93 | -- | 100 |
| 296 | -- | 94.62 | -- | 95.88 |
| 297 | -- | 71.92 | -- | 70.29 |
| 298 | -- | 28.07 | -- | 11.25 |
| 299 | -- | 86.48 | -- | 77.61 |
| 300 | -- | 54.93 | -- | 90.14 |
| 301 | -- | 82.54 | -- | 82.09 |
| 302 | -- | 2.43 | -- | 71.77 |
| 303 | -- | 9.41 | -- | 89.67 |
| 304 | -- | -- | -- | -- |
| 305 | -- | -- | -- | -- |
| 306 | -- | 3.56 | -- | 62.9 |
| 307 | -- | 26.11 | -- | 70.32 |
| 308 | -- | 91.26 | -- | 86.58 |
| 309 | -- | 92.57 | -- | 98.49 |
| 310 | -- | 96.75 | -- | 94.25 |
| 311 | -- | 69.58 | -- | 94.38 |
| 312 | -- | 10.97 | -- | 4.47 |
| 313 | -- | 65.99 | -- | 98.17 |
| 314 | -- | 23.25 | -- | 64.87 |
| 315 | -- | 36.78 | -- | 64.23 |
| 316 | -- | 13.83 | -- | 66.65 |
| 317 | -- | -- | -- | 16.92 |
| 318 | -- | -- | -- | 30.99 |
| 319 | -- | 88.02 | -- | 86.68 |
| 320 | -- | 39.42 | -- | 67.77 |
| 321 | -- | 11.78 | -- | 92.91 |
| 322 | -- | 16.74 | -- | 43.44 |
| 323 | -- | 4.25 | -- | 82.49 |
| 324 | -- | 7.23 | -- | 88.53 |
| 325 | -- | 50.42 | -- | 99.64 |
| 326 | -- | 73.99 | -- | 99.18 |
| 327 | -- | 70.23 | -- | 99.99 |
| 328 | -- | 2.00 | -- | 64.39 |
| 329 | -- | 11.58 | -- | 88.50 |
| 330 | -- | -- | -- | 64.88 |
| 331 | -- | -- | -- | 75.26 |
| 332 | -- | -- | -- | 70.06 |
| 333 | -- | -- | -- | 100.00 |
| 334 | -- | -- | -- | 100.00 |
| 335a | -- | -- | -- | 96.49 |
| 335b | -- | -- | -- | 8.70 |
| 336b | -- | -- | -- | 26.46 |
| 401 | -- | 12.04 | -- | -- |
| 402 | -- | 16.52 | -- | 2.66 |
| 403 | -- | 26.52 | -- | 13.35 |
| 404 | -- | 24.34 | -- | 23.79 |
| 405 | -- | 63.21 | -- | 87.87 |
| 406 | -- | 72.49 | -- | 94.3 |
| 407 | -- | 87.28 | -- | 88.44 |
| 408 | -- | 24.93 | -- | 61.92 |
| 409 | -- | 85.98 | -- | 65.34 |
| 410 | -- | -- | -- | 15.5 |
| 411 | -- | -- | -- | 49.68 |
| 501 | 82.5 | 70.15 | -- | -- |
| 502 | 81.3 | 52.76 | -- | -- |
| 503 | 81.2 | 56.25 | -- | -- |
| 504 | 79.7 | 62.9 | -- | -- |
| 505 | 90.6 | 77.51 | -- | -- |
| 506 | -- | 0 | -- | 52.4 |
| 507 | -- | 76.33 | -- | 91.7 |
| 508 | -- | 95.97 | -- | 67.67 |
| 509 | -- | 93.35 | -- | 67.18 |
| 601 | 2.8 | -- | -- | 0.99 |
| 602 | 4.1 | -- | -- | 16.4 |
| 701 | -- | 46.7 | -- | 28.34 |
| 702 | -- | -- | -- | 33.00 |
| 802 | -- | 81.33 | -- | 100.00 |
Table III
| Method-VIII | ||
| Embodiment number | The stimulation % of itself | The inhibition % that the WIN-55212-2 inductive stimulates |
| 106 | -10.0％ | 65.3％ |
| 107 | 4.0％ | 71.5％ |
| 111 | 6.1％ | 101.1％ |
| 121 | 16.0％ | 81.3％ |
| 122 | 1.2％ | 59.3％ |
| 123 | 13.5％ | 99.1％ |
| 126 | -7.9％ | 104.1％ |
| 127 | 18.0％ | 100.2％ |
| 131 | -1.7％ | 86.0％ |
| 132 | 7.2％ | 89.2％ |
| 137 | 13.0％ | 76.0％ |
| 139 | -8.5％ | 109.1％ |
| 140 | 24.9％ | 71.9％ |
| 143 | 43.1％ | 45.0％ |
| 170 | 17.5％ | 80.3％ |
| 172 | -18.3％ | 115.3％ |
| 173 | 1.3％ | 99.5％ |
| 174 | -20.8％ | 75.5％ |
| 177 | 9.7％ | 109.1％ |
| 178 | -0.7％ | 88.0％ |
| 179 | 7.8％ | 89.7％ |
| 180 | 10.0％ | 87.9％ |
| 183 | 13.0％ | 72.5％ |
| 184 | 9.5％ | 75.9％ |
| 212 | -13.8％ | 97.4％ |
| 221 | -16.7％ | 95.7％ |
| 224 | 5.0％ | 78.1％ |
| 230 | 42.4％ | 99.4％ |
| 233 | -16.3％ | 79.5％ |
| 236 | 8.0％ | 83.0％ |
| 237 | 7.1％ | 74.7％ |
| 238 | 0.4％ | 59.1％ |
| 246 | 0.7％ | 98.9％ |
| 256 | -21.5％ | 69.7％ |
| 257 | -5.1％ | 48.3％ |
| 260 | 38.0％ | 78.8％ |
| 264 | -0.1％ | 94.5％ |
| 268 | 29.1％ | 55.3％ |
| 269 | 6.0％ | 91.4％ |
| 290 | 3.8％ | 35.3％ |
| 501 | 53.7％ | 40.1％ |
| 502 | 1.8％ | 91.1％ |
| 503 | 1.5％ | 92.0％ |
| 505 | 15.6％ | 94.4％ |
| The foregoing description is tested under 1 μ M | ||
| 117 | 4.4％ | 55.7％ |
| 119 | 46.0％ | 38.9％ |
| 134 | -6.0％ | 58.1％ |
| 162 | -29.2％ | 72.0％ |
| 241 | 54.7％ | 32.9％ |
| 242 | 33.4％ | 22.9％ |
| 252 | 48.2 | 58.8 |
| 253 | -9.3％ | 79.9％ |
| 267 | 12.3％ | 43.6％ |
| 294 | 102.8％ | 9.8％ |
| The foregoing description is tested under 300nM | ||
Table IV
| Embodiment number | The functional analysis data | |||
| hCB1 | HCB2 | |||
| Agonism | Antagonistic action | Agonism | Antagonistic action | |
| 106 | |
0％ | 50.90％ | |
| 109 | NT | 61.64%, in 10 μ M | NT | |
| 117 | 18.87nM -IC 50 | 14.91％ | NT | |
| 119 | 38.33nM -IC 50 | 18.42%, in 10 μ M | NT | |
| 122 ＊ | NT | 40.66%, in 10 μ M | NT | |
| 134 | 75.61%, in 10 μ M | 17.53%, in 10 μ M | NT | |
| 140 | 48.88%, in 10 μ M | 19.31%, in 10 μ M | NT | |
| 149 | 79.86%, in 10 μ M | 15.98%, in 10 μ M | NT | |
| 150 | 61.1%, in 10 μ M | 42.93%, in 10 μ M | NT | |
| 186 | 29.4%, in 10 μ M | 0%, in 10 μ M | 8.51nM?IC 50 | 21%, in 10 μ M |
| 202 | 0%, in 10 μ M | 0%, in 10 μ M | 16.79 | 0 |
| 206 | NT | NT | 10.52nM IC 50 | 15.96%, in 10 μ M |
| 211 | 16.87, in 10 μ M | 0%, in 10 μ M | 40.65nM IC 50 | 20.33%, in 10 μ M |
| 212 | NT | 39.13%, in 10 μ M | NT | |
| 213 | 0%, in 10 μ M | 0%, in 10 μ M | 12.67nM IC 50 | 22.05%, in 10 μ M |
| 219 | NT | 33.4%, in 10 μ M | NT | |
| 221 | 0%, in 10 μ M | 0%, in 10 μ M | 36.43nM IC 50 | 30.07%, in 10 μ M |
| 223 | |
0%, in 10 μ M | 1.49nM IC 50 | 24.37%, in 10 μ M |
| 226 | NT | 71.03%, in 10 μ M | NT | |
| 235 | NT | 59.85%, in 10 μ M | NT | |
| 238 | NT | 55.05%, in 10 μ M | 24.54%, in 10 μ M | |
| 239 | NT | 42.52nM IC 50 | 64.1%, in 10 μ M | |
| 244 | 0%, in 10 μ M | 61.52%, in 10 μ M | 5.66nM IC 50 | 25.33%, in 10 μ M |
| 245 | 0%, in 10 μ M | 70.67%, in 10 μ M | 50.42nM IC? 50 | 32.91%, in 10 μ M |
| 247 | 0%, in 10 μ M | 75.31%, in 10 μ M | 5.44nM? |
29.24%, in 10 μ M |
| 251 | 37%, in 10 μ M | 0%, in 10 μ M | 40.24nM IC 50 | 40.78%, in 10 μ M |
| 257 | 0 | 0 | 3.7nM?IC 50 | 37.53%, in 10 μ M |
| 260 | 0 | 0 | 4.1nM IC50 | 34.83%, in 10 μ M |
| 263 | 16.19%, in 10 μ M | 72.13%, in 1 μ M | 2.5nM?IC? 50 | 27.08%, in 10 μ M |
| 265 | NT | 23.11nM IC 50 | 27.24%, in 10 μ M | |
| 266 | 12.14%, in 10 μ M | 0 | 14nM?IC 50 | 27.71%, in 10 μ M |
| 268 | 50.9%, in 1 μ M | |||
| 275 | 16.42%, in 10 μ M | 0%, in 10 μ M | 4.49nM IC 50 | 19.14%, in 10 μ M |
| 288 | 0%, in 10 μ M | 55.26%, in 10 μ M | 4.76nM IC 50 | 17.13%, in 10 μ M |
| 302 | 19%, in 10 μ M | NT | 9.75nM IC 50 | 0%, in 10 μ M |
| 303 | 857nM IC 50 | 0%, in 10 μ M | 0.61nM IC 50 | 17.6%, in 10 μ M |
| 304 | 55%, in 10 μ M | 0%, in 10 μ M | 0.93nM IC 50 | 51.60%, in 10 μ M |
| 305 | 20%, in 10 μ M | 0%, in 10 μ M | 2.16nM IC 50 | 37.45%, in 10 μ M |
| 306 | 11.95nM IC 50 | 14.36%, in 10 μ M | ||
| 307 | 0.81nM IC50 | 21.64%, in 10 μ M | ||
| 314 | 3.41%, in 10 μ M | 0%, in 10 μ M | 8.52nM IC 50 | 22.88%, in 10 μ M |
| 315 | 12.59%, in 10 μ M | 1%, in 10 μ M | 0.16-1.76 nM?IC 50 | 16.09%, in 10 μ M |
| 316 | 18.53%, in 10 μ M | 2%, in 10 μ M | 1.2-4.27nM IC 50 | 37.63%, in 10 μ M |
| 320 | 29.08%, in 10 μ M | 0%, in 10 μ M | 0.76-1.25 nM?IC 50 | 22.48%, in 10 μ M |
| 323 | 0%, in 10 μ M | 0%, in 10 μ M | 14.12nM IC 50 | 18.03%, in 10 μ M |
| 408 | NT | 16.05nM IC 50 | NT | |
| 506 | NT | 0%, in 10 μ M | 80.15%, in 10 μ M | |
NT=does not test
Although the present invention is illustrated with reference to specific embodiments at this, should understands these embodiments and only be used to illustrate principle of the present invention and application.Therefore be appreciated that for the embodiment that is exemplified and carry out many changes, and do not departing from the processing that can derive other under spirit of the present invention described in the claims and the scope.
All publications, patent and the patent application of being quoted among the application are incorporated herein by reference, and as each one publication, patent or patent application the degree that is incorporated herein by reference are described especially and individually.
Claims (51)
1. the compound of following formula,
Its analogue, pharmacologically acceptable salts, the acceptable ester of its pharmacy, its tautomer, its regional isomer, its steric isomer, its enantiomorph, its diastereomer, polymorphic, or its pharmacy acceptable solvent thing,
Wherein,
Dotted line in the formula (1) is represented two keys of choosing wantonly independently of one another;
U and V are C or N independently of one another;
W, X and Y be independently of one another C, N, O, S or-C (O)-, condition be have at least among U, V, W, X or the Y two be independently from each other N, O ,-C (O)-or S;
R, R
1And R
2Can be identical or different, and be independently of one another hydrogen, nitro, cyano group, formyl radical, ethanoyl, halogen ,-OR
3,-SR
3Oxo, sulfo-, replace or unsubstituted alkyl, replace or unsubstituted thiazolinyl, replace or unsubstituted alkynyl, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkylalkyl, replace or unsubstituted cycloalkenyl group, replace or unsubstituted cycloalkenyl alkyl, replace or unsubstituted aryl, replace or unsubstituted arylalkyl, replace or unsubstituted heteroaryl, replace or unsubstituted heteroarylalkyl, replace or unsubstituted heterocyclic, replace or the unsubstituted heterocyclic alkyl,-NR
3R
4,-C (=B)-R
3,-C (O) O-R
3,-C (O) NR
3R
4,-S (O)
m-R
3,-S (O)
m-NR
3R
4, or protecting group, or R
1And R
2Can be combined together to form optional 3 to 7 Yuans the saturated or undersaturated ring that replaces, its can randomly comprise at least two be selected from O,
NR
3Or the heteroatoms of S;
R
3And R
4Can be identical or different when occurring at every turn, and be independently of one another hydrogen, nitro, halogen, cyano group ,-OR
a,-SR
aOxo, sulfo-, replace or unsubstituted alkyl, replace or unsubstituted thiazolinyl, replace or unsubstituted alkynyl, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkylalkyl, replace or unsubstituted cycloalkenyl group, replace or unsubstituted cycloalkenyl alkyl, replace or unsubstituted aryl, replace or unsubstituted arylalkyl, replace or unsubstituted heteroaryl, replace or unsubstituted heteroarylalkyl, replace or unsubstituted heterocyclic, replace or the unsubstituted heterocyclic alkyl,-C (=B)-R
a,-C (O) O-R
a,-C (O) NR
aR
b,-S (O)
m-R
a,-S (O)
m-NR
aR
b,-NR
aR
b, or protecting group, or R
3And R
4Can be bonded together when combining with the common atom forms optional 3 to 7 Yuans the saturated or undersaturated ring that replaces, and it can randomly comprise at least two and be selected from O, NR
3Or the heteroatoms of S;
R
aAnd R
bCan be identical or different when occurring at every turn, and be independently of one another hydrogen, halogen, nitro, cyano group, formyl radical, ethanoyl, oxo, sulfo-,-C (O)-R
c,-C (O) O-R
c,-C (O) NR
cR
d,-S (O)
m-R
c,-S (O)
m-NR
cR
d,-NR
cR
d,-OR
c,-SR
c, protecting group, replacement or unsubstituted alkyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted alkynyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted cycloalkylalkyl, replacement or unsubstituted cycloalkenyl group, replacement or unsubstituted cycloalkenyl alkyl, replacement or unsubstituted aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted heterocyclic, replacement or unsubstituted heterocyclic alkyl, or replacement or unsubstituted heteroarylalkyl;
R
cAnd R
dCan be identical or different when occurring at every turn, and be hydrogen independently of one another, halogen, nitro, cyano group, formyl radical, ethanoyl, oxo, sulfo-, protecting group, replace or unsubstituted alkyl, replace or unsubstituted thiazolinyl, replace or unsubstituted alkynyl, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkylalkyl, replace or unsubstituted cycloalkenyl group, replace or unsubstituted cycloalkenyl alkyl, replace or unsubstituted aryl, replace or unsubstituted arylalkyl, replace or unsubstituted heteroaryl, replace or unsubstituted heterocyclic, replace or the unsubstituted heterocyclic alkyl, or replacement or unsubstituted heteroarylalkyl;
B is O, S or NR at every turn independently of one another when occurring
3
P and m are 0,1 or 2 independently of one another;
A is
Wherein:
Dotted line among the A is represented two keys of choosing wantonly independently of one another;
R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13And R
14Be independently of one another hydrogen, nitro, cyano group, formyl radical, ethanoyl, halogen ,-OR
15,-SR
15Oxo, sulfo-, replace or unsubstituted alkyl, replace or unsubstituted thiazolinyl, replace or unsubstituted alkynyl, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkylalkyl, replace or unsubstituted cycloalkenyl group, replace or unsubstituted cycloalkenyl alkyl, replace or unsubstituted aryl, replace or unsubstituted arylalkyl, replace or unsubstituted heteroaryl, replace or unsubstituted heteroarylalkyl, replace or unsubstituted heterocyclic, replace or the unsubstituted heterocyclic alkyl,-NR
15R
16,-C (=B)-R
15,-C (O) O-R
15,-C (O) NR
15R
16,-S (O)
m-R
15,-S (O)
m-NR
15R
16, or protecting group; R
5And R
6Can be combined together to form optional 3 to 11 Yuans saturated or undersaturated monocycle or two rings that replace, it can randomly comprise at least one and be selected from O, NR
3Or the heteroatoms of S;
R
9And R
10Can be combined together to form optional 3 to 11 Yuans saturated or undersaturated monocycle or two rings that replace, it can randomly comprise at least one and be selected from O, NR
3Or the heteroatoms of S;
R
15And R
16Can be identical or different when occurring at every turn, and be independently of one another hydrogen, nitro, halogen, cyano group ,-OR
3,-SR
3Oxo, sulfo-, replace or unsubstituted alkyl, replace or unsubstituted thiazolinyl, replace or unsubstituted alkynyl, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkylalkyl, replace or unsubstituted cycloalkenyl group, replace or unsubstituted cycloalkenyl alkyl, replace or unsubstituted aryl, replace or unsubstituted arylalkyl, replace or unsubstituted heteroaryl, replace or unsubstituted heteroarylalkyl, replace or unsubstituted heterocyclic, replace or the unsubstituted heterocyclic alkyl,-C (=B)-R
3,-C (O) O-R
3,-C (O) NR
3R
4,-S (O)
m-R
3,-S (O)
m-NR
3R
4,-NR
3R
4, or R
15And R
16, when combining, can be combined together to form optional 3 to 7 Yuans the saturated or undersaturated ring that replaces with a common atom, it can randomly comprise at least two and be selected from O, NR
3Or the heteroatoms of S, wherein, R
3And R
4As defined above;
N is 1,2,3 or 4; And
A, b, c, d and e are selected from 0 to 4 integer independently of one another,
Condition is that this compound does not have following formula:
Wherein, R
1And R
2As defined above.
2. compound as claimed in claim 1, wherein, U and V are C.
3. compound as claimed in claim 1 or 2, wherein, W is C, and Y and X are N.
4. as claim 1,2 or 3 described compounds, wherein R is hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted aryl, or replacement or unsubstituted heteroaryl.
5. compound as claimed in claim 4, wherein, R is methyl, phenyl, 2-chloro-phenyl, 4-chloro-phenyl-, 2,4-dichlorophenyl, 2-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 2-(4-chloro-phenyl-)-phenyl, or 5-chloropyridine-2-base.
6. as claim 1-4 or 5 described compounds, wherein, R
1Be hydrogen.
7. as claim 1-5 or 6 described compounds, wherein, R
2Be replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted cycloalkylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heterocyclic, replacement or unsubstituted heteroaryl, replacement or unsubstituted heteroarylalkyl, or NR
3R
4
8. compound as claimed in claim 7, wherein, R
2It is the tertiary butyl, n-pentyl, cyclopentyl, cyclohexyl, diamantane-1-base, 2-methyl adamantane-2-base, 3-hydroxyadamantane-1-base, 1,3,3-trimethylammonium two ring [2.2.1] heptan-2-base, the 1-phenycyclopropyl, cyclohexyl methyl, phenyl, the 3-chloro-phenyl-, the 4-chloro-phenyl-, the 3-bromophenyl, the 2-p-methoxy-phenyl, the 4-tert-butyl-phenyl, 2, the 4-difluorobenzyl, 2-benzyl chloride base, 4-benzyl chloride base, 2, the 4-dichloro benzyl, the 2-luorobenzyl, the 4-luorobenzyl, 2, the 4-difluorobenzyl, 2, the 6-difluorobenzyl, the 2-bromobenzyl, the 4-bromobenzyl, the 4-trifluoromethyl benzyl, the 1-phenylethyl, 1-methyl isophthalic acid-phenylethyl, the 2-phenylethyl, 1-(2-chloro-phenyl-) ethyl, 2-(4-fluorophenyl) ethyl, the 1-phenyl propyl, 1-ethyl-1-phenyl propyl, 1-(2-chloro-phenyl-) 1-methylethyl, the phenylacetic acid methyl esters, 2-hydroxyl-1-phenylethyl, piperidyl, morpholinyl, pyridyl, 1,2,4-triazole-4-base, the 2-pyridylmethyl, 3-pyridylmethyl, or 4-pyridylmethyl.
9. compound as claimed in claim 7, wherein, R
2Be NR
3R
4Wherein, R
3Be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted aryl, or replacement or unsubstituted cycloalkyl, and R
4Be to replace or unsubstituted aryl, replacement or unsubstituted heteroaryl, or replacement or unsubstituted cycloalkyl.
10. compound as claimed in claim 9, wherein, R
3Be methyl, phenyl or cyclohexyl, and R
4Be phenyl, 2-chloro-phenyl-, 4-chloro-phenyl-, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4 difluorobenzene base, 3,4-difluorophenyl, 2-bromophenyl, 3-chloropyridine-2-base, 5-chloropyridine-2-base or cyclohexyl, or R
3And R
4Be combined together to form piperidines-1 base or morpholine-4-base.
11. as claim 1-4 or 5 described compounds, wherein, R
1And R
2Be combined together to form optional 3 to 7 Yuans the saturated or undersaturated ring that replaces, it can randomly comprise at least two and be selected from O, NR
3Or the heteroatoms of S.
12. compound as claimed in claim 11, wherein, R
1And R
2Be combined together to form piperidines-1-base or morpholine-1-base.
13. as claim 1-11 or 12 described compounds, wherein, A is
14. compound as claimed in claim 13, wherein, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13And R
14Be hydrogen, replacement or unsubstituted alkyl or replacement or unsubstituted aryl independently of one another when occurring at every turn; A, b, c and d are 1, and the dotted line among the A is represented two keys of choosing wantonly independently of one another.
15. compound as claimed in claim 14, wherein, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13And R
14Represent hydrogen or methyl independently of one another.
16. compound as claimed in claim 14, wherein, R
8Expression 4-chloro-phenyl-.
17. as claim 1-13 or 14 described compounds, wherein, B is an oxygen.
18. the compound of formula 1A,
Or its analogue, its pharmacologically acceptable salts, the acceptable ester of its pharmacy, its tautomer, its regional isomer, its steric isomer, its enantiomorph, its diastereomer, its polymorphic, or its pharmacy acceptable solvent thing,
Wherein
R, R
1And R
2Can be identical or different, and be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted cycloalkylalkyl, replacement or unsubstituted aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heterocyclic, replacement or unsubstituted heteroaryl independently of one another, or replacement or unsubstituted heteroarylalkyl, or R
1And R
2Can be combined together to form optional 3 to 7 Yuans the saturated or undersaturated ring that replaces, it can randomly comprise at least two and be selected from O, NR
3Or the heteroatoms of S, or NR
3R
4
R
3And R
4Can be identical or different when occurring at every turn, and be hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl independently of one another, or replacement or unsubstituted heterocyclic, or R
3And R
4Can be combined together to form optional 3 to 7 Yuans the saturated or undersaturated ring that replaces, it can randomly comprise at least two and be selected from O, NR
3Or the heteroatoms of S;
P is 1; And
A is
Wherein
Dotted line among the A is represented two keys of choosing wantonly independently of one another, and
R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13And R
14Can be identical or different when occurring and be selected from hydrogen, replacement or unsubstituted alkyl at every turn, or replacement or unsubstituted aryl; Condition is that this compound does not have following formula:
Wherein, R
1And R
2As defined above.
19. compound as claimed in claim 18, wherein, the compound of formula 1 (A) is
20. compound as claimed in claim 1, wherein, this compound is selected from:
N (7)-piperidyl-5-(2-bromophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-benzyl-5-(2-bromophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-morpholinyl-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(3-pyridylmethyl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(4-pyridylmethyl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-cyclohexyl-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,110
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(N-cyclohexyl-N-methylamino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-cyclohexyl methyl-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(diamantane-1-yl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
N (7)-(1S, in 2-1,3,3-trimethylammonium-two ring [2.2.1] heptan-2-yl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
N (7)-(2-benzyl chloride base)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.3.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(4-benzyl chloride base)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
N (7)-(4-luorobenzyl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
N (7)-(2, the 4-difluorobenzyl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(2, the 6-difluorobenzyl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(4-trifluoromethyl benzyl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(1-phenylethyl))-and 5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(R-1-phenylethyl))-and 5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(1-methyl isophthalic acid-phenylethyl))-and 5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(2-pyridylmethyl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,1104,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(N '-phenyl amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,110
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(N '-phenyl amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,110
4,8] 14 carbon-4 (8), 6-diene-7-carboxamide hydrochloride,
N (7)-(2-chloro-phenyl-amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(2-chloro-phenyl-amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-carboxamide hydrochloride,
N (7)-[(4-chloro-phenyl-) amino)]-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,110
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(2,4 dichloro benzene base amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,110
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-[(2,4 dichloro benzene base-N '-methylamino]-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide, N (7)-[(2,4 dichloro benzene base-N '-methylamino]-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-carboxamide hydrochloride,
N (7)-(2,4 dichloro benzene base-N '-cyclohexyl amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(4-fluorophenyl amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(4-fluorophenyl amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-carboxamide hydrochloride,
N (7)-(2,4 difluorobenzene base amino]-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(3-fluorophenyl amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(3-chloro-2-pyridinylamino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(5-chloro-2-pyridinylamino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(2-phenylethyl)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
N (7)-(N ', N '-diphenyl amino)-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,110
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N7-[1-(2-chloro-phenyl-) ethyl]-5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-benzyl-5-(4 '-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
N (7)-piperidyl-5-(4 '-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
7-(4 '-chloro-phenyl-)-6,7-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-5-diene-5-base-piperidinyl ketone,
N (7)-phenyl-5-(4 '-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
N (7)-piperidyl-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(diamantane-1-yl)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
N (7)-(1S, in 2-1,3,3-trimethylammonium-two ring [2.2.1] heptan-2-yl)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
N (7)-(S-1-phenylethyl))-and 5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(R-1-phenylethyl)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(1-methyl isophthalic acid-phenylethyl)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(2-benzyl chloride base)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(2,4 dichloro benzene base amino)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-[1-(2-chloro-phenyl-) ethyl]-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-[(S)-the 1-phenyl propyl]-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N7-[1-(2-chloro-phenyl-)-1-methylethyl]-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
(2R)-and 2-[7-(2,4 difluorobenzene base)-6,7-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 5-diene-5-base formamido group]-2-phenylacetic acid methyl esters,
(2S)-and 2-[7-(2,4 difluorobenzene base)-6,7-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 5-diene-5-base formamido group]-2-phenylacetic acid methyl esters,
N7-(3-hydroxyadamantane-1-yl)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(1-methyl isophthalic acid-phenylethyl)-5-(4-fluorophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(diamantane-1-yl)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
N7-(diamantane-2-yl)-5-(4-fluorophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,110
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N7-(1,3,3-trimethylammonium two ring [2.2.1] heptan-2-yl)-5-(4-fluorophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,110
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-piperidyl-5-(4-aminomethyl phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(2,4 dichloro benzene base amino)-5-(4-aminomethyl phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(2-benzyl chloride base)-5-(4-aminomethyl phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-piperidyl-5-(4-p-methoxy-phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N7-(2-benzyl chloride base)-5-(4-p-methoxy-phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(2,4 dichloro benzene base amino)-5-(4-p-methoxy-phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-piperidyl-5-[(2-chloro-phenyl-) phenyl] 5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-[(2,4 dichloro benzene base) amino]-5-phenyl-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-phenyl-5-phenyl-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
N (7)-piperidyl-5-phenyl-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
N (7)-benzyl-5-phenyl-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide;
7-phenyl-6,7-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-5-diene-5-base-piperidinyl ketone;
N (7)-(4-luorobenzyl)-5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-phenyl amino-5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(2-chloro-phenyl-amino)-5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(2,4 dichloro benzene base amino)-5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(2-bromophenyl amino)-5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(N ', N '-diphenyl amino)-5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(2-phenylethyl)-5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-benzyl-5-(2 ', 4 '-dichlorophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
N (7)-piperidyl-5-(2 ', 4 '-dichlorophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-(2,4 dichloro benzene base amino)-5-(2-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.04,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-benzyl-5-(2 '-chloro-phenyl-)-5,6-two. azepine Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
N (7)-cyclohexyl-5-(2 '-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
N (7)-piperidyl-5-(2 '-chloro-phenyl-)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
N7-(2-benzyl chloride base)-5-(5-chloro-2-pyridyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4.8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-benzyl-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
N (7)-piperidyl-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
6,7-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-5-diene-5-base-piperidinyl ketone;
N (7)-piperidyl-6-methyl-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
N (7)-piperidyl-5-methyl-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
N (7)-(1-methyl isophthalic acid-phenylethyl)-6-amyl group-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4,7-diene-7-methane amide,
N (7)-(1-methyl isophthalic acid-phenylethyl)-5-amyl group-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-methane amide,
N (7)-[(1R)-2-hydroxyl-1-phenylethyl]-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
N (7)-[(1S)-2-hydroxyl-1-phenylethyl]-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
And pharmacologically acceptable salts.
21. compound as claimed in claim 1, wherein, this compound is selected from:
N (3)-piperidines-1-base-1-phenyl-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-cyclohexyl-1-phenyl-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-benzyl-1-phenyl-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-phenyl amino-1-phenyl-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-piperidines-1-base-1-(2-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-cyclohexyl-1-(2-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-benzyl-1-(2-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-phenyl amino-1-(2-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-piperidines-1-base-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide, 1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-phenylpiperidines base ketone,
N (3)-cyclohexyl-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-cyclopentyl-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(N-cyclohexyl-N-methyl) amino]-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-phenyl-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(3-chloro-phenyl-)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(4-chloro-phenyl-)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(3-bromophenyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(2-p-methoxy-phenyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(4-tert-butyl-phenyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-benzyl-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(2-benzyl chloride base)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(4-benzyl chloride base)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(2, the 4-dichloro benzyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(2-bromobenzyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(4-bromobenzyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(4-luorobenzyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(4-trifluoromethyl benzyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-phenyl amino-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(4-chloro-phenyl-) amino]-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(2,4 dichloro benzene base) amino]-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(3, the 4-dichlorophenyl) amino]-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(2-fluorophenyl) amino]-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(3-fluorophenyl) amino]-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(4-fluorophenyl) amino]-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(2,4 difluorobenzene base) amino]-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(N ', N '-diphenyl amino-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-cyclohexyl-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-cyclohexyl methyl-1-(2,4-two pyridyls)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(N, N-dicyclohexyl amino)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(4H-1,2,4-triazole-4-yl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(1,3,3-trimethylammonium two ring [2.2.1] heptan-2-yl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(diamantane-1-yl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-phenyl-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(2,4 difluorobenzene base)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(2-luorobenzyl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(4-luorobenzyl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(2, the 4-difluorobenzyl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(2, the 6-difluorobenzyl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(2-benzyl chloride base)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(4-benzyl chloride base)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(2, the 4-dichloro benzyl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[S-(1-phenylethyl)]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[R-(1-phenylethyl)]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(2-phenylethyl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[2-(4-fluorophenyl) ethyl]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-phenyl amino-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(2-chloro-phenyl-) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[N-(2-chloro-phenyl-)-N-methylamino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(4-chloro-phenyl-) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(2,4 dichloro benzene base) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(2,4 dichloro benzene base)-N-methylamino]-1-(2, the 4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(3, the 4-dichlorophenyl) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(2-bromophenyl) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(2-fluorophenyl) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(2,4 difluorobenzene base) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(3-fluorophenyl) amino ］-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(3-chloropyridine-2-yl) amino]-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (5)-piperidyl-3-(2 ', 4 '-dichlorophenyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
N (5)-benzyl-3-(2 ', 4 '-dichlorophenyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
N (3)-piperidines-1-base-1-(2-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-cyclohexyl-1-(2-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-benzyl-1-(2-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-phenyl amino-1-(2-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-piperidines-1-base-1-(4-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-cyclohexyl-1-(4-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-benzyl-1-(4-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-phenyl amino-1-(4-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(2-fluorophenyl) amino]-1-(4-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-cyclohexyl-1-(4-fluorophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-benzyl-1-(4-fluorophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N5-(diamantane-2-yl)-3-(4-fluorophenyl)-3,4-diaza tricyclic [5.2.1.0
2.6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
N5-(1-methyl isophthalic acid-phenylethyl)-3-(4-fluorophenyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
N5-(diamantane-1-yl)-3-(4-fluorophenyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
N (3)-phenyl amino-1-(4-fluorophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-phenyl amino-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(2-chloro-phenyl-) amino]-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(2-bromophenyl) amino]-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(2-fluorophenyl) amino]-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-piperidines-1-base-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-cyclohexyl-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(cyclohexyl methyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[S-(1-phenylethyl)]-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(R-1-phenylethyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(1-methyl isophthalic acid-phenylethyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N5-[1-(2-chloro-phenyl-)-1-methylethyl]-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
N (3)-(1,3,3-trimethylammonium two ring [2.2.1] heptan-2-yl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N5-(2-benzyl chloride base)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
N5-(4-benzyl chloride base)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
N5-(1-ethyl-1-phenyl propyl)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
N5-[(1S)-the 1-phenyl propyl]-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
(2S)-and 2-[5-(2,4 difluorobenzene base)-4,5-diaza tricyclic [5.2.1.0.
2,6] last of the ten Heavenly stems-2 (6), 3-diene-3-base formamido group]-2-phenylacetic acid methyl esters,
N5-[(1S)-2-hydroxyl-1-phenylethyl]-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0.
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
N (3)-(tertiary butyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
(4R, 7S)-N (3)-(tertiary butyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
(4S, 7R)-N (3)-(tertiary butyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N5-n-pentyl-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
N5-(2, the 4-dichloro benzyl)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
N5-(1-phenycyclopropyl)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
N5-(2-adamantyl)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
N5-(2-methyl-2-adamantyl)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-methane amide,
N7-(3-hydroxyadamantane-1-yl)-5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-methane amide,
4-[5-(2,4 difluorobenzene base)-4,5-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 3-diene-3-base formamido group] morpholine,
N (3)-(tert-pentyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-cyclopropane methyl isophthalic acid-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-cyclobutyl-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(tetrahydrochysene-2H-4-pyrans methyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-cyclopropyl-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(4-methylpiperazine base)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
(2R)-and 2-[5-(2,4 difluorobenzene base)-4,5-diaza tricyclic [5.2.1.0.
2,6] last of the ten Heavenly stems-2 (6), 3-diene-3-base formamido group]-2-phenylacetic acid methyl esters,
N (3)-[(1R)-2-hydroxyl-1-phenylethyl]-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(tertiary butyl)-1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(tetrahydrochysene-2-furyl methyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(tertiary butyl)-1-(4-fluorophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(tertiary butyl)-1-(4-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(tertiary butyl)-1-(3, the 4-dichlorophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
(2S)-and 2-[5-(2,4 difluorobenzene base)-4,5-diaza tricyclic [5.2.1.0.
2,6] last of the ten Heavenly stems-2 (6), 3-diene-3-base formamido group]-2-(4-fluorophenyl) methyl acetate,
N (3)-(tertiary butyl)-1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(4-hydroxy phenyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(tertiary butyl)-1-(2-oxyethyl group, 4-fluorophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(2-furyl methyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(2-thenyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(1S)-2-hydroxyl-1-(4-fluorophenyl) ethyl]-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
Methyl-(2S)-2-[5-(2,4 difluorobenzene base)-4,5-diaza tricyclic [5.2.1.0.
2,6] last of the ten Heavenly stems-2 (6), 3-diene-3-base formamido group]-4-methylpent acid esters,
N (3)-(diamantane-1-yl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(tertiary butyl)-1-(4-luorobenzyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(tertiary butyl)-2-(4-luorobenzyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(tertiary butyl)-1-(4-methyl-benzyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(2-hydroxyethyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(thienyl ethyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(sec.-propyl)-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(1S)-2-methoxyl group-1-phenylethyl]-1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(tertiary butyl)-2-(4-methyl-benzyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
And pharmacologically acceptable salts.
22. compound as claimed in claim 1, wherein, this compound is selected from:
N (3)-phenyl-1-(2,4 dichloro benzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(2-fluorophenyl) amino]-1-(2,4 dichloro benzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(2,4 difluorobenzene base) amino]-1-(2,4 dichloro benzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-[(3-chloropyridine-2-yl) amino]-1-(2,4 dichloro benzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(diamantane-1-yl)-1-(2,4 difluorobenzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(1,3,3-trimethylammonium two ring [2.2.1] heptan-2-yl)-1-(2,4 difluorobenzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-(1-methyl isophthalic acid-phenylethyl))-and 1-(2,4 difluorobenzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
(4R, 7S)-N (the 3)-tertiary butyl-1-(2,4 difluorobenzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-methylene radical-indazole-3-methane amide,
(2R)-and 2-[1-(2,4 difluorobenzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formamido group]-2-phenylacetic acid methyl esters,
N (3)-[(1R)-2-hydroxyl-1-phenylethyl]-1-(2,4 difluorobenzene base)-7,8, the 8-trimethylammonium)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-methane amide,
N (3)-amyl group-1-(2,4 difluorobenzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-methylene radical-indazole-3-methane amide,
(4S, 7R)-N (the 3)-tertiary butyl-1-(2,4 difluorobenzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-methylene radical-indazole-3-methane amide,
And pharmacologically acceptable salts.
23. compound as claimed in claim 1, wherein, this compound is selected from:
N (12)-benzyl-10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide,
N (12)-piperidyl-10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide,
N (12)-piperidyl-10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide, hydrochloride,
N (12)-[(N '-cyclohexyl-N '-methyl) amino]-10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide,
N (12)-N '-[(2,4 dichloro benzene base)-N '-methyl] amino }-10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide,
N (12)-(diamantane-1-yl)-10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide,
N12-(1,3,3-trimethylammonium two ring [2.2.1] heptan-2-yl)-10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2 (7), 3,5,9 (13), 11-pentaene-12-methane amide,
N12-(1-methyl isophthalic acid-phenylethyl)-10-(2,4, dichlorophenyl)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9.13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide,
N12-(1-methyl isophthalic acid-phenylethyl)-10-(2,4 difluorobenzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9.13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide,
And pharmacologically acceptable salts.
24. compound as claimed in claim 1, wherein, this compound is selected from:
N (12)-benzyl-16-(4-chloro-phenyl-)-10-(2,4 dichloro benzene base)-15,17-dioxo-10,11,16-three azepine five rings [6.5.5.0
2,7.0
9,13.0
14,18] 18 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide, or
N (12)-piperidyl-16-(4-chloro-phenyl-)-10-(2,4 dichloro benzene base)-15,17-dioxo-10,11,16-three azepine five rings [6.5.5.0
2,70
9,13.0
14,18] 18 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide, and pharmacologically acceptable salts.
25. compound as claimed in claim 1, wherein, this compound is selected from:
N12-benzyl-10-(2,4 difluorobenzene base)-10,11-diaza Fourth Ring [6.5.1.0
2,7.0
9,13] 14 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide,
N12-(1-methyl isophthalic acid-phenylethyl)-10-(2,4 difluorobenzene base)-10,11-diaza Fourth Ring [6.5.1.0
2,70
9,13] 14 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide,
N (the 12)-tertiary butyl-10-(2,4 difluorobenzene base)-10,11-diaza Fourth Ring [6.5.1.0
2,7.0
9,13] 14 carbon-2,4,6,9 (13), 11-pentaene-12-methane amide,
And pharmacologically acceptable salts.
26. compound as claimed in claim 1, wherein, this compound is selected from:
N5-(tertiary butyl)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.2.0
2,6] 11 carbon-2 (6), 4-diene-5-methane amide,
N (5)-(tert-pentyl)-3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.2.0
2,6] 11 carbon-2 (6), 4-diene-5-methane amide,
And pharmacologically acceptable salts.
27. compound as claimed in claim 1, wherein, this compound is selected from:
5-(2-bromophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid,
5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid,
5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid,
5-(4-fluorophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid,
5-(4-aminomethyl phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid,
5-(4-p-methoxy-phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid,
5-phenyl-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid,
5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid.
5-(2-chloro-phenyl-)-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid,
5-(5-chloropyridine base)-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid,
5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-formic acid,
6-amyl group-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4,7-diene-7-formic acid,
5-amyl group-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-formic acid,
1-phenyl-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid,
1-(2-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid,
1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid,
1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid,
1-(2-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid,
1-(4-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid,
1-(4-fluorophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid,
1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid,
(R or S) 1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid,
(S or R) 1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid,
1-(2,4 dichloro benzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid,
3-(2,4 difluorobenzene base)-1,10,10-trimethylammonium-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-formic acid,
10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-formic acid,
10-(2,4 difluorobenzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-formic acid,
In 13,14 interior-16-(4-chloro-phenyl-)-15,17-dioxo-10-(2,4 dichloro benzene base)-10,11,16-three azepine five rings [6.5.5.0
2,7.0
9,13.0
14,18] 18 carbon-2,4,6,9 (13), 11-pentaene-12-formic acid,
10-(2,4 difluorobenzene base)-10,11-diaza Fourth Ring [6.5.1.0
2,70
9,13] 14 carbon-2,4,6,9 (13), 11-pentaene-12-formic acid,
3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.2.0
2,6] 11 carbon-2 (6), 4-diene-5-formic acid,
3-(3, the 4-dichlorophenyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-formic acid,
3-(2-oxyethyl group-4-fluorophenyl)-3,4-diaza tricyclic [5.2.1.0
2.6] last of the ten Heavenly stems-2 (6), 4-diene-5-formic acid,
2-(4-methyl-benzyl)-4,5,6,7-tetrahydrochysene-2H-4,7-methylene radical-indazole-3-formic acid,
3-(4-methyl-benzyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-formic acid,
2-(4-luorobenzyl)-4,5,6,7-tetrahydrochysene-2H-4,7-methylene radical-indazole-3-formic acid,
1-(4-luorobenzyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-formic acid,
And pharmacologically acceptable salts.
28. compound as claimed in claim 1, wherein, this compound is selected from:
5-(2-bromophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate,
5-(4-chloro-phenyl-)-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate,
5-(2,4 difluorobenzene base)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate,
5-(4-fluorophenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate,
5-(4-aminomethyl phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate,
5-(4-p-methoxy-phenyl)-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate,
5-phenyl-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate,
5-(2,4 dichloro benzene base)-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate,
5-(2-chloro-phenyl-)-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate,
5-(5-chloropyridine base)-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate,
5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate,
6-methyl-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate,
5-methyl-5,6-diaza Fourth Ring [7,3,1.1
3,11, 0
4,8] 14 carbon-4 (8), 6-diene-7-ethyl formate,
6-amyl group-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4,7-diene-7-ethyl formate,
5-amyl group-5,6-diaza Fourth Ring [7.3.1.1
3,11.0
4,8] 14 carbon-4 (8)-6-diene-7-ethyl formate,
1-phenyl-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-ethyl formate,
1-(2-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-ethyl formate,
1-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-ethyl formate,
1-(2,4 dichloro benzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-ethyl formate,
1-(2-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-ethyl formate,
1-(4-bromophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-ethyl formate,
1-(4-fluorophenyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-ethyl formate,
1-(2,4 difluorobenzene base)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-ethyl formate,
1-(2,4 dichloro benzene base)-7,8,8-trimethylammonium-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-ethyl formate,
3-(2,4 difluorobenzene base)-1,10,10-trimethylammonium-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-ethyl formate,
10-(2,4 dichloro benzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-ethyl formate,
10-(2,4 difluorobenzene base)-10,11-diaza Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6,9 (13), 11-pentaene-12-ethyl formate,
In 13,14 interior-16-(4-chloro-phenyl-)-15,17-dioxo-10-(2,4 dichloro benzene base)-10,11,16-three azepine five rings [6.5.5.0
2,7.0
9,13.0
14,18] 18 carbon-2,4,6,9 (13), 11-pentaene-12-ethyl formate,
10-(2,4 difluorobenzene base)-10,11-diaza Fourth Ring [6.5.1.0
2,7.0
9,13] 14 carbon-2,4,6,9 (13), 11-pentaene-12-ethyl formate,
3-(2,4 difluorobenzene base)-3,4-diaza tricyclic [5.2.2.0
2.6] 11 carbon-2 (6), 4-diene-5-ethyl formate,
3-(3, the 4-dichlorophenyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-ethyl formate,
3-(2-oxyethyl group-4-fluorophenyl)-3,4-diaza tricyclic [5.2.1.0
2,6] last of the ten Heavenly stems-2 (6), 4-diene-5-ethyl formate,
4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-ethyl formate,
2-(4-methyl-benzyl)-4,5,6,7-tetrahydrochysene-2H-4,7-methylene radical-indazole-3-ethyl formate,
1-(4-methyl-benzyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-ethyl formate,
2-(4-luorobenzyl)-4,5,6,7-tetrahydrochysene-2H-4,7-methylene radical-indazole-3-ethyl formate,
1-(4-luorobenzyl)-4,5,6,7-tetrahydrochysene-1H-4,7-methylene radical-indazole-3-ethyl formate,
And pharmacologically acceptable salts.
29. compound as claimed in claim 1, wherein, this compound is selected from:
2-oxo-(5-oxo three ring [4.3.1.1.
3,8] 11 carbon-4-yl) ethyl acetate,
2-oxo-2 (3-oxo two ring [2.2.1] heptan-2-yl) ethyl acetate,
2-(3-hydroxyl-4,7,7-trimethylammonium two ring [2.2.1] hept-2-ene"-2-base-2-oxo ethyl acetate,
2-oxo-2-(10-oxo three ring [6.2.2.0
2,7] 12 carbon-2,4,6-triolefin-9-yl) ethyl acetate,
In 9,13 interior-2-[11-(4-chloro-phenyl-)-10,12,15-three oxygen-11-azepine Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6-triolefin-14-yl]-2-oxo ethyl acetate,
2-oxo-2-(10-oxo three ring [6.2.1.0
2,7] 11 carbon-2 (7), 3,5-triolefin-9-yl) ethyl acetate,
2-hydroxyl-2-(3-oxo two ring [2.2.2] suffering-2-pitch base) ethyl acetate,
In the 9-, in the 13--11-(4-chloro-phenyl-)-11-azepine Fourth Ring [6.5.2.0
2,7.0
9,13] 15 carbon-2,4,6-triolefin-10,12, the 14-triketone,
And pharmacologically acceptable salts.
30. a pharmaceutical composition, comprise free alkali or pharmacologically acceptable salts form as each described compound among the claim 1-29, and the acceptable vehicle of pharmacy.
31. pharmaceutical composition as claimed in claim 30, wherein, the acceptable vehicle of described pharmacy is carrier or thinner.
32. the method for a pharmaceutical compositions, comprise make free alkali or pharmacologically acceptable salts form as each described compound among the claim 1-29 and the acceptable mixed with excipients of pharmacy.
33. a prevention in the individuality that needs is arranged, improve or treatment by the disease that Cannabined receptor mediated, unusual or syndromic method, comprise to described individuality use significant quantity as each described compound among the claim 1-29.
34. method as claimed in claim 33; wherein; described by disease that Cannabined receptor mediated; unusual or syndrome is selected from abnormal food appetite; metabolic disturbance; katabolism is unusual; diabetes; obesity; eye disease; the obstacle relevant with social activity; mood disorder; epileptic seizures; substance abuse; learning disorder; cognitive disorder; dysmnesia; organ shrinks; muscle spasm; dyspnoea and disease; the locomotor activity obstacle; moving obstacle; dysimmunity (such as; the autoimmunization obstacle); inflammation; the cell growth; pain, and the syndrome relevant with nerve degeneration.
35. method as claimed in claim 34; wherein, described by disease that Cannabined receptor mediated, unusual or syndrome be selected from abnormal food appetite, with social relevant obstacle, autoimmunization or inflammation, pain and the syndrome relevant with nerve degeneration, unusually and disease and substance abuse.
36. method as claimed in claim 35 wherein, comprises obesity, overweight state, apositia, disease of eating too much at one meal, evil physique, misadjustment appetite, obesity dependency syndrome, unusual, disease or symptom with appetite diseases associated, unusual or syndrome; By heredity; Diet; Food intake; Metabolism syndrome, unusual or disease; Hypothalamic unusual or disease; Age; Unusual liparitosis distributes; Unusual fatty lattice chamber distributes; Mandatory eating disorder; Motivation is unusual, comprises consumption sugar; Carbohydrate; The obesity that wine or medicine or any desire with composition of enjoyment sexual valence value cause, reactivity reduce.
37. method as claimed in claim 35; wherein; with social diseases associated, unusual or syndrome be dysthymia disorders, comprise bipolarity dysthymia disorders, unipolarity dysthymia disorders, have or do not have vain hope feature, nervous feature, melancholy feature, atypical characteristics or single or the outbreak of recurrent severe dysthymia disorders, the seasonal affective disorder sent out at the beginning of postpartum, have and early send out or tardy and have or do not have light strongly fragrant disease, nervous depression and the social phobia of atypical characteristics, the dysthymia disorders of following dementia, anxiety disorder, psychosis, social affective disorder, a cognitive disorder.
38. method as claimed in claim 35, wherein, diseases related, the unusual or syndrome of described autoimmunization or inflammation comprises that psoriasis, lupus erythematosus, connective tissue disease, siogren's syndrome, stiff property arthritis vertebralis, rheumatoid arthritis, reactive arthritis, undifferentiated type arthritis vertebralis, behcet disease, autoimmune hemolytic anemia, multiple sclerosis, amyotrophic lateral sclerosis funiculus lateralis just change disease, albuminoid degeneration, transplant rejection or influence the disease that plasma cell is; Anaphylactic disease: delayed or type, allergic rhinitis, contact dermatitis or anaphylaxis conjunctivitis, infectivity parasitosis, viral or bacteriosis (such as, AIDS and meningitis), inflammatory diseases (such as, joint disease includes but not limited to sacroiliitis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn disease, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS)) and osteoporosis.
39. method as claimed in claim 35; wherein; described pain and the syndrome relevant with nerve degeneration; unusual or disease comprises the pain of maincenter and the mediation of peripheral approach; bone and arthralgia; migraine; cancer pain; dysmenorrhoea; antenatal throe; chronic inflammatory pain; with allergy; rheumatoid arthritis; the pain that dermatitis or immune deficiency are relevant; chronic neuropathic pain comprises and diabetic neuropathy; sciatica; nonspecific property back pain; fibromyalgia and the relevant pain of HIV dependency DPN; postherpetic neuralgia; trigeminal neuralgia; by the health wound; toothache; amputation; cancer; the pain that toxin or chronic inflammatory state cause; He Jiejinshi disease; myasthenia gravis; nephrotic syndrome; scleroderma and thyroiditis.
40. method as claimed in claim 35; wherein; the syndrome relevant with substance abuse, unusual or disease comprise drug abuse and drug withdrawal; wherein, abuse or dependency material comprise the combination of alcohol, Amphetamine, Amphetamine sample material, caffeine, hemp, Cocaine, psychedelia, inhalation, opiate, Nicotine, heroine abuse, barbiturates, phencyclidine or derivatives thereof, sedative hypnotics, benzodiazepine derivatives or abuse material.
41. method as claimed in claim 35, wherein, described eye disease comprises glaucoma, glaucoma dependency intraocular pressure, the retinitis, retinopathy, uveitis, ocular tissue's acute injury.
42. a CB2 agonist optionally, it has following formula:
Wherein,
R, R
1And R
2Can be identical or different, and be independently of one another hydrogen, nitro, cyano group, formyl radical, ethanoyl, halogen ,-OR
3,-SR
3Oxo, sulfo-, replace or unsubstituted alkyl, replace or unsubstituted thiazolinyl, replace or unsubstituted alkynyl, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkylalkyl, replace or unsubstituted cycloalkenyl group, replace or unsubstituted cycloalkenyl alkyl, replace or unsubstituted aryl, replace or unsubstituted arylalkyl, replace or unsubstituted heteroaryl, replace or unsubstituted heteroarylalkyl, replace or unsubstituted heterocyclic, replace or the unsubstituted heterocyclic alkyl,-NR
3R
4,-C (=B)-R
3,-C (O) O-R
3,-C (O) NR
3R
4,-S (O)
m-R
3,-S (O)
m-NR
3R
4, or protecting group, or R
1And R
2Can lump together and form optional 3 to 7 Yuans the saturated or undersaturated ring that replaces, it can randomly comprise at least two and be selected from O, NR
3Or the heteroatoms of S;
R
3And R
4Can be identical or different when occurring at every turn, and be independently of one another hydrogen, nitro, halogen, cyano group ,-OR
a,-SR
aOxo, sulfo-, replace or unsubstituted alkyl, replace or unsubstituted thiazolinyl, replace or unsubstituted alkynyl, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkylalkyl, replace or unsubstituted cycloalkenyl group, replace or unsubstituted cycloalkenyl alkyl, replace or unsubstituted aryl, replace or unsubstituted arylalkyl, replace or unsubstituted heteroaryl, replace or unsubstituted heteroarylalkyl, replace or unsubstituted heterocyclic, replace or the unsubstituted heterocyclic alkyl,-C (=B)-R
a,-C (O) O-R
a,-C (O) NR
aR
b,-S (O)
m-R
a,-S (O)
m-NR
aR
b,-NR
aR
b, or protecting group, or R
3And R
4Can be bonded together when combining with the common atom forms optional 3 to 7 Yuans the saturated or undersaturated ring that replaces, and it can randomly comprise at least two and be selected from O, NR
3Or the heteroatoms of S;
R
aAnd R
bCan be identical or different when occurring at every turn, and be independently of one another hydrogen, halogen, nitro, cyano group, formyl radical, ethanoyl, oxo, sulfo-,-C (O)-R
c,-C (O) O-R
c,-C (O) NR
cR
d,-S (O)
m-R
c,-S (O)
m-NR
cR
d,-NR
cR
d,-OR
c,-SR
c, protecting group, replacement or unsubstituted alkyl, replacement or unsubstituted thiazolinyl, replacement or unsubstituted alkynyl, replacement or unsubstituted cycloalkyl, replacement or unsubstituted cycloalkylalkyl, replacement or unsubstituted cycloalkenyl group, replacement or unsubstituted cycloalkenyl alkyl, replacement or unsubstituted aryl, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroaryl, replacement or unsubstituted heterocyclic, replacement or unsubstituted heterocyclic alkyl, or replacement or unsubstituted heteroarylalkyl;
R
cAnd R
dCan be identical or different when occurring at every turn, and be hydrogen independently of one another, halogen, nitro, cyano group, formyl radical, ethanoyl, oxo, sulfo-, protecting group, replace or unsubstituted alkyl, replace or unsubstituted thiazolinyl, replace or unsubstituted alkynyl, replace or unsubstituted cycloalkyl, replace or unsubstituted cycloalkylalkyl, replace or unsubstituted cycloalkenyl group, replace or unsubstituted cycloalkenyl alkyl, replace or unsubstituted aryl, replace or unsubstituted arylalkyl, replace or unsubstituted heteroaryl, replace or unsubstituted heterocyclic, replace or the unsubstituted heterocyclic alkyl, or replacement or unsubstituted heteroarylalkyl;
B is O, S or NR when occurring at every turn independently of one another
3And m is 0,1 or 2.
43. selectivity CB2 agonist as claimed in claim 42, wherein, R replaces or unsubstituted aryl.
44. selectivity CB2 agonist as claimed in claim 42, wherein, the phenyl that R is replaced by 1 or 2 halogen atom.
45. in the individuality that needs is arranged, treat eye disease, dyspnoea, dysimmunity, inflammation, pain or the syndromic method relevant for one kind with nerve degeneration, this method comprise to described individuality use significant quantity as each described compound among the claim 42-44.
46. the method for a treatment pain in the individuality that needs is arranged, this method comprise to described individuality use significant quantity as each described compound among the claim 42-44.
47. method as claimed in claim 46, wherein, described pain is neuropathic pain.
48. a method for preparing compound as claimed in claim 1, wherein, Y is N, and U is C, and one of W, V and X are that N and all the other two are C, and B is O, and this method comprises makes formula HNR
1R
2
The step of the compound coupling of amine and following formula:
Wherein, L
2Be leaving group, thus the compound of the formula of formation (1).
49. a method for preparing compound as claimed in claim 1, wherein, W and Y are N, and U, V and X are C, and B is O, and this method comprises the steps:
(a) make the compound oxidation of formula K:
The compound of production B:
(h) make the compound of this formula B carry out reductive amination process to form the ortho position diamines of formula C:
(c) make the ortho position diamines of this formula C carry out single acylation reaction to form single N-acyl group diamines of formula D:
Wherein, pg is a protecting group;
(d) make the compound of this formula D carry out cyclization to form the compound of formula E:
(e) make the compound of this formula E carry out dehydrogenation reaction to form the compound of formula F:
(f) make the compound derivation of this formula F form compound G1, compound G2, or their mixture:
(g) make compound G1, compound G2 or the two hydrolysis form compound H 1, compound H 2 or the two:
(h) make formula HNR
1R
2Amine and compound H 1, compound H 2 or the two coupling compound that forms formula (1).
50. the method for the compound of a preparation formula 1A:
Wherein, A, R, R
1And R
2It is identical with the definition in the claim 1,
It comprises the steps:
(a) make the compound of formula K carry out the deprotonation reaction:
Carry out the compound of acylation reaction production L subsequently:
(b) make compound and the formula RNHNH of formula L
2Hydrazine reaction form compound M, compound N or the two:
(c) compound M, compound N or the two are hydrolyzed and with formula HNR
1R
2The amine coupling form formula
(1) compound.
51. the method for the compound of a preparation formula 1, wherein, V and Y are N, and U, W and X are C, and B is O, and p is 0 or 1, and this method comprises the steps:
(a) make the compound of formula O:
Transform the compound of accepted way of doing sth P:
(b) make the amine coupling of Compound P and formula Q:
Form the compound of formula R:
(c) make the compound of formula R go protection, form the compound of formula S with after:
(d) make formula S compound hydrolysis and with formula HNR
1R
2The amine coupling form the compound of formula (1).
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN659MU2005 | 2005-06-02 | ||
| IN659/MUM/2005 | 2005-06-02 | ||
| US60/696,433 | 2005-07-01 | ||
| IN1370/MUM/2005 | 2005-10-10 | ||
| IN344/MUM/2006 | 2006-03-09 | ||
| US60/744,071 | 2006-03-31 | ||
| IN689/MUM/2006 | 2006-05-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101238107A true CN101238107A (en) | 2008-08-06 |
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ID=39921101
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800285688A Pending CN101238107A (en) | 2005-06-02 | 2006-06-01 | Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN101238107A (en) |
| ES (1) | ES2362369T3 (en) |
| UA (1) | UA93390C2 (en) |
| ZA (1) | ZA200711106B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103608343A (en) * | 2011-02-25 | 2014-02-26 | 艾尼纳制药公司 | Crystalline forms and processes for preparation of condensed azacycles (cannabinoid receptor modulators) |
| CN110123813A (en) * | 2019-06-19 | 2019-08-16 | 深圳先进技术研究院 | Application and drug of the heterocyclic compound that plant of Solanaceae is extracted in the drug of preparation treatment multiple sclerosis |
-
2006
- 2006-06-01 UA UAA200805952A patent/UA93390C2/en unknown
- 2006-06-01 ES ES06755930T patent/ES2362369T3/en active Active
- 2006-06-01 CN CNA2006800285688A patent/CN101238107A/en active Pending
-
2007
- 2007-12-20 ZA ZA200711106A patent/ZA200711106B/en unknown
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103608343A (en) * | 2011-02-25 | 2014-02-26 | 艾尼纳制药公司 | Crystalline forms and processes for preparation of condensed azacycles (cannabinoid receptor modulators) |
| CN103608343B (en) * | 2011-02-25 | 2019-02-01 | 艾尼纳制药公司 | It is used to prepare the crystalline form and preparation method of the condensed azacyclo- as Cannibinoid receptor modulators |
| CN110123813A (en) * | 2019-06-19 | 2019-08-16 | 深圳先进技术研究院 | Application and drug of the heterocyclic compound that plant of Solanaceae is extracted in the drug of preparation treatment multiple sclerosis |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200711106B (en) | 2008-11-26 |
| ES2362369T3 (en) | 2011-07-04 |
| UA93390C2 (en) | 2011-02-10 |
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Application publication date: 20080806 |